More Information

Submitted: November 27, 2023 | Approved: December 20, 2023 | Published: December 21, 2023

How to cite this article: Al-Anazi KA. Update on the Clinical Applications of Mesenchymal Stem Cells. J Stem Cell Ther Transplant. 2023; 7: 043-064.

DOI: 10.29328/journal.jsctt.1001034

Copyright License: © 2023 Al-Anazi KA. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Keywords: Mesenchymal stem cells; Extracellular vesicles; Exosomes; Autoimmune diseases; Hematopoietic stem cell transplantation; Regenerative medicine

 FullText PDF

Update on the Clinical Applications of Mesenchymal Stem Cells

Khalid A Al-Anazi

Consultant Hemato-Oncologist, Department of Hematology and Hematopoietic Stem Cell Transplantation, Oncology Center, King Fahad Specialist Hospital, P.O. Box: 15215, Dammam 31444, Saudi Arabia

*Address for Correspondence: Dr. Khalid Ahmed Al-Anazi, Consultant Hemato-Oncologist, Department of Hematology and Hematopoietic Stem Cell Transplantation, Oncology Center, King Fahad Specialist Hospital, P.O. Box: 15215, Dammam 31444, Saudi Arabia, Email:

Mesenchymal stem cells are heterogenous adult multipotent stromal cells that can be isolated from various sources including bone marrow, peripheral blood, umbilical cord blood, dental pulp, and adipose tissue. They have certain regenerative, anti-inflammatory, immunomodulatory, immunosuppressive, antimicrobial, and other properties that enable them to have several therapeutic and clinical applications including treatment of various autoimmune disorders; role in hematopoietic stem cell transplantation and regenerative medicine; treatment of skin, pulmonary and cardiovascular disorders; treatment of neurological and eye diseases; as well as treatment of various infections and their complications.

Different factors including donor age, biological source, route of administration, and signaling pathways have an impact on the functions and consequently the clinical applications of mesenchymal stromal cells. The products of mesenchymal stem cells such as extracellular vesicles and exosomes reproduce the biological effects and most of the therapeutic actions of the parent stem cells. Genetic engineering and the use of specific mesenchymal stromal cell products have improved their clinical efficacy and decreased their adverse effects. However, despite the recent progress in the use of mesenchymal stem cells, the clinical application of these cells in the treatment of several diseases still faces real challenges that need to be resolved. The current status of mesenchymal stem cells and the controversies related to their clinical utilization in various disease conditions will be thoroughly discussed in this review.

Mesenchymal Stem Cells (MSCs) are heterogeneous, non-hematopoietic, adult multipotent stromal progenitor cells that are capable of self-renewal and differentiation into multiple lineages and various cell types [1-9]. Adult MSCs were first isolated from Bone Marrow (BM) by Alexander Friedenstein and his colleagues in the year 1976 [2,10,11]. Subsequently, MSCs have been isolated from several adult as well as neonatal sources such as Adipose Tissue (AT), peripheral blood, Umbilical Cord (UC), placenta, amniotic fluid, breast milk, skin, and skeletal muscles (Table 1) [2,11-24]. MSCs have the following distinguishing features: (1) the ability to adhere to the plastic vessel under optimal culture conditions; (2) the capability to differentiate into osteoblasts, adipocytes, and chondrocytes; and (3) having a characteristic immunophenotypic profile on flowcytometry (Table 2) [2,21,25-32]. In the year 2006, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy (ISCT) issued a position statement that proposed the following minimal criteria for defining multipotent MSCs: (1) MSC must be plastic-adherent when maintained in standard culture conditions; (2) MSC must express CD105, CD73 and CD90, and lack the expression of CD45, CD34, CD14 or CD11b, CD79a or CD19 and HLA-DR surface molecules; and (3) MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro [8,31,33]. However, certain types of MSCs can occasionally show positivity or negativity for specific surface markers as illustrated in Table 2 [1-3,5,6,8,31,34-38]. Several studies have shown that MSCs can differentiate into other cell types such as cardiomyocytes, myocytes, and neurons, and that MSCs derived from BM, AT, and other sources do express CD 34 surface markers under certain circumstances [5,9,39-42]. Additionally, MSCs can be seen in abundant numbers in the circulation under the following conditions: stem cell mobilization with growth factors, stroke, hypoxia, tissue injuries, as well as inflammatory conditions [9,43-48]. Unfortunately, little is known about the molecular basis underlying the stemness of MSCs and it is still unclear whether the recently discovered transcriptional factors and genes regulate stemness or only differentiation of MSCs [7]. In the year 2019, the International Society for Cell & Gene Therapy (ISCT®) Mesenchymal Stromal Cell (ISCT-MSC) committee issued a position statement to continue supporting the acronym MSCs but it recommended that the acronym MSCs must be: (1) supplemented by the tissue-source origin of the cells, which would highlight tissue-specific properties; (2) intended as MSCs unless rigorous evidence for stemness exists that can be supported by both in vitro and in vivo data; and (3) associated with robust matrix of functional assays to demonstrate MSC properties, which are not generically defined but informed by the intended therapeutic mode of actions [32].

Table 1: Sources of mesenchymal stem cells.
1. Bone marrow.
2. Peripheral blood.
3. Umbilical cord blood and Wharton's jelly of the umbilical cord.
4. Chorionic villi and chorionic membrane of the placenta.
5. Human amniotic fluid and decidua of the uterus.
6. Menstrual blood.
7. Fallopian tubes and cervical tissues.
8. Breast milk.
9. Adipose tissues: body fat.
10. Dental pulp, periodontal ligaments, exfoliated deciduous teeth.
11. Oral mucosa, palatal tonsils and salivary glands.
12. Skeletal muscle, muscle tendons and dermal tissues.
13. Lung tissues and alveolar epithelium.
14. Adult human liver tissues and fetal liver.
15. Synovial membrane and synovial fluid.
16. Parathyroid glands.
Table 2: Surface Markers of Mesenchymal Stem Cells on Flowcytometry.
  Positive Negative
Characteristic surface markers CD 105
CD 73
CD 90
CD 45
CD 34
CD 14
CD 11b
CD 19
CD 79a
Other surface markers that may/may not be expressed CD 117
CD 166
CD 29
CD 44
CD 106
CD 9
CD 10
CD 13
CD 28
CD 33
CD 49b
CD 71
CD 164
CD 271
HLA-class I
CD 3
CD 33
CD 133
MSCs: Mesenchymal Stem Cells; HLA: Human Leukocyte Antigen.
Factors affecting the functions and clinical applications of mesenchymal stem cells

Human MSCs are multipotent stem cells capable of self-renewal and differentiation in vitro into cells of different lineages [33,49,50]. They interact with immune cells both in innate and adaptive immune systems so as to: (1) enable immunosuppression and tolerance induction, and (2) modulate the immune responses [51]. MSCs possess immunomodulatory functions that enable them to be investigated as potential treatments for various immune disorders [35,50].

The past decade has seen an explosion of research directed toward a better understanding of the mechanisms of MSC function during the rescue and repair of injured tissue and organs. An improved understanding of MSC function holds great promise for the application of cell therapy and also for the development of powerful cell-derived therapeutics in regenerative medicine. However, the field has made particular progress in (1) delineating cell-cell signaling and molecular controls for MSC differentiation, and (2) defining several other mechanisms through which administered MSCs can promote tissue repair [52]. Properties and functions of MSCs that are essential in their clinical therapeutic effects include (1) self-renewal and high proliferation capacity, (2) multipotency, (3) secretory and trophic ability, (4) migration and homing properties with tropism towards inflamed and injured tissues, (5) immunosuppressive functions, (6) potent immunoregulatory and immunomodulatory properties, (7) tissue remodeling and regeneration, (8) regulation of cellular hemostasis, and (9) easy access and isolation [53-56]. The mechanisms by which MSCs promote tissue repair include (1) strong paracrine activity that involves secretion of proteins, cytokines, chemokines, and hormones; (2) transfer of mitochondria by way of tunneling nanotubes or microvesicles; and (3) transfer of exosomes or microvesicles containing RNA and other molecules [52,57]. The high immunomodulatory capacity of MSCs is reflected by: (1) their migration to the sites of injury and inflammation, (2) their differentiation into various functional cells at the sites of injury and inflammation, (3) their boosting of immunity, (4) their tumor suppression effects, and (5) their anti-angiogenic effects [56]. MSCs are characterized by: (1) an extraordinary capacity to modulate the phenotype and functional properties of various immune cells that play an essential role in the pathogenesis of inflammatory disorders, and (2) immunosuppressive properties that have enabled MSCs to emerge as promising tools for the treatment of inflammatory disorders such as acute Graft-Versus-Host Disease (GVHD), graft rejection in patients undergoing organ/cell transplantation, and Autoimmune Diseases (AIDs) [58].

Features of MSCs that favor their utilization in clinical practice include: (1) MSCs are immunologically tolerated in the recipient, (2) they do not show signs of cellular senescence, including compromised proliferation and differentiation capabilities, (3) compatibility with the biological sex of the recipient in regard to sex-specific immune processes, and (4) they are known to be effective in attenuating hyperactivated cytokine and immune cell activities in the recipient from transplantation clinical studies [59].

MSCs have been widely utilized for the treatment of diverse inflammatory diseases, due to their potent immunoregulatory functions. MSCs exert their therapeutic effects largely through their paracrine actions. Growth factors, cytokines, chemokines, extracellular matrix components, and metabolic products were all found to be functional molecules of MSCs in various therapeutic paradigms. These secretory factors contribute to immune modulation, tissue remodeling, and cellular homeostasis during regeneration. The paracrine actions of MSCs are powerful bioactive agents for treating various diseases, especially for refractory immune disorders and tissue damage [55]. Functions of MSCs are mediated by: (1) paracrine factors, (2) mitochondrial transfer, and (3) secretion of Extracellular Vesicles (ECVs) [56]. Ideally, autologous MSCs are the choice of safety as allogenic transplantation could lead to cell rejection, but cells obtained from patients suffering from AIDs may behave differently than those from healthy donors, including deficiency in the ability to proliferate and successfully differentiate. So, it is preferable to obtain MSCs from BMs of young healthy donors or from UCs directly after birth [59]. Recent studies suggest that factors including age, gender, and biological sources of MSCs can have a significant impact on therapy outcomes [54,56,59-61]. Hence, it is worthwhile to further establish MSC banks from multiple donors that span a range of biological ages, tissue sources, and genders for the selection of future transplantation therapies [59].

Impact of sources of mesenchymal stem cells on their clinical applications

Bone marrow-mesenchymal stem cells: As BM-derived MSCs were discovered first, they were initially considered the main source of MSCs for clinical application [62]. BM-MSCs are capable of differentiation into various mesodermal lineages but the availability of conventional BM-MSCs is limited [63,64]. BM-MSCs constitute an essential component of the hematopoietic niche, responsible for stimulating and enhancing the proliferation of HSCs by secreting regulatory molecules and cytokines to regulate hematopoiesis in the BM microenvironment [63,65-67]. Osteogenesis of BM-MSCs plays a central role in hematopoiesis, while adipogenesis of BM-MSCs has a negative effect on hematopoietic recovery [66]. Recently, by lineage tracing and single-cell sequencing, several new subgroups of BM-MSCs and their roles in normal physiological and pathological conditions have been clarified. The key regulators and mechanisms controlling the fate of BM-MSCs are being revealed and cross-talk among subgroups of BM-MSCs has been demonstrated [67]. Many factors, including aging, obesity, irradiation, and chemotherapy, can lead to the differentiation bias of BM-MSCs and related hematopoietic disorders. Rescuing the dysregulation of BM-MSC differentiation is crucial to bone hematopoietic recovery [66].

Human BM-MSCs differentially regulate the functional compartments of CD4(+) and CD8(+) T cells, which may differentially impact their therapeutic effect in immune disorders. The influence of MSCs on IL-9 expression can open new possibilities for MSC-based therapy in allergic diseases [68]. BM-MSCs displayed a striking inhibitory action over T cells from Rheumatoid Arthritis (RA) patients, reducing the expression of cytokines involved in RA physiopathology. Remarkably, BM-MSC-derived immunomodulation affected naive, effector, as well as memory T cells [69].

ECVs derived from BM-MSCs have similar therapeutic effects to BM-MSCs, including repairing damaged tissues, inhibiting macrophage polarization, and promoting angiogenesis. ECVs derived from BM-MSC, as efficient and feasible natural nanocarriers for drug delivery, have the advantages of low immunogenicity, no ethical controversy, good stability, and easy storage, thus providing a promising therapeutic strategy for many diseases. ECVs derived from BM-MSC have shown great potential in the treatment of bone metabolic diseases [70]. Exosomes derived from BM-MSCs showed superior regeneration ability, and exosomes derived from AT-MSCs played a significant role in immune regulation, whereas exosomes derived from UC-MSCs were more prominent in tissue damage repair [71].

Adipose tissue-mesenchymal stem cells: MSCs have been isolated from various other less invasive sources that comprise alternatives to BM including AT. AT-MSCs can be more easily isolated and considerably larger amounts of MSCs can be obtained from fat or AT compared with the BM. AT-MSCs and BM-MSCs share many biological characteristics but have some differences in their immunophenotype, differentiation potential, transcriptome, proteome, and immunomodulatory activity [62,64-72]. Human AT-MSCs support hematopoiesis in vitro and in vivo and thus provide the rationale for their use in supporting hematopoietic reconstitution in clinical settings [73]. AT represents a promising alternative to BM as a source of MSC to maintain hematopoiesis, but UC matrix-derived MSC demonstrated inferior hematopoietic supportive capacity compared to MSC from adult tissues [72]. AT-MSCs and BM-MSCs from the same donor have been found to display similar immunomodulatory capacities on both innate and acquired immunity cells. However, other variables such as the accessibility of samples or the frequency of MSCs in the tissue, should be considered to select the source of MSC for cell therapy [74].

BM-MSCs and AT-MSCs share a similar immunophenotype and capacity for in vitro multilineage differentiation. The immunomodulatory capacities of BM-MSCs and AT-MSCs are similar, but the differences in cytokine secretion cause AT-MSCs to have more potent immunomodulatory effects than BM-MSCs indicating that AT-MSCs can be considered a good alternative to BM-MSCs for immunomodulatory therapy [75]. Transplantation of BM-MSCs and UC-MSCs can alleviate the symptoms of neuropathic pain and result in subsequent motor recovery after spinal cord injury. However, the survival rate and electrophysiological findings of UCMSCs are significantly better than BM-MSCs [76]. AT-MSCs are an attractive alternative to BM-MSCs for the treatment of severe Spinal Cord Injury (SCI) due to their enhanced stress resistance and secreted factor profile [77].

Wound healing is a complex process with a linear development that involves many actors in a multistep timeline commonly divided into four stages: hemostasis, inflammation, proliferation, and remodeling [78]. Studies on wound healing have shown that murine AT-MSCs and BM-MSCs have shown equivalent effects in enhancing diabetic wound healing. However, ECVs derived from BM-MSCs have been shown to promote proliferation, while ECVs derived from AT-MSCs exert major effects on angiogenesis [79,80]. Great interest is being focused on the paracrine activity of AT-MSCs for its potential therapeutic impact on chronic non-healing wounds [78]. The secretome from AT-MSCs and fibroblasts provides a safe and efficacious means for therapeutic development in contrast to the significant health problems that can result from using BM-MSCs and blood-derived MSCs and their secretome [81]. The secretome of AT-MSC represents a novel, promising alternative to cell-based therapy for wound repair as it has the following advantages over MSCs: (i) its feasible long-term storage, eliminating the need for toxic cryoprotectants, (ii) use of filter sterilization as the principal components as opposed to cells that cannot be terminally sterilized, (iii) convenience to alter the secretome profile for specific targeted applications, and (iv) cost-effective mass production overcoming the need for maintenance of huge clonal populations [82].

The main advantages of AT-MSCs over MSCs derived from other sources such as BM include: (1) the ease of methodology utilized in tissue collection, cell isolation using minimally invasive techniques with low morbidity compared to BM-MSCs; (2) obtaining abundant cells during isolation from a specific AT source; (3) ability to differentiate into various cell types of the tri-germ lineages, including osteocytes, adipocytes, neural cells, vascular endothelial cells, cardiomyocytes, pancreatic β-cells, and hepatocytes; (4) high self-renewal and proliferation capacity; (5) having anti-fibrotic, anti-apoptotic, anti-inflammation, and immunomodulatory properties; (6) having immunoregulatory and immunosuppressive properties with low immunogenicity; (7) ability to migrate to sites of inflamed and damaged tissues; (8) ability to act through autocrine and paracrine mechanisms including the secretion of broad spectrum of cytokines, growth factors, nucleic acids, and ECVs; and (9) ability of their secretome to: alter tissue biology, stimulate tissue resident stem cells, change immune cell activity, and mediate therapeutic outcome [83-86].

Umbilical cord-mesenchymal stem cells: Considered for a long time as a medical waste, UC appears these days as a promising source of MSCs. Several reports have shown that UC-derived MSCs are more primitive, proliferative, and immunosuppressive than their adult counterparts. Although UC-MSCs are until now not particularly used as an MSC source in clinical practice, accumulating evidence shows that they may have a therapeutic advantage in treating several diseases, especially autoimmune and neurodegenerative diseases [87]. MSCs derived from the Wharton’s Jelly (WJ) of UC can easily differentiate into a plethora of cell types leading to a variety of applications. WJ-MSCs are slightly easier to harvest compared with other MSCs such as BM-derived MSCs. The fascinating stemness properties and therapeutic potential of WJ-MSCs provide great promise in many aspects of regenerative medicine and should be considered for further investigations as safe and effective donor cells for transplantation therapy in many debilitating disorders [88]. MSCs derived from WJ-UC have recently gained considerable attention in the field of regenerative medicine. The high proliferation rate, differentiation ability into various cell lineages, easy collection procedure, immuno-privileged status, and nontumorigenic properties along with minor ethical issues make WJ-MSCs an ideal approach for tissue repair. The number of WJ-MSCs in the UC samples is high as compared to other sources. WJ-MSCs have rapidly advanced into clinical trials for the treatment of a wide range of disorders [89]. Compared to other sources of MSCs including BM, placenta, and AT, MSCs derived from WJ-UC have the strongest immunomodulatory and immunosuppressive potential. So, WJ-MSCs are the most attractive cell population for use in immune cellular therapy when immunosuppressive action is required [90]. MSC from fetal sources can undergo more cell divisions before they reach senescence than MSC from adult tissue such as BM or AT [15].

The advantages of UC-MSCs include (1) a painless collection procedure, (2) fast and high self-renewal potential, (3) multilineage differentiation potential with ability to differentiate into the 3 germ layers, (4) having low immunogenicity, (5) secretion of effective molecules that regulate apoptosis, fibrosis, and neovascularization, (6) ability to modulate immune responses, (7) ability to accumulate in damaged tissues or inflamed sites, (8) ability to promote tissue repair, (9) ability to improve engraftment and suppress the immune system after HSCT, and (10) inhibition of tumor cell proliferation and migration to nest of cancer [91-93].

Products of mesenchymal stem cells

Extracellular vesicles of mesenchymal stem cells: MSC-ECVs are submicron circular lipid membrane vesicles that may be released from all human cells [94,95]. They were described as platelet dust in the year 1967 [96]. MSC-ECVs are involved in many cellular processes, both in physiological and pathological conditions [95,97]. They are mediators of cell-cell communication and they are active players in cell differentiation, tissue homeostasis, and organ remodeling [95,98,99]. ECVs carry or transfer biologically active molecules such as proteins, nucleic acids (mRNA/miRNA), and bioactive lipids from stem cells to injured or diseased cells [97,98]. The efficiency of ECVs of MSCs can be further enhanced by: (1) selecting the appropriate ECV-producing cells and cell phenotypes, (2) optimizing the conditions in which the donor MSCs are cultured, and (3) engineering the ECVs produced to transport therapeutic and targeting molecules [96,100]. ECVs are fundamental paracrine effectors of MSCs that can overcome most of the limitations of MSC applications and they have allowed major advances in preclinical and clinical studies [96,99]. ECVs of MSCs maintain the stemness of the parent MSCs and retain their functions including modulation of the immune system, regulation of inflammation, inhibition of apoptosis, and induction of tissue regeneration [94,96,99].

ECVs of MSCs have several advantages that include: (1) ability to reproduce the biological effects and most of the therapeutic actions obtained by using the patent MSCs; (2) stability for long periods of time; (3) easy isolation; (4) lower immunogenicity than MSCs; (5) higher safety profile and less adverse effects than MSCs; (6) their heterogeneity is dependent on the stromas of origin; (7) ability to alleviate cell aging; (8) regulation of immune responses and inflammation, that is, they play critical role in immunomodulation; (9) their therapeutic effects can be improved further by bioengineering to induce more precise targeting and transfer of drugs; (10) great contribution to homeostasis and intercellular communication through transportation of a wide variety of biomolecules including nucleic acids, signalling lipids, regulatory proteins, transcription factors, cytokines and growth factors to recipient cells; (11) alleviation of sepsis and protection against sepsis-induced organ dysfunction; and (12) having antitumor effects, thus they can be used as cell-free cancer therapy [101-110].

Despite the progress achieved in introducing ECVs of MSCs in clinical therapeutics, the use of ECVs has several disadvantages and challenges that limit their clinical applications and these include: (1) inconsistent manufacturing processes including scalability and isolation; (2) stability, biodistribution, and pharmacokinetics; (4) quantification and characterization; (5) transfer and specific tissue targeting; (6) safety concerns; (7) poor cell survival; (8) efficient and optimal cell dosing; (9) storage and handling of clinical grade ECVs; (10) immune rejection; (11) high costs; and (12) lack of quality control and validation assays and measurements [103,108,109,111-116].

Exosomes of mesenchymal stem cells: Exosomes are ECVs secreted by various cells and they are mainly composed of lipid bilayers without organelles [117]. Compared to MSCs themselves, MSC-derived exosomes have provided significant advantages by efficiently decreasing unfavorable adverse effects, such as infusion-related toxicities [118]. The exosomes secreted by MSCs have been broadly researched due to their elastic, immune, and tumor-homing properties [117].

MSCs are recognized to generate a wide range of exosomes in a clinically appropriate measure as compared to other cell origins. Exosomes of MSCs have been widely investigated because of their immune attributes, tumor-homing attributes, and flexible characteristics. The therapeutic efficiency of exosomes and their safety for transferring different cellular biological components to the recipient cell have attracted significant attention for their capability as miRNA carriers [119]. MSC-exosomes are becoming a promising cell-free therapeutic tool and an increasing number of clinical studies started to assess the therapeutic effect of exosomes of MSC in different diseases [118]. Targeted drug delivery in the body is a promising method for treating many refractory diseases such as tumors and Alzheimer’s disease [117]. Accumulating literature shows that exosomes have great potential in the treatment of SCIs [120]. While exosomes of MSC have apparent advantages, some unresolved problems also exist [117].

Impact of signaling pathways on the functions of mesenchymal stem cells

Signaling pathways, transcription factors, and growth factors modulate the differentiation of MSCs into different cell lineages [121]. Successful MSC therapy, along with the homing, relies on the secretion of biologically active molecules including cytokines, growth factors, and chemokines known as the secretome of MSCs [122]. A critical problem for MSCs in tissue engineering is their low survival ability and functionality as most MSCs become apoptotic after transplantation. Increasing MSC survival ability and functionalities is the key to potential applications of MSCs. Hence, several approaches have been studied to increase MSC tissue forming capacity including application of growth factors, overexpression of stem cell regulatory genes, and improvement of biomaterials for scaffolds [123]. The effects of these approaches on MSCs have been associated with the activation of one of the intracellular signaling pathways; the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway; which plays central regulatory roles in MSC survival, proliferation, differentiation, migration, angiogenesis, cytokine production, and apoptosis [122,123].

MSCs express and secrete a broad spectrum of bioactive molecules, including Notch and Wnt molecules, that support all the phases of the hematopoiesis, including self-renewal, proliferation, and differentiation [124]. The peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling pathway regulates the differentiation of MSCs into adipocytes, while the Wnt signaling pathway regulates the differentiation of MSCs into osteoblasts, that is, Wnt is the master moderator of osteogenesis [125]. However, the key signaling pathways that are involved in MSC differentiation and growth include: (1) activin-mediated transforming growth factor (TGF)-beta signaling, (2) Platelet-Derived Growth Factor (PDGF) signaling, and (3) Fibroblast Growth Factor (FGF) signaling [126].

Current and potential clinical applications of mesenchymal stem cells

The proliferative, immunomodulatory, anti-inflammatory, regenerative, and other properties of MSCs make them ideal candidates for use as therapeutic agents in several autoimmune, systemic inflammatory, and infectious diseases in addition to the fields of regenerative medicine and tissue engineering. Consequently, their potential clinical applications have expanded rapidly over the years as shown in Table 3 [2,6,15,21,24,49,60,127-140].

Table 3: Current and potential therapeutic indications of mesenchymal stem cells.
1. Hematopoietic stem cell transplantation:
a. Enhancement of engraftment.
b. Prevention of graft versus host disease (GVHD).
c. Treatment of acute and chronic GVHD.
2. Solid organ transplantation (SOT): Improvement of outcome of SOT by:
a. Immunomodulation.
b. Induction of transplantation tolerance.
3. Treatment of autoimmune diseases:
a. Systemic lupus erythromatosus.
b. Rheumatoid arthritis.
c. Systemic sclerosis.
d. Ankylosing spondylitis.
e. Multiple sclerosis.
f. Type 1 diabetes mellitus.
g. Ulcerative colitis.
h. Crohn's disease.
i.  Type II refractory celiac disease.
j.  Other autoimmune disorders: myasthenia gravis, uveitis, neuromyelitis optica and hearing loss.
4. Regenerative medicine and tissue repair:
a. Myocardial ischemia.
b. Acute myocardial infarction .
c. Cardiac dysfunction.
d. Dilated cardiomyopathy.
e. Chronic non-healing wounds.
f. Critical limb ischemia
g. Peripheral vascular disease.
h. Ischemic stroke.
i.  Traumatic brain injury.
j.  Spinal cord injuries.
k. Liver injury.
l.  Radiation-induced lung fibrosis.
m.Tissue repair: bone, cartilage, muscle, skin, myocardium, trachea, etc.
5. Treatment of various infections and their complications:
a. Bacterial infections including sepsis and its associated adult respiratory distress syndrome.
b. Viral infections such as human immunodeficiency virus, hepatitis B and C viruses, and COVID-19 infections.
c. Parasitic infections such as Chagas disease, schistosomiasis, and malaria.
d. Mycobacterial infections such as tuberculosis.
6. Other indications:
a. Macular degeneration, corneal regeneration or reconstruction and corneal transplantation.
b. Liver fibrosis, liver cirrhosis, end-stage liver disease and hepatic failure.
c. Bones and joints: osteogenesis imperfecta, osteoarthritis, osteoporosis, osteonecrosis, meniscus injury.
d. Cancer gene therapy and anti-cancer cellular therapy such as breast and lung cancers.
e. Aging frailty.
f. Amyotrophic lateral sclerosis.
g. Parkinson’s Disease.
h. Idiopathic pulmonary fibrosis.
i.  Chronic obstructive airway disease.
j.  Renal disorders.

Examples of the therapeutic applications of MSCs are discussed below.

Use of mesenchymal stem cells in autoimmune diseases: AIDs are associated with an abnormal immune system, chronic inflammation, and immune reaction against self-antigens leading to injury and failure of several tissues and organs [141]. Even with the advancements in developing novel therapies and biological agents, AIDs are still incurable [142].

MSCs can migrate to the sites of inflammation and exert potent immunosuppressive and anti-inflammatory effects through the interaction between lymphocytes associated with both the innate and adaptive immune systems [6]. Recently, MSCs have been used in clinical trials to treat various AIDs because of their beneficial properties such as safety and ease of isolation, high proliferation ability, multipotent differentiation capacity, as well as their anti-inflammatory, immunomodulatory, and regenerative properties [141]. After widespread in-vitro and in-vivo preclinical studies, autologous and allogeneic MSCs and their ECVs have been applied in the treatment of several AIDs including type 1 Diabetes Mellitus (DM); GVHD; Multiple Sclerosis (MS); Systemic Lupus Erythematosus (SLE); RA; systemic sclerosis; Sjogren’s syndrome; and Inflammatory Bowel Diseases (IBDs) such as Crohn’s disease [142-144]. Studies on the use of MSCs in AIDs have shown no remarkable association with the evolution of malignancies or infectious diseases [141]. Additionally, genetic modification of MSCs to express anti-tumor genes has provided a rationale for their utilization as anticancer therapy [6].

The results of 6 systematic reviews and meta-analyses on the use of MSCs in several AIDs showed the following findings: in patients with DM, 2 systematic reviews and meta-analyses that included 36 Randomized Clinical Trials (RCTs) comprising 900 patients showed that treatment with MSCs ± hematopoietic stem cells (HSCs) resulted in: transient insulin independence or decrease in daily insulin requirements, significant decrease in Hb A1C level, and improvement in C-peptide levels, and that administration of MSCs was shown to be generally safe with the exception of some hypoglycemic episodes [145,146]; (2) in patients with RA, 1 systematic review and metaanalysis showed that administration of MSCs resulted in clinical effectiveness in 54% of treated patients as the following results were reported: decrease in disease activity, improvement in symptoms, and improvement in laboratory indices [147]; (3) in patients with SLE, the results of 2 systematic reviews and meta-analyses showed that MSC administration resulted in: reduction in the rate of flare-ups, reduction in urinary protein levels, and increase in serum C3 complement levels, while some of the RCTs included reported adverse effects such as fever, headache, and diarrhea during MSC infusion [147,148]; (4) in patients with systemic sclerosis, 1 systematic review and meta-analysis that included 9 studies comprising 133 patients showed that the use of MSC therapy resulted in improvement in: lung function, skin thickening, mouth opening, digital ulcerations, and pain in the absence of severe adverse effects [149]; (5) in patients with ankylosing spondylitis, MSC administration resulted in improvement in activity, reduction in pain, and reduction in disease indices such as erythrocyte sedimentation rate and tumor necrosis factor-α (147); (6) in patients with IBD, the use of MSCs resulted in improvement in clinical conditions of the treated patients [147]; and (7) in patients with MS, 2 systematic reviews and meta-analyses showed that the use of MSCs showed equivocal results [147,150].

Use of mesenchymal stem cells in hematopoietic stem cell transplantation: BM-derived MSCs play a crucial role in the regulation of hematopoiesis [151]. In addition to supporting hematopoiesis, MSCs are capable of modulating immune and inflammatory responses and participating in tissue repair [152,153]. Also, once ECVs of MSCs are given in combination with HSCs, they can modulate the immune system and inhibit the development of GVHD following HSCT [151,152].

The clinical applications of MSCs in HSCT include (1) prevention and treatment of GVHD, (2) enhancement of hematopoietic engraftment and prevention of engraftment failure, (3) acceleration of lymphocyte recovery, (4) repair of tissue damage, and (5) reduction in aplasia post-chemotherapy [152-156]. The safety and therapeutic potential of the clinical application of MSCs in HSCT have been well established by numerous clinical trials. Commercial MSC products for pediatric steroid-refractory GVHD have already been licensed in Japan, conditionally licensed in Canada and New Zealand, and may get approval by the Food and Drug Administration (FDA) in the United States of America (USA) soon [155].

Three systematic reviews and meta-analyses, that included 85 studies comprising 2334 patients, on the use of MSCs in prevention of GVHD, treatment of both acute including steroid-refractory and chronic GVHD showed the following results: (1) in patients with acute GVHD, 39% - 67% of patients achieved Complete Response (CR) and one-third of patients achieved partial response (PR); (2) in patients with chronic GVHD, 23% of patients achieved CR while 66% of patients achieved PR; (3) acute GVHD grade II responded to MSCs much better than grades III and IV acute GVHD; (4) acute GVHD of the skin responded to MSC therapy better than acute GVHD of the liver or gastrointestinal tract; (5) children with acute GVHD showed better responses than adults with acute GVHD; (6) response to MSC therapy correlated well with the dose of MSCs administered; and (7) once used prophylactically, MSC treatment was effective in reducing the incidence of chronic GVHD and the overall survival (OS) was increased by 17% [157-159]. However, prophylactic co-transplantation of MSCs in addition to HSCs in patients with severe aplastic anemia undergoing haploidentical HSCT failed to show efficacy [160]. Additionally, one major review that included 9 studies on the use of MSCs in the treatment of steroid-refractory acute GVHD showed: (1) CR of steroid-refractory acute GVHD was achieved in up to 50% - 83% of patients; (2) CR, but not PR, was associated with prolonged OS; and (3) no serious adverse effects of MSC therapy were reported [161].

Use of mesenchymal stem cell therapies in lung diseases: Systematically infused MSCs have been found to migrate directly to the lung where they can: ameliorate cytokine release, protect alveolar epithelial cells, aid in alveolar fluid clearance, promote epithelial and endothelial recovery, repair injured airways, reduce the risk of allograft rejection, resist pulmonary fibrosis, and improve lung function by secreting many factors and modulating multiple biological processes involved in the immune response. Hence, MSCs have shown great potential and benefit in treating severe incurable pulmonary disorders [162]. Clinical trials on the use of autologous or allogeneic MSCs to treat various respiratory conditions have shown adequate evidence of safety as well as evidence of significant improvement in the quality of life of patients [163,164].

MSCs and their secretome have been used in the treatment of various respiratory diseases including viral and community-acquired pneumonia; emphysema, bronchial asthma, chronic obstructive airway disease; bronchiolitis obliterans; chronic idiopathic pulmonary fibrosis; acute lung injury and Acute Respiratory Distress Syndrome (ARDS); pulmonary fibrosis due to bleomycin or radiation; cystic fibrosis; and pulmonary hypertension [162-168]. Due to their potent and broad-spectrum properties and activities including immunomodulation, inhibition of bacterial growth and enhancement of bacterial clearance, anti-inflammatory; tissue-regenerative, pro-angiogenic, and anti-fibrotic properties which rely on cell-to-cell contact and paracrine mechanisms, MSCs offer novel and promising therapeutic options for several acute and chronic lung disorders [162,163,166,167,169]. However, the use of MSCs in the treatment of radiation-induced lung injury has shown beneficial as well as adverse effects such as enhancement of the progression of lung injuries [168].

Use of mesenchymal stem cells in the treatment of cardiovascular disorders: The therapeutic effects of MSCs in the treatment of cardiovascular diseases are based on the following: (1) their antifibrotic and anti-inflammatory actions in reducing cardiac fibrosis and inflammation; (2) their migration into the sites of infarcted cardiac tissues; (3) neovascularization or their promotion of new blood vessel formation; (4) their differentiation into cardiomyocyte-like cells; (5) their contribution to the repair of infarcted myocardium; and (6) their other distinguished properties such as the wide range of sources, the easy isolation and amplification, the low immunogenicity, their immunomodulatory effects, and the ability of MSCs to exert effects through their paracrine activities [170-173]. The following cardiac conditions can benefit from MSC therapy: ischemic heart disease and Acute Myocardial Infection (AMI); heart failure; and cardiac fibrosis [170-177].

The results of 4 systematic reviews and meta-analyses, which included 53 RCTs comprising 3043 patients, on the use of MSCs in the treatment of various cardiac disorders have shown: (1) safety and efficacy of MSCs in the treatment of AMI and heart failure with no significant increase in mortality; (2) significant improvement in overall left ventricular ejection fraction by 3.2% to 5.7%; (3) improvement in prognosis and exercise capacity; and (4) significant reduction (47%) in the incidence of hospitalization. However, the factors that favored better responses included: allogeneic sources of MSCs; intracoronary injections; and MSC doses of 1 x 108 - 10 x 108 cells [174-177].

Use of mesenchymal stem cells in the treatment of neurological and eye diseases: MSCs have proliferative, immunomodulatory, neuroprotective, and regenerative properties that make them promising cell-therapy candidates for various neurological disorders [178]. MSCs have been widely studied as cellular therapies for several neurological disorders in animal studies and early clinical trials and their use has shown safety, tolerability, and functional improvement, in addition to delay in disease progression after transplantation [178,179]. Genetic engineering and modification of MSCs as well as the use of ECVs of MSCs have emerged as new tools to enhance the therapeutic efficacy of MSCs in treating various neurological diseases [178]. Several studies have shown that MSCs and their exosomes can differentiate into dopaminergic neurons thus they can replace the neuronal loss in neurodegenerative diseases such as Parkinson’s disease (PD) [180-183]. In a PD model, exosomes of human UC-MSCs have been shown to traverse the blood-brain barrier indicating their potential to treat patients with PD [184].

The immunoregulatory, anti-inflammatory, anti-apoptotic, and regenerative properties of MSCs in addition to their safety profile make them ideal cell therapy candidates to treat various eye diseases such as diabetic retinopathy, glaucoma, retinal degeneration, and retinitis pigmentosa [185-187]. The use of ECVs of MSCs and genetic manipulation of MSCs can further improve their ability to treat various eye disorders [186-188].

Use of mesenchymal stem cells in the treatment of various infectious diseases: MSCs are applied in the treatment of various infectious diseases due to: (1) having immunomodulatory effects, that is, modulation of host innate and adaptive immune cells; (2) having anti-inflammatory properties; (3) having antimicrobial effects against the major classes of human pathogens [bacteria, viruses, fungi, and parasites]; and (4) their ability to promote the restoration of the epithelium and to stimulate tissue regeneration [189,190]. MSCs are being investigated in more than 80 clinical trials for difficult-to-treat infectious diseases including sepsis, intra-abdominal and cutaneous infections, as well as viral infections. The completed clinical trials have reported not only safety but also promising efficacy against some infectious diseases [190]. Cell-free treatments such as ECVs of MSCs have demonstrated high therapeutic efficacy in preclinical studies. Hence, they can become a promising tool for the treatment of various infectious diseases particularly in combination with antimicrobial drugs [189]. MSCs have shown promising potential to inhibit bacterial infections. Therefore, MSCs can be considered a novel strategy to enhance antibiotic activity against Multidrug-Resistant (MDR) organisms [191].

Sepsis and septic shock are serious and life-threatening disorders that are associated with high rates of morbidity and mortality [192,193]. Due to the failure of conventional therapies in recent years, research is focusing on innovative treatments such as cellular therapies [192]. The immunomodulatory, anti-inflammatory, anti-apoptotic, regenerative, and antimicrobial properties of MSCs can protect against organ failure caused by sepsis and septic shock. Hence, MSCs have been extensively utilized in both preclinical and clinical trials in various infectious diseases [192,193]. However, the way in which MSCs exert their beneficial effects to control inflammation and prolong survival in septic conditions remains unclear [194]. ECVs of MSCs exert therapeutic effects that are similar to MSCs and they can protect against sepsis-induced organ dysfunction [193]. In animal studies, the use of ECVs derived from BM-MSCs was associated with less organ damage in comparison to ECVs derived from MSCs obtained from other sources [195]. Additionally, ECVs derived from MSCs have shown superior safety profiles and the ability to be stored safely without loss of function compared to the parent cells. Therefore, MSC-ECVs may be used as a novel alternative to MSC-based therapy in sepsis [193].

Several studies have shown that MSCs are recruited at the periphery of tuberculous granulomas that harbor Mycobacterial Tuberculosis (MTB) bacilli and that MTB uses MSCs as a niche to evade host protective immunity surveillance mechanisms and to establish dormancy [196-199]. MSCs help MTB organisms to tolerate and even resist treatment with antiTB drugs [197,200]. MSCs have emerged as a fifth element capable of regulating immune responses during TB infection [201]. MSCs play a role in the dormancy and reactivation of MTB and in the capacity of MTB to evade host immune responses [202,203]. Transplantation of MSCs and their exosomes have been used in the treatment of MDR-TB. MSCs have been used in 3 clinical trials that included 135 patients to treat MDR-TB and extensively DR (XDR)-TB [201,204]. The results of these studies were as follows: (1) MSCs induced clinical and radiological improvements in 70% - 80% of patients; (2) MSC transplantation induced persistent remission and even cure in 53% - 56% of patients; and (3) the addition of autologous MSC transplantation to conventional anti-TB therapy significantly enhanced the response rates in patients with MDR-TB and XDR-TB [205-207].

Five systematic reviews and meta-analyses; that included 62 RCTs comprising 2316 patients; on the use of MSCs in the treatment of COVID-19 infection and its complications have shown the following results: (1) MSCs can reduce the mortality rates in patients with COVID-19 infection; (2) MSCs can induce remission of symptoms related to COVID-19 infection; (3) MSCs can reduce the severity of COVID-19 pneumonia; (4) MSCs can improve lung function and radiological appearances in patients with COVID-19 pneumonia; (5) MSCs can reduce the levels of C-reactive protein and interferon-gamma in patients with severe COVID-19 infection; and (6) MSCs can reduce the duration of hospitalization and the requirement for invasive mechanical ventilation; [208-212]. Additionally, the included RCTs showed safety of MSC therapy in COVID-19 infection without an increase in the incidence of adverse effects [208-211].

Use of mesenchymal stem cells in the treatment of skin disorders: Stem cells are present in different locations in the skin; interfollicular epidermis, hair follicles, dermis, and adipose tissue; in order to maintain normal skin homeostasis and they are involved in tissue repair and skin regeneration during injury [213]. Several studies have demonstrated the involvement of MSCs in the pathogenesis of certain skin disorders such as psoriasis [214]. Due to their immunomodulatory, anti-inflammatory, antimicrobial, and regenerative capabilities, MSCs can be used in the treatment of various congenital, acquired, inflammatory, and autoimmune skin diseases [214]. Two systematic reviews and several other studies have shown that MSCs obtained from various sources including AT and their secretome; ECVs and exosomes; have been used in the treatment of several skin disorders including psoriasis; vitiligo; epidermolysis bullosae; atopic dermatitis; scarring, androgenic, and areata alopecia; skin fibrosis due to aging, burns and scelomyxedema; Merkel cell carcinoma; and cutaneous photoprotection, wound healing, and promotion of hair growth [213-218].

Mesenchymal stem cells in regenerative medicine

and musculoskeletal disorders: Advances in isolation, culture, differentiation, and expansion techniques for MSCs have enabled their large-scale therapeutic utilization [60,219]. The following properties make MSCs optimal for tissue regeneration: (1) immunomodulatory capacity to alleviate abnormal immune responses; (2) paracrine or autocrine functions that generate growth factors; (3) the ability to differentiate into target cells; (4) anti-inflammatory and immunosuppressive properties; (5) migration to the areas having tissue injury; and (6) anti-aging, reconstructive, and wound healing potentials [60,219,220]. As a result of 5 decades of research and investigations, MSCs have emerged as a versatile and frequently utilized cell source in the fields of tissue engineering and regenerative medicine [221]. Studies in regenerative medicine have shown: (1) administration of MSCs in the treatment of bone and heart diseases appears to be effective, useful, and broadly established; (2) several clinical trials have reported the value of both autologous and allogeneic MSCs in tissue formation; (3) no significant association was established between the use of MSCs and cancer or infections; (4) intravenous (IV) route has been established as the optimal route of administration of MSCs and doses between 1 x 106 and 2 x 108 cell/kg body weight; and (5) repeated administration of MSCs is more beneficial than single injection [60].

Studies suggest that expanded MSCs have multiple therapeutic effects on musculoskeletal disorders that can be applied in bone regeneration, restoration of cartilage defects, and treatment of OA, spinal fusion, disc regeneration, and tendon repair [222]. MSC-related osteobiologic products are available either in the market or in development [222]. Several approaches using MSCs for regenerating damaged periodontium are under study with variable degrees of clinical applications [223].

Autologous MSCs represent the primary source considered safe for transplantation and minimization of immunological risk despite the lack of documented complaints regarding allogeneic MSC-based therapies [220]. However, MSCs have been shown to be able to survive and engraft in allogeneic recipients [222]. Scaffold; materials that have been engineered to cause desirable cellular interactions to contribute to the formation of new functional tissues; have the following advantages: (1) they provide the environment and stimulation of MSCs to proliferate and differentiate, and (2) they enhance the therapeutic effects of MSCs as they are loaded with the required induction factors [220]. Despite the current challenges, MSC-based tissue engineering represents a promising clinical strategy in the field of regenerative medicine. However, improving the cultural environment of MSCs and selecting appropriate scaffolds and induction factors are essential components of MSC therapy [220,221].

With high expectations, many ongoing clinical trials are investigating the safety and efficacy of MSCs in the treatment of arthritic diseases [224]. Over the last few decades, MSCs have been extensively explored as an emerging technique for the treatment of OA. However, therapeutic efficacy depends on a number of factors including the source of MSCs and the technique used in the treatment of OA [225]. However, studies on OA have shown positive clinical outcomes and improvement of joint function, pain level, and quality of life without serious adverse events [224]. MSCs may limit cartilage degeneration in OA by interfering with cellular immunity and secreting a number of active chemicals [225].

Mesenchymal stem cells derived from induced pluripotent stem cells

Studies have shown that conventional tissue-derived MSCs are heterogeneous in nature as they have donor-specific and tissue-specific differences such as age, sex, and tissue source which limit their proliferative capacity and lead to inconsistent long-term therapeutic outcomes [226-228]. Due to the clinical potential of MSCs, there has been considerable interest in the generation of functional MSC preparations from induced pluripotent stem cells (iPSCs) [229,230]. iPSCs can differentiate through several techniques including: growth factor induction, three-dimensional cell culture, biomaterials, and epigenetics into induced MSCs (iMSCs) [227,228]. Currently, iPSCs represent a new reliable source to generate MSCs from iPSCs (iMSCs) from heterogeneous and well-characterized cell lines and are now regarded as a potential source of unlimited standardized high-quality cells for therapeutic applications in regenerative medicine [229,230]. Studies have shown that: (1) irrespective of donor age and cell source, iMSCs acquire a rejuvenation gene signature thus overcoming the age-associated drawbacks of native MSCs, and (2) iMSCs have specific features such as their single-cell clone origins as well as defined and controllable cultural conditions for their derivation and proliferation [231-233]. Autologous iMSCs represent a unique source of standardized cellular therapy that can be used to fulfill unmet clinical needs and to overcome most of the obstacles still facing the broad clinical application of MSCs as advanced medicinal products [226,233-237]. Recent studies have shown that, compared to adult MSCs and UC-MSCs, iMSCs have demonstrated superior immunosuppressive capacity and clinical superiority when applied in tissue regeneration such as wound healing [226,228,234,235,237]. Compared to adult MSCs, exosomes derived from iMSCs have shown superior therapeutic quality with enhanced growth proliferation and migration in tissue regeneration [228,236].

Mesenchymal stem cells as advanced therapeutic medicinal products and their approvals for clinical use

Stem cell research has resulted in the emergence of cell-based therapies for disorders that are resistant to conventional drugs and therapies, and these cell therapies are considered under the category of an Advanced Therapeutic Medicinal Product (ATMP) [238]. ATMPs are innovative medicinal products, developed mainly as individualized and patient-specific treatments, and represent new opportunities for diseases characterized by unmet medical needs, including rare, genetic and neurodegenerative disorders, hematological malignancies, cancer, AIDs, and inflammatory conditions [239]. Since ATMPs often target serious diseases, the industry and authorities are interested in providing treatment to patients in a timely manner through optimized and expedited regulatory pathways [240]. The FDA in the USA and the European Medicines Agency (EMA) devised a new strategy in 2017 with the aim of unifying the standards for the development of ATMPs such that it is easy to exchange information at the international level [238]. Various diseases have been treated by MSCs in animal models and hundreds of human clinical trials related to the potential benefits of MSCs are in progress [241]. Autologous MSCs can be affected by the disease status of patients and this compromises their clinical utilization. Consequently, allogeneic therapy seems to be the most cost-effective method [241,242]. Standardized procedures based on instrumented single-use bioreactors have been shown to provide billions of MSCs with consistent product quality and to be superior to traditional expansions in planar cultivation systems [242,243]. Currently, more than 27 human MSC-derived therapeutics are currently commercially available [243]. However, the immunomodulatory and anti-inflammatory properties of UC-MSCs, associated with fewer ethical, availability, and safety issues, position UCMSCs as promising active substances to develop medicinal products to treat immune and inflammatory diseases. Since 2007, UC-MSC-based products have been classified as ATMP according to the European Regulation 1394/2007/EC [244].

Currently, there is no FDA-approved MSC therapy on the market in the USA [133]. However, regulatory authorities have already approved MSC therapies for several clinical conditions including GVHD in Japan, Canada, and New Zeeland, perianal fistula due to Crohn’s disease in Europe, and critical limb ischemia in India [137,245-247]. In the year 2018, the EMA authorized the first marketing of allogeneic AT-derived MSCs for the treatment of complex perianal fistulas in Crohn’s disease and this represented a breakthrough in the field of MSC therapy [248]. Due to the complexity of the production process of MSCs, the prices of MSC medicinal products have been reported to range between 25,000 and 40,000 US dollars per dose of MSCs [249]. Nevertheless, the development of enhanced MSC products of clinical relevance in a cost-effective manner holds the potential to offer therapeutic solutions with fewer adverse effects compared to the drugs that are currently available for the treatment of inflammatory and autoimmune disorders [250].

Safety and efficacy of mesenchymal stem cell therapies

Eleven systematic reviews and meta-analyses that included 266 studies; 105 of them were RCTs; on the clinical utilization of MSCs in more than 34 different disease conditions revealed the safety of MSC therapies in general, with few and tolerable adverse effects, regardless of the source or the route of administration of MSCs [147,174,177,208,251-258]. 24 systematic reviews and meta-analyses that included 445 studies; 69 of them were RCTs; on the clinical utilization of MSCs in 47 different disease conditions; including autoimmune, infectious, liver, cardiac, and neurological disorders; revealed the efficacy of MSC therapies in general with improvement in clinical status and improvement in laboratory indices reflecting disease activity regardless the source, the dose, or the route of administration of MSCs [147-150,176,177,208,223,254, 256-269].

Challenges facing the clinical utilization of mesenchymal stem cells

There are several challenges that face the clinical application of MSCs and these include: (1) safety issues related to the immediate and late adverse events such as: aggravation of arthritis, promotion of tumor growth and metasteses, and transmission of infectious diseases; (2) clinical grade production of MSCs requires large numbers of cells so in vitro expansion of MSCs is required and that MSCs which are used in clinical trials must be manufactured under the conditions required by the good manufacturing practice; (3) quality control measures covering all aspects including: cell production and harvest, viability and phenotype testing, oncogenicity tests, endotoxin assays, timing of administration, cell dose and schedule of administration, engraftment of MSCs, sources of MSCs (peripheral blood versus BM versus AT versus UC), autologous versus allogeneic transplantation, use of certain products such as ECVs of MSCs, donor related issues such as age and comorbidities, and use of fresh versus frozen and thawed MSCs; (4) in the period of clinical transition, plenty of work is still needed to: (a) increase knowledge on mechanisms involved in development, homeostasis, and tissue repair, (b) provide new tools to implement the efficacy of trials on MSC therapy, and (c) implement stringent regulations, standards, and protocols to cover all stages of MSCbased therapies including: isolation, ex vivo expansion, culture, storage, shipment, and administration; (5) performance of more RCTs and prospective studies to determine the optimal conditions of MSC therapy; (6) development of more robust pharmacodynamic, pharmacokinetic models that need to be applied in different clinical situations and to study failure of therapy and resistance to treatment; (7) stemness stability, and immunocompatibility; (8) the high economic costs of MSC therapies; (9) heterogeneity and limited expansion of MSCs; (10) requirement of inflammatory environment to induce immunosuppression; (11) loss of extracellular matrix upon delivery; (12) deprivation of nutrients and oxygen at the recipient site; and (13) linking research teams, cell therapy laboratories, and clinical teams in an integrated network [6,21,129,130,133,270-278].

Conclusions and future directions

Recently, the clinical applications of MSCs have rapidly expanded to include: AIDs; HSCT; several viral, bacterial, fungal, and parasitic infections and their complications; skin, pulmonary, and cardiovascular disorders; neurodegenerative, musculoskeletal and eye diseases; as well as regenerative medicine. The safety and efficacy of MSCs have been well illustrated in several clinical trials, systematic reviews, and meta-analyses.

Genetic engineering as well as the use of iMSCs and specific products of MSCs such as ECVs and exosomes have further improved their clinical efficacy and decreased their adverse effects including predisposition to cancer and infections.

The use of specific sources of MSCs, the administration of MSCs through certain routes, and the use of certain stem cell doses are expected to produce more fruitful short-term as well as long-term outcomes. Unification of preparation and administration protocols and implementation of strict regulations, standards, and quality control measures will result in the elimination of most of the remaining challenges that face the widespread utilization of MSCs in the clinical arena. The performance of more RCTs and multicenter prospective studies will ultimately determine the optimal conditions of MSC therapies in various acute and chronic diseases.

  1. Auletta JJ, Deans RJ, Bartholomew AM. Emerging roles for multipotent, bone marrow-derived stromal cells in host defense. Blood. 2012 Feb 23;119(8):1801-9. doi: 10.1182/blood-2011-10-384354. Epub 2012 Jan 6. PMID: 22228625; PMCID: PMC3293637.
  2. Al-Anazi KA, Al-Jasser AM. Mesenchymal stem cells-their antimicrobial effects and their promising future role as novel therapies of infectious complications in high-risk patients. In: Progress in stem cell transplantation. Edited by: Demirer T. Intech Open. 2015. doi: 10.5772/60640
  3. Abdal Dayem A, Lee SB, Kim K, Lim KM, Jeon TI, Seok J, Cho AS. Production of Mesenchymal Stem Cells Through Stem Cell Reprogramming. Int J Mol Sci. 2019 Apr 18;20(8):1922. doi: 10.3390/ijms20081922. PMID: 31003536; PMCID: PMC6514654.
  4. Al-Anazi KA, Al-Anazi WK, Al-Jasser AM. Update on COVID-19 infections and the promising role of mesenchymal stem cell therapies in their management. Heighten Science Publications Corporations (HSPI).2020.doi: 10.29328/ebook1002
  5. Bobis S, Jarocha D, Majka M. Mesenchymal stem cells: characteristics and clinical applications. Folia Histochem Cytobiol. 2006;44(4):215-30. PMID: 17219716.
  6. Kim N, Cho SG. Clinical applications of mesenchymal stem cells. Korean J Intern Med. 2013 Jul;28(4):387-402. doi: 10.3904/kjim.2013.28.4.387. Epub 2013 Jul 1. PMID: 23864795; PMCID: PMC3712145.
  7. Liu TM. Stemness of mesenchymal stem cells. Preliminary study. J Stem Cell Ther Transplant. 2017; 1: 071-073. doi: 10.29328/journal. jsctt.1001008
  8. Squillaro T, Peluso G, Galderisi U. Clinical Trials With Mesenchymal Stem Cells: An Update. Cell Transplant. 2016;25(5):829-48. doi: 10.3727/096368915X689622. Epub 2015 Sep 29. PMID: 26423725.
  9. Al-Anazi KA, Bakhit K, Al-Sagheir A, AlHashmi H, Abdulbaqi M, Alshibani Z, Apostolidis I, Estanislo A. Cure of insulin-dependent diabetes mellitus by an autologous hematopoietic stem cell transplantation performed to control multiple myeloma in a patient with chronic renal failure on regular hemodialysis. J Stem Cell Biol Transplant. 2017; 1: 2; 11. doi: 10.21767/ 2575-7725.100011
  10. Nancarrow-Lei R, Mafi P, Mafi R, Khan W. A Systemic Review of Adult Mesenchymal Stem Cell Sources and their Multilineage Differentiation Potential Relevant to Musculoskeletal Tissue Repair and Regeneration. Curr Stem Cell Res Ther. 2017;12(8):601-610. doi: 10.2174/1574888X12666170608124303. PMID: 28595566.
  11. Mafi R, Hindocha S, Mafi P, Griffin M, Khan WS. Sources of adult mesenchymal stem cells applicable for musculoskeletal applications - a systematic review of the literature. Open Orthop J. 2011;5 Suppl 2:242-8. doi: 10.2174/1874325001105010242. Epub 2011 Jul 28. PMID: 21886689; PMCID: PMC3149887.
  12. Hass R, Kasper C, Böhm S, Jacobs R. Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal. 2011 May 14;9:12. doi: 10.1186/1478-811X-9-12. PMID: 21569606; PMCID: PMC3117820.
  13. Berebichez-Fridman R, Montero-Olvera PR. Sources and Clinical Applications of Mesenchymal Stem Cells: State-of-the-art review. Sultan Qaboos Univ Med J. 2018 Aug;18(3):e264-e277. doi: 10.18295/squmj.2018.18.03.002. Epub 2018 Dec 19. PMID: 30607265; PMCID: PMC6307657.
  14. Costela-Ruiz VJ, Melguizo-Rodríguez L, Bellotti C, Illescas-Montes R, Stanco D, Arciola CR, Lucarelli E. Different Sources of Mesenchymal Stem Cells for Tissue Regeneration: A Guide to Identifying the Most Favorable One in Orthopedics and Dentistry Applications. Int J Mol Sci. 2022 Jun 6;23(11):6356. doi: 10.3390/ijms23116356. PMID: 35683035; PMCID: PMC9181542.
  15. Klingemann H, Matzilevich D, Marchand J. Mesenchymal Stem Cells - Sources and Clinical Applications. Transfus Med Hemother. 2008;35(4):272-277. doi: 10.1159/000142333. Epub 2008 Jul 21. PMID: 21512642; PMCID: PMC3076359.
  16. Via AG, Frizziero A, Oliva F. Biological properties of mesenchymal Stem Cells from different sources. Muscles Ligaments Tendons J. 2012 Oct 16;2(3):154-62. PMID: 23738292; PMCID: PMC3666517.
  17. Kholodenko IV, Kurbatov LK, Kholodenko RV, Manukyan GV, Yarygin KN. Mesenchymal Stem Cells in the Adult Human Liver: Hype or Hope? Cells. 2019 Sep 22;8(10):1127. doi: 10.3390/cells8101127. PMID: 31546729; PMCID: PMC6830330.
  18. Mane S, Taneja S, Madala JS, Agarkhedkar S, Khetan M. Study of Stem Cells in Human Milk. Cureus. 2022 Mar 31;14(3):e23701. doi: 10.7759/cureus.23701. PMID: 35505743; PMCID: PMC9056078.
  19. Nageeb MM, Saadawy SF, Attia SH. Breast milk mesenchymal stem cells abate cisplatin-induced cardiotoxicity in adult male albino rats via modulating the AMPK pathway. Sci Rep. 2022 Oct 20;12(1):17554. doi: 10.1038/s41598-022-22095-2. PMID: 36266413; PMCID: PMC9585145.
  20. Shih YR, Kuo TK, Yang AH, Lee OK, Lee CH. Isolation and characterization of stem cells from the human parathyroid gland. Cell Prolif. 2009 Aug;42(4):461-70. doi: 10.1111/j.1365-2184.2009.00614.x. Epub 2009 May 29. Erratum in: Cell Prolif. 2009 Aug;42(4):569. PMID: 19489980; PMCID: PMC6495903.
  21. Al-Anazi KA, Al-Anazi WK, Al-Jasser AM. The rising role of mesenchymal stem cells in the treatment of various infectious complications. In: Update on Mesenchymal and Induced Pluripotent Stem Cells. 2020. doi:10.5772/intechopen.91475.
  22. Vázquez A, Fernández-Sevilla LM, Jiménez E, Pérez-Cabrera D, Yañez R, Subiza JL, Varas A, Valencia J, Vicente A. Involvement of Mesenchymal Stem Cells in Oral Mucosal Bacterial Immunotherapy. Front Immunol. 2020 Nov 19;11:567391. doi: 10.3389/fimmu.2020.567391. PMID: 33329530; PMCID: PMC7711618.
  23. Di Francesco P, Cajon P, Desterke C, Perron Lepage MF, Lataillade JJ, Kadri T, Lepage OM. Effect of Allogeneic Oral Mucosa Mesenchymal Stromal Cells on Equine Wound Repair. Vet Med Int. 2021 Dec 14;2021:5024905. doi: 10.1155/2021/5024905. PMID: 34950446; PMCID: PMC8692048.
  24. Tu H, Xiao E, Liu O. Taking Microbiota into Consideration in Mesenchymal Stem Cell Research. J Dent Res. 2022 Jul;101(8):880-886. doi: 10.1177/00220345221077986. Epub 2022 Feb 23. PMID: 35196924.
  25. Nery AA, Nascimento IC, Glaser T, Bassaneze V, Krieger JE, Ulrich H. Human mesenchymal stem cells: from immunophenotyping by flow cytometry to clinical applications. Cytometry A. 2013 Jan;83(1):48-61. doi: 10.1002/cyto.a.22205. Epub 2012 Oct 1. PMID: 23027703.
  26. Sousa BR, Parreira RC, Fonseca EA, Amaya MJ, Tonelli FM, Lacerda SM, Lalwani P, Santos AK, Gomes KN, Ulrich H, Kihara AH, Resende RR. Human adult stem cells from diverse origins: an overview from multiparametric immunophenotyping to clinical applications. Cytometry A. 2014 Jan;85(1):43-77. doi: 10.1002/cyto.a.22402. Epub 2013 Nov 25. PMID: 24700575.
  27. Zhang Z, Yang X, Cao X, Qin A, Zhao J. Current applications of adipose-derived mesenchymal stem cells in bone repair and regeneration: A review of cell experiments, animal models, and clinical trials. Front Bioeng Biotechnol. 2022 Sep 7;10:942128. doi: 10.3389/fbioe.2022.942128. PMID: 36159705; PMCID: PMC9490047.
  28. Corselli M, Crisan M, Murray IR, West CC, Scholes J, Codrea F, Khan N, Péault B. Identification of perivascular mesenchymal stromal/stem cells by flow cytometry. Cytometry A. 2013 Aug;83(8):714-20. doi: 10.1002/cyto.a.22313. Epub 2013 Jul 1. PMID: 23818229.
  29. Ducret M, Farges JC, Pasdeloup M, Perrier-Groult E, Mueller A, Mallein-Gerin F, Fabre H. Phenotypic Identification of Dental Pulp Mesenchymal Stem/Stromal Cells Subpopulations with Multiparametric Flow Cytometry. Methods Mol Biol. 2019;1922:77-90. doi: 10.1007/978-1-4939-9012-2_8. PMID: 30838566.
  30. Liu P, An Y, Zhu T, Tang S, Huang X, Li S, Fu F, Chen J, Xuan K. Mesenchymal stem cells: Emerging concepts and recent advances in their roles in organismal homeostasis and therapy. Front Cell Infect Microbiol. 2023 Mar 9;13:1131218. doi: 10.3389/fcimb.2023.1131218. PMID: 36968100; PMCID: PMC10034133.
  31. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop Dj, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-7. doi: 10.1080/14653240600855905. PMID: 16923606.
  32. Viswanathan S, Shi Y, Galipeau J, Krampera M, Leblanc K, Martin I, Nolta J, Phinney DG, Sensebe L. Mesenchymal stem versus stromal cells: International Society for Cell & Gene Therapy (ISCT®) Mesenchymal Stromal Cell committee position statement on nomenclature. Cytotherapy. 2019 Oct;21(10):1019-1024. doi: 10.1016/j.jcyt.2019.08.002. Epub 2019 Sep 13. PMID: 31526643.
  33. Fernández Vallone VB, Romaniuk MA, Choi H, Labovsky V, Otaegui J, Chasseing NA. Mesenchymal stem cells and their use in therapy: what has been achieved? Differentiation. 2013 Jan;85(1-2):1-10. doi: 10.1016/j.diff.2012.08.004. Epub 2013 Jan 11. PMID: 23314286.
  34. Nauta AJ, Kruisselbrink AB, Lurvink E, Willemze R, Fibbe WE. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. J Immunol. 2006 Aug 15;177(4):2080-7. doi: 10.4049/jimmunol.177.4.2080. PMID: 16887966.
  35. Murray IR, Péault B. Q&A: Mesenchymal stem cells - where do they come from and is it important? BMC Biol. 2015 Nov 23;13:99. doi: 10.1186/s12915-015-0212-7. PMID: 26596888; PMCID: PMC4656175.
  36. Wexler SA, Donaldson C, Denning-Kendall P, Rice C, Bradley B, Hows JM. Adult bone marrow is a rich source of human mesenchymal 'stem' cells but umbilical cord and mobilized adult blood are not. Br J Haematol. 2003 Apr;121(2):368-74. doi: 10.1046/j.1365-2141.2003.04284.x. PMID: 12694261.
  37. Lv FJ, Tuan RS, Cheung KM, Leung VY. Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells. 2014 Jun;32(6):1408-19. doi: 10.1002/stem.1681. PMID: 24578244.
  38. Kundrotas G. Surface markers distinguishing mesenchymal stem cells from fibroblasts. Acta Med Lituanica. 2012; 19: 75-79.
  39. Lin CS, Ning H, Lin G, Lue TF. Is CD34 truly a negative marker for mesenchymal stromal cells? Cytotherapy. 2012 Nov;14(10):1159-63. doi: 10.3109/14653249.2012.729817. PMID: 23066784; PMCID: PMC3846603.
  40. Sidney LE, Branch MJ, Dunphy SE, Dua HS, Hopkinson A. Concise review: evidence for CD34 as a common marker for diverse progenitors. Stem Cells. 2014 Jun;32(6):1380-9. doi: 10.1002/stem.1661. PMID: 24497003; PMCID: PMC4260088.
  41. Stzepourginski I, Nigro G, Jacob JM, Dulauroy S, Sansonetti PJ, Eberl G, Peduto L. CD34+ mesenchymal cells are a major component of the intestinal stem cells niche at homeostasis and after injury. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E506-E513. doi: 10.1073/pnas.1620059114. Epub 2017 Jan 10. PMID: 28074039; PMCID: PMC5278455.
  42. Eto H, Ishimine H, Kinoshita K, Watanabe-Susaki K, Kato H, Doi K, Kuno S, Kurisaki A, Yoshimura K. Characterization of human adipose tissue-resident hematopoietic cell populations reveals a novel macrophage subpopulation with CD34 expression and mesenchymal multipotency. Stem Cells Dev. 2013 Mar 15;22(6):985-97. doi: 10.1089/scd.2012.0442. Epub 2012 Dec 21. PMID: 23137270; PMCID: PMC3585481.
  43. Alvarez P, Carrillo E, Vélez C, Hita-Contreras F, Martínez-Amat A, Rodríguez-Serrano F, Boulaiz H, Ortiz R, Melguizo C, Prados J, Aránega A. Regulatory systems in bone marrow for hematopoietic stem/progenitor cells mobilization and homing. Biomed Res Int. 2013;2013:312656. doi: 10.1155/2013/312656. Epub 2013 Jun 17. PMID: 23844360; PMCID: PMC3703413.
  44. Rochefort GY, Delorme B, Lopez A, Hérault O, Bonnet P, Charbord P, Eder V, Domenech J. Multipotential mesenchymal stem cells are mobilized into peripheral blood by hypoxia. Stem Cells. 2006 Oct;24(10):2202-8. doi: 10.1634/stemcells.2006-0164. Epub 2006 Jun 15. PMID: 16778152.
  45. Lund TC, Tolar J, Orchard PJ. Granulocyte colony-stimulating factor mobilized CFU-F can be found in the peripheral blood but have limited expansion potential. Haematologica. 2008 Jun;93(6):908-12. doi: 10.3324/haematol.12384. Epub 2008 Apr 9. PMID: 18403392.
  46. Gilevich IV, Fedorenko TV, Pashkova IA, Porkhanov VA, Chekhonin VP. Effects of Growth Factors on Mobilization of Mesenchymal Stem Cells. Bull Exp Biol Med. 2017 Mar;162(5):684-686. doi: 10.1007/s10517-017-3687-0. Epub 2017 Mar 31. PMID: 28361423.
  47. Xu L, Li G. Circulating mesenchymal stem cells and their clinical implications. J Orthop Transl. 2014; 2: 1-7. doi: 10.1016/
  48. Koning JJ, Kooij G, de Vries HE, Nolte MA, Mebius RE. Mesenchymal stem cells are mobilized from the bone marrow during inflammation. Front Immunol. 2013 Mar 4;4:49. doi: 10.3389/fimmu.2013.00049. PMID: 23459632; PMCID: PMC3586765.
  49. Rodríguez-Fuentes DE, Fernández-Garza LE, Samia-Meza JA, Barrera-Barrera SA, Caplan AI, Barrera-Saldaña HA. Mesenchymal Stem Cells Current Clinical Applications: A Systematic Review. Arch Med Res. 2021 Jan;52(1):93-101. doi: 10.1016/j.arcmed.2020.08.006. Epub 2020 Sep 22. PMID: 32977984.
  50. Li N, Hua J. Interactions between mesenchymal stem cells and the immune system. Cell Mol Life Sci. 2017 Jul;74(13):2345-2360. doi: 10.1007/s00018-017-2473-5. Epub 2017 Feb 18. PMID: 28214990.
  51. Wu X, Jiang J, Gu Z, Zhang J, Chen Y, Liu X. Mesenchymal stromal cell therapies: immunomodulatory properties and clinical progress. Stem Cell Res Ther. 2020 Aug 8;11(1):345. doi: 10.1186/s13287-020-01855-9. PMID: 32771052; PMCID: PMC7414268.
  52. Spees JL, Lee RH, Gregory CA. Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Res Ther. 2016 Aug 31;7(1):125. doi: 10.1186/s13287-016-0363-7. PMID: 27581859; PMCID: PMC5007684.
  53. Naji A, Eitoku M, Favier B, Deschaseaux F, Rouas-Freiss N, Suganuma N. Biological functions of mesenchymal stem cells and clinical implications. Cell Mol Life Sci. 2019 Sep;76(17):3323-3348. doi: 10.1007/s00018-019-03125-1. Epub 2019 May 4. PMID: 31055643.
  54. Yang G, Fan X, Liu Y, Jie P, Mazhar M, Liu Y, Dechsupa N, Wang L. Immunomodulatory Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells. Stem Cell Rev Rep. 2023 Jul;19(5):1214-1231. doi: 10.1007/s12015-023-10539-9. Epub 2023 Apr 14. PMID: 37058201; PMCID: PMC10103048.
  55. Han Y, Yang J, Fang J, Zhou Y, Candi E, Wang J, Hua D, Shao C, Shi Y. The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduct Target Ther. 2022 Mar 21;7(1):92. doi: 10.1038/s41392-022-00932-0. PMID: 35314676; PMCID: PMC8935608.
  56. Zhuang WZ, Lin YH, Su LJ, Wu MS, Jeng HY, Chang HC, Huang YH, Ling TY. Mesenchymal stem/stromal cell-based therapy: mechanism, systemic safety and biodistribution for precision clinical applications. J Biomed Sci. 2021 Apr 14;28(1):28. doi: 10.1186/s12929-021-00725-7. PMID: 33849537; PMCID: PMC8043779.
  57. Liang X, Ding Y, Zhang Y, Tse HF, Lian Q. Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives. Cell Transplant. 2014;23(9):1045-59. doi: 10.3727/096368913X667709. PMID: 23676629.
  58. Müller L, Tunger A, Wobus M, von Bonin M, Towers R, Bornhäuser M, Dazzi F, Wehner R, Schmitz M. Immunomodulatory Properties of Mesenchymal Stromal Cells: An Update. Front Cell Dev Biol. 2021 Feb 9;9:637725. doi: 10.3389/fcell.2021.637725. PMID: 33634139; PMCID: PMC7900158.
  59. Carp DM, Liang Y. Universal or Personalized Mesenchymal Stem Cell Therapies: Impact of Age, Sex, and Biological Source. Cells. 2022 Jun 30;11(13):2077. doi: 10.3390/cells11132077. PMID: 35805161; PMCID: PMC9265811.
  60. Margiana R, Markov A, Zekiy AO, Hamza MU, Al-Dabbagh KA, Al-Zubaidi SH, Hameed NM, Ahmad I, Sivaraman R, Kzar HH, Al-Gazally ME, Mustafa YF, Siahmansouri H. Clinical application of mesenchymal stem cell in regenerative medicine: a narrative review. Stem Cell Res Ther. 2022 Jul 28;13(1):366. doi: 10.1186/s13287-022-03054-0. PMID: 35902958; PMCID: PMC9330677.
  61. Fraile M, Eiro N, Costa LA, Martín A, Vizoso FJ. Aging and Mesenchymal Stem Cells: Basic Concepts, Challenges and Strategies. Biology (Basel). 2022 Nov 18;11(11):1678. doi: 10.3390/biology11111678. PMID: 36421393; PMCID: PMC9687158.
  62. Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev. 2012 Sep 20;21(14):2724-52. doi: 10.1089/scd.2011.0722. Epub 2012 May 9. PMID: 22468918.
  63. Pontikoglou C, Deschaseaux F, Sensebé L, Papadaki HA. Bone marrow mesenchymal stem cells: biological properties and their role in hematopoiesis and hematopoietic stem cell transplantation. Stem Cell Rev Rep. 2011 Sep;7(3):569-89. doi: 10.1007/s12015-011-9228-8. PMID: 21249477.
  64. Nakao N, Nakayama T, Yahata T, Muguruma Y, Saito S, Miyata Y, Yamamoto K, Naoe T. Adipose tissue-derived mesenchymal stem cells facilitate hematopoiesis in vitro and in vivo: advantages over bone marrow-derived mesenchymal stem cells. Am J Pathol. 2010 Aug;177(2):547-54. doi: 10.2353/ajpath.2010.091042. Epub 2010 Jun 17. PMID: 20558580; PMCID: PMC2913350.
  65. Gonzaga VF, Wenceslau CV, Lisboa GS, Frare EO, Kerkis I. Mesenchymal Stem Cell Benefits Observed in Bone Marrow Failure and Acquired Aplastic Anemia. Stem Cells Int. 2017;2017:8076529. doi: 10.1155/2017/8076529. Epub 2017 Dec 3. PMID: 29333168; PMCID: PMC5733198.
  66. Wu J, Zhang W, Ran Q, Xiang Y, Zhong JF, Li SC, Li Z. The Differentiation Balance of Bone Marrow Mesenchymal Stem Cells Is Crucial to Hematopoiesis. Stem Cells Int. 2018 Apr 3;2018:1540148. doi: 10.1155/2018/1540148. PMID: 29765406; PMCID: PMC5903338.
  67. Gao Q, Wang L, Wang S, Huang B, Jing Y, Su J. Bone Marrow Mesenchymal Stromal Cells: Identification, Classification, and Differentiation. Front Cell Dev Biol. 2022 Jan 3;9:787118. doi: 10.3389/fcell.2021.787118. PMID: 35047499; PMCID: PMC8762234.
  68. Laranjeira P, Pedrosa M, Pedreiro S, Gomes J, Martinho A, Antunes B, Ribeiro T, Santos F, Trindade H, Paiva A. Effect of human bone marrow mesenchymal stromal cells on cytokine production by peripheral blood naive, memory, and effector T cells. Stem Cell Res Ther. 2015 Jan 5;6(1):3. doi: 10.1186/scrt537. PMID: 25559824; PMCID: PMC4417198.
  69. Pedrosa M, Gomes J, Laranjeira P, Duarte C, Pedreiro S, Antunes B, Ribeiro T, Santos F, Martinho A, Fardilha M, Domingues MR, Abecasis M, P da Silva JA, Paiva A. Immunomodulatory effect of human bone marrow-derived mesenchymal stromal/stem cells on peripheral blood T cells from rheumatoid arthritis patients. J Tissue Eng Regen Med. 2020 Jan;14(1):16-28. doi: 10.1002/term.2958. Epub 2019 Nov 11. PMID: 31502378.
  70. Zhou X, Cao H, Guo J, Yuan Y, Ni G. Effects of BMSC-Derived EVs on Bone Metabolism. Pharmaceutics. 2022 May 8;14(5):1012. doi: 10.3390/pharmaceutics14051012. PMID: 35631601; PMCID: PMC9146387.
  71. Wang ZG, He ZY, Liang S, Yang Q, Cheng P, Chen AM. Comprehensive proteomic analysis of exosomes derived from human bone marrow, adipose tissue, and umbilical cord mesenchymal stem cells. Stem Cell Res Ther. 2020 Nov 27;11(1):511. doi: 10.1186/s13287-020-02032-8. PMID: 33246507; PMCID: PMC7694919.
  72. Bucar S, Branco ADM, Mata MF, Milhano JC, Caramalho Í, Cabral JMS, Fernandes-Platzgummer A, da Silva CL. Influence of the mesenchymal stromal cell source on the hematopoietic supportive capacity of umbilical cord blood-derived CD34+-enriched cells. Stem Cell Res Ther. 2021 Jul 13;12(1):399. doi: 10.1186/s13287-021-02474-8. PMID: 34256848; PMCID: PMC8278708.
  73. De Toni F, Poglio S, Youcef AB, Cousin B, Pflumio F, Bourin P, Casteilla L, Laharrague P. Human adipose-derived stromal cells efficiently support hematopoiesis in vitro and in vivo: a key step for therapeutic studies. Stem Cells Dev. 2011 Dec;20(12):2127-38. doi: 10.1089/scd.2011.0044. Epub 2011 Apr 13. PMID: 21388235.
  74. Valencia J, Blanco B, Yáñez R, Vázquez M, Herrero Sánchez C, Fernández-García M, Rodríguez Serrano C, Pescador D, Blanco JF, Hernando-Rodríguez M, Sánchez-Guijo F, Lamana ML, Segovia JC, Vicente Á, Del Cañizo C, Zapata AG. Comparative analysis of the immunomodulatory capacities of human bone marrow- and adipose tissue-derived mesenchymal stromal cells from the same donor. Cytotherapy. 2016 Oct;18(10):1297-311. doi: 10.1016/j.jcyt.2016.07.006. PMID: 27637760.
  75. Melief SM, Zwaginga JJ, Fibbe WE, Roelofs H. Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Transl Med. 2013 Jun;2(6):455-63. doi: 10.5966/sctm.2012-0184. Epub 2013 May 21. PMID: 23694810; PMCID: PMC3673757.
  76. Yousefifard M, Nasirinezhad F, Shardi Manaheji H, Janzadeh A, Hosseini M, Keshavarz M. Human bone marrow-derived and umbilical cord-derived mesenchymal stem cells for alleviating neuropathic pain in a spinal cord injury model. Stem Cell Res Ther. 2016 Mar 8;7:36. doi: 10.1186/s13287-016-0295-2. PMID: 26957122; PMCID: PMC4784350.
  77. Takahashi A, Nakajima H, Uchida K, Takeura N, Honjoh K, Watanabe S, Kitade M, Kokubo Y, Johnson WEB, Matsumine A. Comparison of Mesenchymal Stromal Cells Isolated from Murine Adipose Tissue and Bone Marrow in the Treatment of Spinal Cord Injury. Cell Transplant. 2018 Jul;27(7):1126-1139. doi: 10.1177/0963689718780309. Epub 2018 Jun 27. PMID: 29947256; PMCID: PMC6158550.
  78. Lombardi F, Palumbo P, Augello FR, Cifone MG, Cinque B, Giuliani M. Secretome of Adipose Tissue-Derived Stem Cells (ASCs) as a Novel Trend in Chronic Non-Healing Wounds: An Overview of Experimental In Vitro and In Vivo Studies and Methodological Variables. Int J Mol Sci. 2019 Jul 30;20(15):3721. doi: 10.3390/ijms20153721. PMID: 31366040; PMCID: PMC6696601.
  79. Guo J, Hu H, Gorecka J, Bai H, He H, Assi R, Isaji T, Wang T, Setia O, Lopes L, Gu Y, Dardik A. Adipose-derived mesenchymal stem cells accelerate diabetic wound healing in a similar fashion as bone marrow-derived cells. Am J Physiol Cell Physiol. 2018 Dec 1;315(6):C885-C896. doi: 10.1152/ajpcell.00120.2018. Epub 2018 Nov 7. PMID: 30404559; PMCID: PMC6336941.
  80. Pomatto M, Gai C, Negro F, Cedrino M, Grange C, Ceccotti E, Togliatto G, Collino F, Tapparo M, Figliolini F, Lopatina T, Brizzi MF, Camussi G. Differential Therapeutic Effect of Extracellular Vesicles Derived by Bone Marrow and Adipose Mesenchymal Stem Cells on Wound Healing of Diabetic Ulcers and Correlation to Their Cargoes. Int J Mol Sci. 2021 Apr 8;22(8):3851. doi: 10.3390/ijms22083851. PMID: 33917759; PMCID: PMC8068154.
  81. Maguire G. The Safe and Efficacious Use of Secretome From Fibroblasts and Adipose-derived (but not Bone Marrow-derived) Mesenchymal Stem Cells for Skin Therapeutics. J Clin Aesthet Dermatol. 2019 Aug;12(8):E57-E69. Epub 2019 Aug 1. PMID: 31531174; PMCID: PMC6715117.
  82. Ajit A, Ambika Gopalankutty I. Adipose-derived stem cell secretome as a cell-free product for cutaneous wound healing. 3 Biotech. 2021 Sep;11(9):413. doi: 10.1007/s13205-021-02958-7. Epub 2021 Aug 16. PMID: 34476171; PMCID: PMC8368523.
  83. Sheykhhasan M, Wong JKL, Seifalian AM. Human Adipose-Derived Stem Cells with Great Therapeutic Potential. Curr Stem Cell Res Ther. 2019;14(7):532-548. doi: 10.2174/1574888X14666190411121528. PMID: 30973112.
  84. Mazini L, Ezzoubi M, Malka G. Overview of current adipose-derived stem cell (ADSCs) processing involved in therapeutic advancements: flow chart and regulation updates before and after COVID-19. Stem Cell Res Ther. 2021 Jan 4;12(1):1. doi: 10.1186/s13287-020-02006-w. PMID: 33397467; PMCID: PMC7781178.
  85. Frese L, Dijkman PE, Hoerstrup SP. Adipose Tissue-Derived Stem Cells in Regenerative Medicine. Transfus Med Hemother. 2016 Jul;43(4):268-274. doi: 10.1159/000448180. Epub 2016 Jul 26. PMID: 27721702; PMCID: PMC5040903.
  86. Bunnell BA. Adipose Tissue-Derived Mesenchymal Stem Cells. Cells. 2021 Dec 6;10(12):3433. doi: 10.3390/cells10123433. PMID: 34943941; PMCID: PMC8700397.
  87. El Omar R, Beroud J, Stoltz JF, Menu P, Velot E, Decot V. Umbilical cord mesenchymal stem cells: the new gold standard for mesenchymal stem cell-based therapies? Tissue Eng Part B Rev. 2014 Oct;20(5):523-44. doi: 10.1089/ten.TEB.2013.0664. Epub 2014 Apr 22. PMID: 24552279.
  88. Watson N, Divers R, Kedar R, Mehindru A, Mehindru A, Borlongan MC, Borlongan CV. Discarded Wharton jelly of the human umbilical cord: a viable source for mesenchymal stromal cells. Cytotherapy. 2015 Jan;17(1):18-24. doi: 10.1016/j.jcyt.2014.08.009. Epub 2014 Oct 18. PMID: 25442786; PMCID: PMC4274214.
  89. Abbaszadeh H, Ghorbani F, Derakhshani M, Movassaghpour AA, Yousefi M, Talebi M, Shamsasenjan K. Regenerative potential of Wharton's jelly-derived mesenchymal stem cells: A new horizon of stem cell therapy. J Cell Physiol. 2020 Dec;235(12):9230-9240. doi: 10.1002/jcp.29810. Epub 2020 Jun 18. PMID: 32557631.
  90. Li X, Bai J, Ji X, Li R, Xuan Y, Wang Y. Comprehensive characterization of four different populations of human mesenchymal stem cells as regards their immune properties, proliferation and differentiation. Int J Mol Med. 2014 Sep;34(3):695-704. doi: 10.3892/ijmm.2014.1821. Epub 2014 Jun 25. PMID: 24970492; PMCID: PMC4121354.
  91. Nagamura-Inoue T, He H. Umbilical cord-derived mesenchymal stem cells: Their advantages and potential clinical utility. World J Stem Cells. 2014 Apr 26;6(2):195-202. doi: 10.4252/wjsc.v6.i2.195. PMID: 24772246; PMCID: PMC3999777.
  92. Shang Y, Guan H, Zhou F. Biological Characteristics of Umbilical Cord Mesenchymal Stem Cells and Its Therapeutic Potential for Hematological Disorders. Front Cell Dev Biol. 2021 May 3;9:570179. doi: 10.3389/fcell.2021.570179. PMID: 34012958; PMCID: PMC8126649.
  93. Chen Y, Shen H, Ding Y, Yu Y, Shao L, Shen Z. The application of umbilical cord-derived MSCs in cardiovascular diseases. J Cell Mol Med. 2021 Sep;25(17):8103-8114. doi: 10.1111/jcmm.16830. Epub 2021 Aug 11. PMID: 34378345; PMCID: PMC8419197.
  94. Karnas E, Dudek P, Zuba-Surma EK. Stem cell- derived extracellular vesicles as new tools in regenerative medicine - Immunomodulatory role and future perspectives. Front Immunol. 2023 Jan 24;14:1120175. doi: 10.3389/fimmu.2023.1120175. PMID: 36761725; PMCID: PMC9902918.
  95. Campanella C, Caruso Bavisotto C, Logozzi M, Marino Gammazza A, Mizzoni D, Cappello F, Fais S. On the Choice of the Extracellular Vesicles for Therapeutic Purposes. Int J Mol Sci. 2019 Jan 9;20(2):236. doi: 10.3390/ijms20020236. PMID: 30634425; PMCID: PMC6359369.
  96. Yin L, Liu X, Shi Y, Ocansey DKW, Hu Y, Li X, Zhang C, Xu W, Qian H. Therapeutic Advances of Stem Cell-Derived Extracellular Vesicles in Regenerative Medicine. Cells. 2020 Mar 13;9(3):707. doi: 10.3390/cells9030707. PMID: 32183102; PMCID: PMC7140663.
  97. Bruno S, Chiabotto G, Favaro E, Deregibus MC, Camussi G. Role of extracellular vesicles in stem cell biology. Am J Physiol Cell Physiol. 2019 Aug 1;317(2):C303-C313. doi: 10.1152/ajpcell.00129.2019. Epub 2019 May 15. PMID: 31091143; PMCID: PMC6732418.
  98. Zhang B, Yeo RW, Tan KH, Lim SK. Focus on Extracellular Vesicles: Therapeutic Potential of Stem Cell-Derived Extracellular Vesicles. Int J Mol Sci. 2016 Feb 6;17(2):174. doi: 10.3390/ijms17020174. PMID: 26861305; PMCID: PMC4783908.
  99. Kou M, Huang L, Yang J, Chiang Z, Chen S, Liu J, Guo L, Zhang X, Zhou X, Xu X, Yan X, Wang Y, Zhang J, Xu A, Tse HF, Lian Q. Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: a next generation therapeutic tool? Cell Death Dis. 2022 Jul 4;13(7):580. doi: 10.1038/s41419-022-05034-x. PMID: 35787632; PMCID: PMC9252569.
  100. Tsiapalis D, O'Driscoll L. Mesenchymal Stem Cell Derived Extracellular Vesicles for Tissue Engineering and Regenerative Medicine Applications. Cells. 2020 Apr 16;9(4):991. doi: 10.3390/cells9040991. PMID: 32316248; PMCID: PMC7226943.
  101. Fiore EJ, Domínguez LM, Bayo J, García MG, Mazzolini GD. Taking advantage of the potential of mesenchymal stromal cells in liver regeneration: Cells and extracellular vesicles as therapeutic strategies. World J Gastroenterol. 2018 Jun 21;24(23):2427-2440. doi: 10.3748/wjg.v24.i23.2427. PMID: 29930465; PMCID: PMC6010941.
  102. Racchetti G, Meldolesi J. Extracellular Vesicles of Mesenchymal Stem Cells: Therapeutic Properties Discovered with Extraordinary Success. Biomedicines. 2021 Jun 10;9(6):667. doi: 10.3390/biomedicines9060667. PMID: 34200818; PMCID: PMC8230522.
  103. Kahmini FR, Shahgaldi S. Therapeutic potential of mesenchymal stem cell-derived extracellular vesicles as novel cell-free therapy for treatment of autoimmune disorders. Exp Mol Pathol. 2021 Feb;118:104566. doi: 10.1016/j.yexmp.2020.104566. Epub 2020 Nov 6. PMID: 33160961.
  104. Matheakakis A, Batsali A, Papadaki HA, Pontikoglou CG. Therapeutic Implications of Mesenchymal Stromal Cells and Their Extracellular Vesicles in Autoimmune Diseases: From Biology to Clinical Applications. Int J Mol Sci. 2021 Sep 20;22(18):10132. doi: 10.3390/ijms221810132. PMID: 34576296; PMCID: PMC8468750.
  105. Zheng G, Huang R, Qiu G, Ge M, Wang J, Shu Q, Xu J. Mesenchymal stromal cell-derived extracellular vesicles: regenerative and immunomodulatory effects and potential applications in sepsis. Cell Tissue Res. 2018 Oct;374(1):1-15. doi: 10.1007/s00441-018-2871-5. Epub 2018 Jun 28. PMID: 29955951.
  106. Weng Z, Zhang B, Wu C, Yu F, Han B, Li B, Li L. Therapeutic roles of mesenchymal stem cell-derived extracellular vesicles in cancer. J Hematol Oncol. 2021 Sep 3;14(1):136. doi: 10.1186/s13045-021-01141-y. PMID: 34479611; PMCID: PMC8414028.
  107. Cheng Y, Cao X, Qin L. Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Novel Cell-Free Therapy for Sepsis. Front Immunol. 2020 Apr 21;11:647. doi: 10.3389/fimmu.2020.00647. PMID: 32373121; PMCID: PMC7186296.
  108. Williams T, Salmanian G, Burns M, Maldonado V, Smith E, Porter RM, Song YH, Samsonraj RM. Versatility of mesenchymal stem cell-derived extracellular vesicles in tissue repair and regenerative applications. Biochimie. 2023 Apr;207:33-48. doi: 10.1016/j.biochi.2022.11.011. Epub 2022 Nov 23. PMID: 36427681.
  109. Gowen A, Shahjin F, Chand S, Odegaard KE, Yelamanchili SV. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Challenges in Clinical Applications. Front Cell Dev Biol. 2020 Mar 12;8:149. doi: 10.3389/fcell.2020.00149. PMID: 32226787; PMCID: PMC7080981.
  110. Wiest EF, Zubair AC. Challenges of manufacturing mesenchymal stromal cell-derived extracellular vesicles in regenerative medicine. Cytotherapy. 2020 Nov;22(11):606-612. doi: 10.1016/j.jcyt.2020.04.040. Epub 2020 Jun 10. PMID: 32532592.
  111. Fuloria S, Subramaniyan V, Dahiya R, Dahiya S, Sudhakar K, Kumari U, Sathasivam K, Meenakshi DU, Wu YS, Sekar M, Malviya R, Singh A, Fuloria NK. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Regenerative Potential and Challenges. Biology (Basel). 2021 Feb 25;10(3):172. doi: 10.3390/biology10030172. PMID: 33668707; PMCID: PMC7996168.
  112. Fujita Y, Kadota T, Araya J, Ochiya T, Kuwano K. Clinical Application of Mesenchymal Stem Cell-Derived Extracellular Vesicle-Based Therapeutics for Inflammatory Lung Diseases. J Clin Med. 2018 Oct 14;7(10):355. doi: 10.3390/jcm7100355. PMID: 30322213; PMCID: PMC6210470.
  113. Maumus M, Rozier P, Boulestreau J, Jorgensen C, Noël D. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Opportunities and Challenges for Clinical Translation. Front Bioeng Biotechnol. 2020 Sep 10;8:997. doi: 10.3389/fbioe.2020.00997. PMID: 33015001; PMCID: PMC7511661.
  114. Allan D, Tieu A, Lalu M, Burger D. Mesenchymal stromal cell-derived extracellular vesicles for regenerative therapy and immune modulation: Progress and challenges toward clinical application. Stem Cells Transl Med. 2020 Jan;9(1):39-46. doi: 10.1002/sctm.19-0114. Epub 2019 Aug 14. PMID: 31411820; PMCID: PMC6954691.
  115. Rani S, Ryan AE, Griffin MD, Ritter T. Mesenchymal Stem Cell-derived Extracellular Vesicles: Toward Cell-free Therapeutic Applications. Mol Ther. 2015 May;23(5):812-823. doi: 10.1038/mt.2015.44. Epub 2015 Mar 19. PMID: 25868399; PMCID: PMC4427881.
  116. Chua JKE, Lim J, Foong LH, Mok CY, Tan HY, Tung XY, Ramasamy TS, Govindasamy V, Then KY, Das AK, Cheong SK. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Progress and Remaining Hurdles in Developing Regulatory Compliant Quality Control Assays. Adv Exp Med Biol. 2022;1401:191-211. doi: 10.1007/5584_2022_728. PMID: 35816249.
  117. Sun Y, Liu G, Zhang K, Cao Q, Liu T, Li J. Mesenchymal stem cells-derived exosomes for drug delivery. Stem Cell Res Ther. 2021 Oct 30;12(1):561. doi: 10.1186/s13287-021-02629-7. PMID: 34717769; PMCID: PMC8557580.
  118. Lotfy A, AboQuella NM, Wang H. Mesenchymal stromal/stem cell (MSC)-derived exosomes in clinical trials. Stem Cell Res Ther. 2023 Apr 7;14(1):66. doi: 10.1186/s13287-023-03287-7. PMID: 37024925; PMCID: PMC10079493.
  119. Oveili E, Vafaei S, Bazavar H, Eslami Y, Mamaghanizadeh E, Yasamineh S, Gholizadeh O. The potential use of mesenchymal stem cells-derived exosomes as microRNAs delivery systems in different diseases. Cell Commun Signal. 2023 Jan 23;21(1):20. doi: 10.1186/s12964-022-01017-9. PMID: 36690996; PMCID: PMC9869323.
  120. Liu WZ, Ma ZJ, Li JR, Kang XW. Mesenchymal stem cell-derived exosomes: therapeutic opportunities and challenges for spinal cord injury. Stem Cell Res Ther. 2021 Feb 3;12(1):102. doi: 10.1186/s13287-021-02153-8. PMID: 33536064; PMCID: PMC7860030.
  121. Bhaskar B, Mekala NK, Baadhe RR, Rao PS. Role of signaling pathways in mesenchymal stem cell differentiation. Curr Stem Cell Res Ther. 2014;9(6):508-12. doi: 10.2174/1574888x09666140812112002. PMID: 25116449.
  122. Samakova A, Gazova A, Sabova N, Valaskova S, Jurikova M, Kyselovic J. The PI3k/Akt pathway is associated with angiogenesis, oxidative stress and survival of mesenchymal stem cells in pathophysiologic condition in ischemia. Physiol Res. 2019 Nov 30;68(Suppl 2):S131-S138. doi: 10.33549/physiolres.934345. PMID: 31842576.
  123. Chen J, Crawford R, Chen C, Xiao Y. The key regulatory roles of the PI3K/Akt signaling pathway in the functionalities of mesenchymal stem cells and applications in tissue regeneration. Tissue Eng Part B Rev. 2013 Dec;19(6):516-28. doi: 10.1089/ten.TEB.2012.0672. Epub 2013 Jul 10. PMID: 23651329.
  124. Takam Kamga P, Bazzoni R, Dal Collo G, Cassaro A, Tanasi I, Russignan A, Tecchio C, Krampera M. The Role of Notch and Wnt Signaling in MSC Communication in Normal and Leukemic Bone Marrow Niche. Front Cell Dev Biol. 2021 Jan 8;8:599276. doi: 10.3389/fcell.2020.599276. PMID: 33490067; PMCID: PMC7820188.
  125. Li Y, Jin D, Xie W, Wen L, Chen W, Xu J, Ding J, Ren D. PPAR-γ and Wnt Regulate the Differentiation of MSCs into Adipocytes and Osteoblasts Respectively. Curr Stem Cell Res Ther. 2018 Feb 23;13(3):185-192. doi: 10.2174/1574888X12666171012141908. PMID: 29034841.
  126. Ng F, Boucher S, Koh S, Sastry KS, Chase L, Lakshmipathy U, Choong C, Yang Z, Vemuri MC, Rao MS, Tanavde V. PDGF, TGF-beta, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages. Blood. 2008 Jul 15;112(2):295-307. doi: 10.1182/blood-2007-07-103697. Epub 2008 Mar 10. PMID: 18332228.
  127. Kobolak J, Dinnyes A, Memic A, Khademhosseini A, Mobasheri A. Mesenchymal stem cells: Identification, phenotypic characterization, biological properties and potential for regenerative medicine through biomaterial micro-engineering of their niche. Methods. 2016 Apr 15;99:62-8. doi: 10.1016/j.ymeth.2015.09.016. Epub 2015 Sep 15. PMID: 26384580.
  128. Berebichez-Fridman R, Montero-Olvera PR. Sources and Clinical Applications of Mesenchymal Stem Cells: State-of-the-art review. Sultan Qaboos Univ Med J. 2018 Aug;18(3):e264-e277. doi: 10.18295/squmj.2018.18.03.002. Epub 2018 Dec 19. PMID: 30607265; PMCID: PMC6307657.
  129. Wang S, Qu X, Zhao RC. Clinical applications of mesenchymal stem cells. J Hematol Oncol. 2012 Apr 30;5:19. doi: 10.1186/1756-8722-5-19. PMID: 22546280; PMCID: PMC3416655.
  130. Zhou T, Yuan Z, Weng J, Pei D, Du X, He C, Lai P. Challenges and advances in clinical applications of mesenchymal stromal cells. J Hematol Oncol. 2021 Feb 12;14(1):24. doi: 10.1186/s13045-021-01037-x. PMID: 33579329; PMCID: PMC7880217.
  131. Wu J, Chen LH, Sun SY, Li Y, Ran XW. Mesenchymal stem cell-derived exosomes: The dawn of diabetic wound healing. World J Diabetes. 2022 Dec 15;13(12):1066-1095. doi: 10.4239/wjd.v13.i12.1066. PMID: 36578867; PMCID: PMC9791572.
  132. Hu JC, Zheng CX, Sui BD, Liu WJ, Jin Y. Mesenchymal stem cell-derived exosomes: A novel and potential remedy for cutaneous wound healing and regeneration. World J Stem Cells. 2022 May 26;14(5):318-329. doi: 10.4252/wjsc.v14.i5.318. PMID: 35722196; PMCID: PMC9157601.
  133. Wright A, Arthaud-Day ML, Weiss ML. Therapeutic Use of Mesenchymal Stromal Cells: The Need for Inclusive Characterization Guidelines to Accommodate All Tissue Sources and Species. Front Cell Dev Biol. 2021 Feb 16;9:632717. doi: 10.3389/fcell.2021.632717. PMID: 33665190; PMCID: PMC7921162.
  134. Gorman E, Millar J, McAuley D, O'Kane C. Mesenchymal stromal cells for acute respiratory distress syndrome (ARDS), sepsis, and COVID-19 infection: optimizing the therapeutic potential. Expert Rev Respir Med. 2021 Mar;15(3):301-324. doi: 10.1080/17476348.2021.1848555. Epub 2020 Nov 26. PMID: 33172313.
  135. Mattoli S, Schmidt M. Investigational Use of Mesenchymal Stem/Stromal Cells and Their Secretome as Add-On Therapy in Severe Respiratory Virus Infections: Challenges and Perspectives. Adv Ther. 2023 Jun;40(6):2626-2692. doi: 10.1007/s12325-023-02507-z. Epub 2023 Apr 17. PMID: 37069355; PMCID: PMC10109238.
  136. Yao W, Shi L, Zhang Y, Dong H, Zhang Y. Mesenchymal stem/stromal cell therapy for COVID-19 pneumonia: potential mechanisms, current clinical evidence, and future perspectives. Stem Cell Res Ther. 2022 Mar 24;13(1):124. doi: 10.1186/s13287-022-02810-6. PMID: 35321737; PMCID: PMC8942612.
  137. Ringdén O, Moll G, Gustafsson B, Sadeghi B. Mesenchymal Stromal Cells for Enhancing Hematopoietic Engraftment and Treatment of Graft-Versus-Host Disease, Hemorrhages and Acute Respiratory Distress Syndrome. Front Immunol. 2022 Mar 18;13:839844. doi: 10.3389/fimmu.2022.839844. PMID: 35371003; PMCID: PMC8973075.
  138. Khandelwal V, Sharma T, Gupta S, Singh S, Sharma MK, Parashar D, Kashyap VK. Stem cell therapy: a novel approach against emerging and re-emerging viral infections with special reference to SARS-CoV-2. Mol Biol Rep. 2023 Mar;50(3):2663-2683. doi: 10.1007/s11033-022-07957-2. Epub 2022 Dec 19. PMID: 36536185; PMCID: PMC9762873.
  139. Nandina RQ, Eriani K, Asrizal CW, Azhar A. Mesenchymal stem cell as a successful therapy for COVID-19 patient: Systematic review. Biosaintifika: J Biol Biol Edu. 2022; 14 (1): 36-47. doi: 10.15294/biosaintifika.v14i1.32367
  140. Liu P, An Y, Zhu T, Tang S, Huang X, Li S, Fu F, Chen J, Xuan K. Mesenchymal stem cells: Emerging concepts and recent advances in their roles in organismal homeostasis and therapy. Front Cell Infect Microbiol. 2023 Mar 9;13:1131218. doi: 10.3389/fcimb.2023.1131218. PMID: 36968100; PMCID: PMC10034133.
  141. Jasim SA, Yumashev AV, Abdelbasset WK, Margiana R, Markov A, Suksatan W, Pineda B, Thangavelu L, Ahmadi SH. Shining the light on clinical application of mesenchymal stem cell therapy in autoimmune diseases. Stem Cell Res Ther. 2022 Mar 7;13(1):101. doi: 10.1186/s13287-022-02782-7. PMID: 35255979; PMCID: PMC8900359.
  142. Chen Y, Yu Q, Hu Y, Shi Y. Current Research and Use of Mesenchymal Stem Cells in the Therapy of Autoimmune Diseases. Curr Stem Cell Res Ther. 2019;14(7):579-582. doi: 10.2174/1574888X14666190429141421. PMID: 31729289.
  143. Figueroa FE, Carrión F, Villanueva S, Khoury M. Mesenchymal stem cell treatment for autoimmune diseases: a critical review. Biol Res. 2012;45(3):269-77. doi: 10.4067/S0716-97602012000300008. PMID: 23283436.
  144. Huldani H, Abdalkareem Jasim S, Olegovich Bokov D, Abdelbasset WK, Nader Shalaby M, Thangavelu L, Margiana R, Qasim MT. Application of extracellular vesicles derived from mesenchymal stem cells as potential therapeutic tools in autoimmune and rheumatic diseases. Int Immunopharmacol. 2022 May;106:108634. doi: 10.1016/j.intimp.2022.108634. Epub 2022 Feb 19. PMID: 35193053.
  145. Wu Q, Zheng S, Qin Y, Zheng X, Chen H, Yang T, Zhang M. Efficacy and safety of stem cells transplantation in patients with type 1 diabetes mellitus-a systematic review and meta-analysis. Endocr J. 2020 Aug 28;67(8):827-840. doi: 10.1507/endocrj.EJ20-0050. Epub 2020 May 23. PMID: 32321876.
  146. He J, Kong D, Yang Z, Guo R, Amponsah AE, Feng B, Zhang X, Zhang W, Liu A, Ma J, O'Brien T, Cui H. Clinical efficacy on glycemic control and safety of mesenchymal stem cells in patients with diabetes mellitus: Systematic review and meta-analysis of RCT data. PLoS One. 2021 Mar 11;16(3):e0247662. doi: 10.1371/journal.pone.0247662. PMID: 33705413; PMCID: PMC7951834.
  147. Zeng L, Yu G, Yang K, Xiang W, Li J, Chen H. Efficacy and Safety of Mesenchymal Stem Cell Transplantation in the Treatment of Autoimmune Diseases (Rheumatoid Arthritis, Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Multiple Sclerosis, and Ankylosing Spondylitis): A Systematic Review and Meta-Analysis of Randomized Controlled Trial. Stem Cells Int. 2022 Mar 24;2022:9463314. doi: 10.1155/2022/9463314. PMID: 35371265; PMCID: PMC8970953.
  148. Liu S, Guo YL, Yang JY, Wang W, Xu J. [Efficacy of mesenchymal stem cells on systemic lupus erythematosus:a meta-analysis]. Beijing Da Xue Xue Bao Yi Xue Ban. 2018 Dec 18;50(6):1014-1021. Chinese. PMID: 30562774.
  149. Cui J, Jin L, Ding M, He J, Yang L, Cui S, Wang X, Ma J, Liu A. Efficacy and safety of mesenchymal stem cells in the treatment of systemic sclerosis: a systematic review and meta-analysis. Stem Cell Res Ther. 2022 Mar 21;13(1):118. doi: 10.1186/s13287-022-02786-3. PMID: 35313985; PMCID: PMC8935249.
  150. Oliveira AG, Gonçalves M, Ferreira H, M Neves N. Growing evidence supporting the use of mesenchymal stem cell therapies in multiple sclerosis: A systematic review. Mult Scler Relat Disord. 2020 Feb;38:101860. doi: 10.1016/j.msard.2019.101860. Epub 2019 Nov 18. PMID: 31765999.
  151. Sarvar DP, Effatpanah H, Akbarzadehlaleh P, Shamsasenjan K. Mesenchymal stromal cell-derived extracellular vesicles: novel approach in hematopoietic stem cell transplantation. Stem Cell Res Ther. 2022 May 16;13(1):202. doi: 10.1186/s13287-022-02875-3. PMID: 35578300; PMCID: PMC9109321.
  152. De Luca L, Trino S, Laurenzana I, Lamorte D, Caivano A, Del Vecchio L, Musto P. Mesenchymal Stem Cell Derived Extracellular Vesicles: A Role in Hematopoietic Transplantation? Int J Mol Sci. 2017 May 9;18(5):1022. doi: 10.3390/ijms18051022. PMID: 28486431; PMCID: PMC5454935.
  153. Battiwalla M, Hematti P. Mesenchymal stem cells in hematopoietic stem cell transplantation. Cytotherapy. 2009;11(5):503-15. doi: 10.1080/14653240903193806. PMID: 19728189; PMCID: PMC2766085.
  154. Kim EJ, Kim N, Cho SG. The potential use of mesenchymal stem cells in hematopoietic stem cell transplantation. Exp Mol Med. 2013 Jan 10;45(1):e2. doi: 10.1038/emm.2013.2. PMID: 23306700; PMCID: PMC3584660.
  155. Burnham AJ, Daley-Bauer LP, Horwitz EM. Mesenchymal stromal cells in hematopoietic cell transplantation. Blood Adv. 2020 Nov 24;4(22):5877-5887. doi: 10.1182/bloodadvances.2020002646. PMID: 33232479; PMCID: PMC7686890.
  156. Wu KH, Wu HP, Chan CK, Hwang SM, Peng CT, Chao YH. The role of mesenchymal stem cells in hematopoietic stem cell transplantation: from bench to bedsides. Cell Transplant. 2013;22(4):723-9. doi: 10.3727/096368912X655217. Epub 2012 Oct 12. PMID: 23068433.
  157. Chen X, Wang C, Yin J, Xu J, Wei J, Zhang Y. Efficacy of Mesenchymal Stem Cell Therapy for Steroid-Refractory Acute Graft-Versus-Host Disease following Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis. PLoS One. 2015 Aug 31;10(8):e0136991. doi: 10.1371/journal.pone.0136991. PMID: 26323092; PMCID: PMC4554731.
  158. Morata-Tarifa C, Macías-Sánchez MDM, Gutiérrez-Pizarraya A, Sanchez-Pernaute R. Mesenchymal stromal cells for the prophylaxis and treatment of graft-versus-host disease-a meta-analysis. Stem Cell Res Ther. 2020 Feb 18;11(1):64. doi: 10.1186/s13287-020-01592-z. PMID: 32070420; PMCID: PMC7027118.
  159. Hashmi S, Ahmed M, Murad MH, Litzow MR, Adams RH, Ball LM, Prasad VK, Kebriaei P, Ringden O. Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis. Lancet Haematol. 2016 Jan;3(1):e45-52. doi: 10.1016/S2352-3026(15)00224-0. Epub 2015 Nov 27. PMID: 26765648.
  160. Li R, Tu J, Zhao J, Pan H, Fang L, Shi J. Mesenchymal stromal cells as prophylaxis for graft-versus-host disease in haplo-identical hematopoietic stem cell transplantation recipients with severe aplastic anemia?-a systematic review and meta-analysis. Stem Cell Res Ther. 2021 Feb 4;12(1):106. doi: 10.1186/s13287-021-02170-7. PMID: 33541414; PMCID: PMC7860635.
  161. Munneke JM, Spruit MJ, Cornelissen AS, van Hoeven V, Voermans C, Hazenberg MD. The Potential of Mesenchymal Stromal Cells as Treatment for Severe Steroid-Refractory Acute Graft-Versus-Host Disease: A Critical Review of the Literature. Transplantation. 2016 Nov;100(11):2309-2314. doi: 10.1097/TP.0000000000001029. PMID: 26714122.
  162. Chen X, Wang F, Huang Z, Wu Y, Geng J, Wang Y. Clinical applications of mesenchymal stromal cell-based therapies for pulmonary diseases: An Update and Concise Review. Int J Med Sci. 2021 Jun 1;18(13):2849-2870. doi: 10.7150/ijms.59218. PMID: 34220313; PMCID: PMC8241779.
  163. Antoniou KM, Karagiannis K, Tsitoura E, Bibaki E, Lasithiotaki I, Proklou A, Spandidos DA, Tzanakis N. Clinical applications of mesenchymal stem cells in chronic lung diseases. Biomed Rep. 2018 Apr;8(4):314-318. doi: 10.3892/br.2018.1067. Epub 2018 Feb 16. PMID: 29556380; PMCID: PMC5844081.
  164. Le Thi Bich P, Nguyen Thi H, Dang Ngo Chau H, Phan Van T, Do Q, Dong Khac H, Le Van D, Nguyen Huy L, Mai Cong K, Ta Ba T, Do Minh T, Vu Bich N, Truong Chau N, Van Pham P. Allogeneic umbilical cord-derived mesenchymal stem cell transplantation for treating chronic obstructive pulmonary disease: a pilot clinical study. Stem Cell Res Ther. 2020 Feb 13;11(1):60. doi: 10.1186/s13287-020-1583-4. PMID: 32054512; PMCID: PMC7020576.
  165. Caretti A, Peli V, Colombo M, Zulueta A. Lights and Shadows in the Use of Mesenchymal Stem Cells in Lung Inflammation, a Poorly Investigated Topic in Cystic Fibrosis. Cells. 2019 Dec 19;9(1):20. doi: 10.3390/cells9010020. PMID: 31861724; PMCID: PMC7016730.
  166. Monsel A, Zhu YG, Gudapati V, Lim H, Lee JW. Mesenchymal stem cell derived secretome and extracellular vesicles for acute lung injury and other inflammatory lung diseases. Expert Opin Biol Ther. 2016 Jul;16(7):859-71. doi: 10.1517/14712598.2016.1170804. Epub 2016 Apr 12. PMID: 27011289; PMCID: PMC5280876.
  167. Li X, Yue S, Luo Z. Mesenchymal stem cells in idiopathic pulmonary fibrosis. Oncotarget. 2017 May 23;8(60):102600-102616. doi: 10.18632/oncotarget.18126. PMID: 29254275; PMCID: PMC5731985.
  168. Yao Y, Zheng Z, Song Q. Mesenchymal stem cells: A double-edged sword in radiation-induced lung injury. Thorac Cancer. 2018 Feb;9(2):208-217. doi: 10.1111/1759-7714.12573. Epub 2017 Dec 13. PMID: 29235254; PMCID: PMC5792737.
  169. Zanoni M, Cortesi M, Zamagni A, Tesei A. The Role of Mesenchymal Stem Cells in Radiation-Induced Lung Fibrosis. Int J Mol Sci. 2019 Aug 8;20(16):3876. doi: 10.3390/ijms20163876. PMID: 31398940; PMCID: PMC6719901.
  170. Guo Y, Yu Y, Hu S, Chen Y, Shen Z. The therapeutic potential of mesenchymal stem cells for cardiovascular diseases. Cell Death Dis. 2020 May 11;11(5):349. doi: 10.1038/s41419-020-2542-9. PMID: 32393744; PMCID: PMC7214402.
  171. Gubert F, da Silva JS, Vasques JF, de Jesus Gonçalves RG, Martins RS, de Sá MPL, Mendez-Otero R, Zapata-Sudo G. Mesenchymal Stem Cells Therapies on Fibrotic Heart Diseases. Int J Mol Sci. 2021 Jul 12;22(14):7447. doi: 10.3390/ijms22147447. PMID: 34299066; PMCID: PMC8307175.
  172. Wang Y, Qi Z, Yan Z, Ji N, Yang X, Gao D, Hu L, Lv H, Zhang J, Li M. Mesenchymal Stem Cell Immunomodulation: A Novel Intervention Mechanism in Cardiovascular Disease. Front Cell Dev Biol. 2022 Jan 12;9:742088. doi: 10.3389/fcell.2021.742088. PMID: 35096808; PMCID: PMC8790228.
  173. Poomani MS, Mariappan I, Perumal R, Regurajan R, Muthan K, Subramanian V. Mesenchymal Stem Cell (MSCs) Therapy for Ischemic Heart Disease: A Promising Frontier. Glob Heart. 2022 Mar 3;17(1):19. doi: 10.5334/gh.1098. PMID: 35342702; PMCID: PMC8916054.
  174. Lalu MM, Mazzarello S, Zlepnig J, Dong YYR, Montroy J, McIntyre L, Devereaux PJ, Stewart DJ, David Mazer C, Barron CC, McIsaac DI, Fergusson DA. Safety and Efficacy of Adult Stem Cell Therapy for Acute Myocardial Infarction and Ischemic Heart Failure (SafeCell Heart): A Systematic Review and Meta-Analysis. Stem Cells Transl Med. 2018 Dec;7(12):857-866. doi: 10.1002/sctm.18-0120. Epub 2018 Sep 26. PMID: 30255989; PMCID: PMC6265630.
  175. Fan M, Huang Y, Chen Z, Xia Y, Chen A, Lu D, Wu Y, Zhang N, Qian J. Efficacy of mesenchymal stem cell therapy in systolic heart failure: a systematic review and meta-analysis. Stem Cell Res Ther. 2019 May 31;10(1):150. doi: 10.1186/s13287-019-1258-1. Erratum in: Stem Cell Res Ther. 2019 Jul 15;10(1):206. PMID: 31151406; PMCID: PMC6544951.
  176. Shen T, Xia L, Dong W, Wang J, Su F, Niu S, Wang Q, Fang Y. A Systematic Review and Meta-Analysis: Safety and Efficacy of Mesenchymal Stem Cells Therapy for Heart Failure. Curr Stem Cell Res Ther. 2021;16(3):354-365. doi: 10.2174/1574888X15999200820171432. PMID: 32867655.
  177. Yu J, Zhang RF, Mao YL, Zhang H. Efficacy and Safety of Mesenchymal Stem Cell Therapy in Patients with Acute Myocardial Infarction: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Curr Stem Cell Res Ther. 2022;17(8):793-807. doi: 10.2174/1574888X16666210816111031. PMID: 34397334.
  178. Soares MBP, Gonçalves RGJ, Vasques JF, da Silva-Junior AJ, Gubert F, Santos GC, de Santana TA, Almeida Sampaio GL, Silva DN, Dominici M, Mendez-Otero R. Current Status of Mesenchymal Stem/Stromal Cells for Treatment of Neurological Diseases. Front Mol Neurosci. 2022 Jun 16; 15:883378. doi: 10.3389/fnmol.2022.883378. PMID: 35782379; PMCID: PMC9244712.
  179. Andrzejewska A, Dabrowska S, Lukomska B, Janowski M. Mesenchymal Stem Cells for Neurological Disorders. Adv Sci (Weinh). 2021 Feb 24;8(7):2002944. doi: 10.1002/advs.202002944. PMID: 33854883; PMCID: PMC8024997.
  180. Zhang ZX, Zhou YJ, Gu P, Zhao W, Chen HX, Wu RY, Zhou LY, Cui QZ, Sun SK, Zhang LQ, Zhang K, Xu HJ, Chai XQ, An SJ. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate Parkinson's disease and neuronal damage through inhibition of microglia. Neural Regen Res. 2023 Oct;18(10):2291-2300. doi: 10.4103/1673-5374.368300. PMID: 37056150; PMCID: PMC10328268.
  181. Heris RM, Shirvaliloo M, Abbaspour-Aghdam S, Hazrati A, Shariati A, Youshanlouei HR, Niaragh FJ, Valizadeh H, Ahmadi M. The potential use of mesenchymal stem cells and their exosomes in Parkinson's disease treatment. Stem Cell Res Ther. 2022 Jul 28;13(1):371. doi: 10.1186/s13287-022-03050-4. PMID: 35902981; PMCID: PMC9331055.
  182. Kitada M, Dezawa M. Parkinson's disease and mesenchymal stem cells: potential for cell-based therapy. Parkinsons Dis. 2012; 2012:873706. doi: 10.1155/2012/873706. Epub 2012 Feb 28. PMID: 22530164; PMCID: PMC3317001.
  183. Venkatesh K, Sen D. Mesenchymal Stem Cells as a Source of Dopaminergic Neurons: A Potential Cell Based Therapy for Parkinson's Disease. Curr Stem Cell Res Ther. 2017;12(4):326-347. doi: 10.2174/1574888X12666161114122059. PMID: 27842480.
  184. Chen HX, Liang FC, Gu P, Xu BL, Xu HJ, Wang WT, Hou JY, Xie DX, Chai XQ, An SJ. Exosomes derived from mesenchymal stem cells repair a Parkinson's disease model by inducing autophagy. Cell Death Dis. 2020 Apr 27;11(4):288. doi: 10.1038/s41419-020-2473-5. PMID: 32341347; PMCID: PMC7184757.
  185. Holan V, Palacka K, Hermankova B. Mesenchymal Stem Cell-Based Therapy for Retinal Degenerative Diseases: Experimental Models and Clinical Trials. Cells. 2021 Mar 7;10(3):588. doi: 10.3390/cells10030588. PMID: 33799995; PMCID: PMC8001847.
  186. Mannino G, Russo C, Longo A, Anfuso CD, Lupo G, Lo Furno D, Giuffrida R, Giurdanella G. Potential therapeutic applications of mesenchymal stem cells for the treatment of eye diseases. World J Stem Cells. 2021 Jun 26;13(6):632-644. doi: 10.4252/wjsc.v13.i6.632. PMID: 34249232; PMCID: PMC8246249.
  187. Adak S, Magdalene D, Deshmukh S, Das D, Jaganathan BG. A Review on Mesenchymal Stem Cells for Treatment of Retinal Diseases. Stem Cell Rev Rep. 2021 Aug;17(4):1154-1173. doi: 10.1007/s12015-020-10090-x. Epub 2021 Jan 6. PMID: 33410097; PMCID: PMC7787584.
  188. Chen X, Jiang Y, Duan Y, Zhang X, Li X. Mesenchymal-Stem-Cell-Based Strategies for Retinal Diseases. Genes (Basel). 2022 Oct 19;13(10):1901. doi: 10.3390/genes13101901. PMID: 36292786; PMCID: PMC9602395.
  189. Yudintceva N, Mikhailova N, Fedorov V, Samochernych K, Vinogradova T, Muraviov A, Shevtsov M. Mesenchymal Stem Cells and MSCs-Derived Extracellular Vesicles in Infectious Diseases: From Basic Research to Clinical Practice. Bioengineering (Basel). 2022 Nov 8;9(11):662. doi: 10.3390/bioengineering9110662. PMID: 36354573; PMCID: PMC9687734.
  190. Shaw TD, Krasnodembskaya AD, Schroeder GN, Zumla A, Maeurer M, O'Kane CM. Mesenchymal Stromal Cells: an Antimicrobial and Host-Directed Therapy for Complex Infectious Diseases. Clin Microbiol Rev. 2021 Dec 15;34(4):e0006421. doi: 10.1128/CMR.00064-21. Epub 2021 Oct 6. PMID: 34612662; PMCID: PMC8510528.
  191. Battah B. Mesenchymal stem cells: Potential role against bacterial infection. J Biosci Med. 2022; 10 (3): 97-113. doi: 10.4236/jbm.2022.103011 
  192. Laroye C, Gibot S, Reppel L, Bensoussan D. Concise Review: Mesenchymal Stromal/Stem Cells: A New Treatment for Sepsis and Septic Shock? Stem Cells. 2017 Dec;35(12):2331-2339. doi: 10.1002/stem.2695. Epub 2017 Sep 16. PMID: 28856759.
  193. Cheng Y, Cao X, Qin L. Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Novel Cell-Free Therapy for Sepsis. Front Immunol. 2020 Apr 21; 11:647. doi: 10.3389/fimmu.2020.00647. PMID: 32373121; PMCID: PMC7186296.
  194. Daniel M, Bedoui Y, Vagner D, Raffray L, Ah-Pine F, Doray B, Gasque P. Pathophysiology of Sepsis and Genesis of Septic Shock: The Critical Role of Mesenchymal Stem Cells (MSCs). Int J Mol Sci. 2022 Aug 17;23(16):9274. doi: 10.3390/ijms23169274. PMID: 36012544; PMCID: PMC9409099.
  195. Blanco NG, Machado NM, Castro LL, Antunes MA, Takiya CM, Trugilho MRO, Silva LR, Paes Leme AF, Domingues RR, Pauletti BA, Miranda BT, Silva JD, Dos Santos CC, Silva PL, Rocco PRM, Cruz FF. Extracellular Vesicles from Different Sources of Mesenchymal Stromal Cells Have Distinct Effects on Lung and Distal Organs in Experimental Sepsis. Int J Mol Sci. 2023 May 4;24(9):8234. doi: 10.3390/ijms24098234. PMID: 37175936; PMCID: PMC10179270.
  196. Devi A, Pahuja I, Singh SP, Verma A, Bhattacharya D, Bhaskar A, Dwivedi VP, Das G. Revisiting the role of mesenchymal stem cells in tuberculosis and other infectious diseases. Cell Mol Immunol. 2023 Jun;20(6):600-612. doi: 10.1038/s41423-023-01028-7. Epub 2023 May 12. PMID: 37173422; PMCID: PMC10176304.
  197. Jain N, Kalam H, Singh L, Sharma V, Kedia S, Das P, Ahuja V, Kumar D. Mesenchymal stem cells offer a drug-tolerant and immune-privileged niche to Mycobacterium tuberculosis. Nat Commun. 2020 Jun 16;11(1):3062. doi: 10.1038/s41467-020-16877-3. PMID: 32546788; PMCID: PMC7297998.
  198. Fatima S, Kamble SS, Dwivedi VP, Bhattacharya D, Kumar S, Ranganathan A, Van Kaer L, Mohanty S, Das G. Mycobacterium tuberculosis programs mesenchymal stem cells to establish dormancy and persistence. J Clin Invest. 2020 Feb 3;130(2):655-661. doi: 10.1172/JCI128043. PMID: 31647784; PMCID: PMC6994115.
  199. Singh VK, Mishra A, Bark S, Mani A, Subbian S, Hunter RL, Jagannath C, Khan A. Human mesenchymal stem cell based intracellular dormancy model of Mycobacterium tuberculosis. Microbes Infect. 2020 Oct;22(9):423-431. doi: 10.1016/j.micinf.2020.05.015. Epub 2020 Jun 17. PMID: 32562667; PMCID: PMC8059136.
  200. Zhang X, Xie Q, Ye Z, Li Y, Che Z, Huang M, Zeng J. Mesenchymal Stem Cells and Tuberculosis: Clinical Challenges and Opportunities. Front Immunol. 2021 Jul 22; 12:695278. doi: 10.3389/fimmu.2021.695278. PMID: 34367155; PMCID: PMC8340780.
  201. Khan A, Hunter RL, Jagannath C. Emerging role of mesenchymal stem cells during tuberculosis: The fifth element in cell mediated immunity. Tuberculosis (Edinb). 2016 Dec; 101S:S45-S52. doi: 10.1016/ Epub 2016 Sep 28. PMID: 27743705.
  202. Pathak L, Das B. Initiation of Post-Primary Tuberculosis of the Lungs: Exploring the Secret Role of Bone Marrow Derived Stem Cells. Front Immunol. 2021 Jan 21;11: 594572. doi: 10.3389/fimmu.2020.594572. PMID: 33584661; PMCID: PMC7873989.
  203. Raghuvanshi S, Sharma P, Singh S, Van Kaer L, Das G. Mycobacterium tuberculosis evades host immunity by recruiting mesenchymal stem cells. Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21653-8. doi: 10.1073/pnas.1007967107. Epub 2010 Dec 6. PMID: 21135221; PMCID: PMC3003090.
  204. Liu M, Wang Z, Ren S, Zhao H. Exosomes derived from mycobacterium tuberculosis-infected MSCs induce a pro-inflammatory response of macrophages. Aging (Albany NY). 2021 Apr 19;13(8):11595-11609. doi: 10.18632/aging.202854. Epub 2021 Apr 19. PMID: 33872217; PMCID: PMC8109131.
  205. Erokhin VV, Vasil'eva IA, Konopliannikov AG, Chukanov VI, Tsyb AF, Bagdasarian TR, Danilenko AA, Lepekhina LA, Kal'sina SSh, Semenkova IV, Agaeva EV. [Systemic transplantation of autologous mesenchymal stem cells of the bone marrow in the treatment of patients with multidrug-resistant pulmonary tuberculosis]. Probl Tuberk Bolezn Legk. 2008;(10):3-6. Russian. PMID: 19086127.
  206. Skrahin A, Ahmed RK, Ferrara G, Rane L, Poiret T, Isaikina Y, Skrahina A, Zumla A, Maeurer MJ. Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial. Lancet Respir Med. 2014 Feb;2(2):108-22. doi: 10.1016/S2213-2600(13)70234-0. Epub 2014 Jan 9. PMID: 24503266.
  207. Skrahin AE, Jenkins HE, Hurevich H, Solodovnokova V, Isaikina Y, Klimuk D, Rohava Z, Skrahina A. Potential role of autologous mesenchymal stromal cells in the treatment of multidrug and extensively drug-resistant tuberculosis. Eur Respir J. 2016; 48: PA1919. doi: 10.1183/13993003. congress-2016.PA1919
  208. Wang J, Shi P, Chen D, Wang S, Wang P, Feng X, Zhang L. Research Status of the Safety and Efficacy of Mesenchymal Stem Cells in the Treatment of COVID-19-Related Pneumonia: A Systematic Review and Meta-Analysis. Stem Cells Dev. 2021 Oct 1;30(19):947-969. doi: 10.1089/scd.2021.0179. PMID: 34416823.
  209. Zhang Z, Shao S, Liu X, Tong Z. Effect and safety of mesenchymal stem cells for patients with COVID-19: Systematic review and meta-analysis with trial sequential analysis. J Med Virol. 2023 Apr;95(4):e28702. doi: 10.1002/jmv.28702. PMID: 36964933.
  210. Liu Q, Ma F, Zhong Y, Wang G, Hu L, Zhang Y, Xie J. Efficacy and safety of human umbilical cord-derived mesenchymal stem cells for COVID-19 pneumonia: a meta-analysis of randomized controlled trials. Stem Cell Res Ther. 2023 May 4;14(1):118. doi: 10.1186/s13287-023-03286-8. PMID: 37143167; PMCID: PMC10159228.
  211. Taufiq H, Shaik Fakiruddin K, Muzaffar U, Lim MN, Rusli S, Kamaluddin NR, Esa E, Abdullah S. Systematic review and meta-analysis of mesenchymal stromal/stem cells as strategical means for the treatment of COVID-19. Ther Adv Respir Dis. 2023 Jan-Dec; 17:17534666231158276. doi: 10.1177/17534666231158276. PMID: 37128999; PMCID: PMC10140776.
  212. Chen L, Xu Q, Sheng F, Wang B. Efficacy and Safety of Mesenchymal Stem Cells for COVID-19 Infection: A Meta-Analysis and Systematic Review. Discov Med. 2023 Apr 1;35(175):201-207. doi: 10.24976/Discov.Med.202335175.21. PMID: 37105930.
  213. Khandpur S, Gupta S, Gunaabalaji DR. Stem cell therapy in dermatology. Indian J Dermatol Venereol Leprol. 2021 Nov-Dec;87(6):753-767. doi: 10.25259/IJDVL_19_20. PMID: 34245532.
  214. Diotallevi F, Di Vincenzo M, Martina E, Radi G, Lariccia V, Offidani A, Orciani M, Campanati A. Mesenchymal Stem Cells and Psoriasis: Systematic Review. Int J Mol Sci. 2022 Dec 1;23(23):15080. doi: 10.3390/ijms232315080. PMID: 36499401; PMCID: PMC9740222.
  215. Haseqawa T, Ikeda S. Mesenchymal stem cells for the treatment of skin diseases. AIMS Cell Tiss Eng. 2017; 1(2): 104-117. doi: 10.3934/celltissue. 2017.2.104
  216. Damayanti RH, Rusdiana T, Wathoni N. Mesenchymal Stem Cell Secretome for Dermatology Application: A Review. Clin Cosmet Investig Dermatol. 2021 Oct 5;14:1401-1412. doi: 10.2147/CCID.S331044. PMID: 34675575; PMCID: PMC8502696.
  217. Bellei B, Papaccio F, Filoni A, Caputo S, Lopez G, Migliano E, Picardo M. Extracellular fraction of adipose tissue as an innovative regenerative approach for vitiligo treatment. Exp Dermatol. 2019 Jun;28(6):695-703. doi: 10.1111/exd.13954. PMID: 31066942.
  218. Bellei B, Migliano E, Picardo M. Research update of adipose tissue-based therapies in regenerative dermatology. Stem Cell Rev Rep. 2022 Aug;18(6):1956-1973. doi: 10.1007/s12015-022-10328-w. Epub 2022 Mar 1. PMID: 35230644.
  219. Merimi M, Fahmi H, De Kock J, Beguin C, Burny A, Moll G, Poggi A, Najar M. Mesenchymal Stem/Stromal Cells as a Therapeutic Tool in Cell-Based Therapy and Regenerative Medicine: An Introduction Expertise to the Topical Collection. Cells. 2022 Oct 8;11(19):3158. doi: 10.3390/cells11193158. PMID: 36231120; PMCID: PMC9562654.
  220. Han Y, Li X, Zhang Y, Han Y, Chang F, Ding J. Mesenchymal Stem Cells for Regenerative Medicine. Cells. 2019 Aug 13;8(8):886. doi: 10.3390/cells8080886. PMID: 31412678; PMCID: PMC6721852.
  221. Fitzsimmons REB, Mazurek MS, Soos A, Simmons CA. Mesenchymal Stromal/Stem Cells in Regenerative Medicine and Tissue Engineering. Stem Cells Int. 2018 Aug 19;2018:8031718. doi: 10.1155/2018/8031718. PMID: 30210552; PMCID: PMC6120267.
  222. Wei CC, Lin AB, Hung SC. Mesenchymal stem cells in regenerative medicine for musculoskeletal diseases: bench, bedside, and industry. Cell Transplant. 2014;23(4-5):505-12. doi: 10.3727/096368914X678328. PMID: 24816447.
  223. Portron S, Soueidan A, Marsden AC, Rakic M, Verner C, Weiss P, Badran Z, Struillou X. Periodontal regenerative medicine using mesenchymal stem cells and biomaterials: A systematic review of pre-clinical studies. Dent Mater J. 2019 Dec 1;38(6):867-883. doi: 10.4012/dmj.2018-315. Epub 2019 Sep 11. PMID: 31511473.
  224. Hwang JJ, Rim YA, Nam Y, Ju JH. Recent Developments in Clinical Applications of Mesenchymal Stem Cells in the Treatment of Rheumatoid Arthritis and Osteoarthritis. Front Immunol. 2021 Mar 8;12:631291. doi: 10.3389/fimmu.2021.631291. PMID: 33763076; PMCID: PMC7982594.
  225. Lv Z, Cai X, Bian Y, Wei Z, Zhu W, Zhao X, Weng X. Advances in Mesenchymal Stem Cell Therapy for Osteoarthritis: From Preclinical and Clinical Perspectives. Bioengineering (Basel). 2023 Feb 2;10(2):195. doi: 10.3390/bioengineering10020195. PMID: 36829689; PMCID: PMC9952673.
  226. Wang Q, Wang Y, Chang C, Ma F, Peng D, Yang S, An Y, Deng Q, Wang Q, Gao F, Wang F, Tang H, Qi X, Jiang X, Cai D, Zhou G. Comparative analysis of mesenchymal stem/stromal cells derived from human induced pluripotent stem cells and the cognate umbilical cord mesenchymal stem/stromal cells. Heliyon. 2023 Jan 4;9(1):e12683. doi: 10.1016/j.heliyon.2022.e12683. PMID: 36647346; PMCID: PMC9840238.
  227. Prakash N, Kim J, Jeon J, Kim S, Arai Y, Bello AB, Park H, Lee SH. Progress and emerging techniques for biomaterial-based derivation of mesenchymal stem cells (MSCs) from pluripotent stem cells (PSCs). Biomater Res. 2023 Apr 18;27(1):31. doi: 10.1186/s40824-023-00371-0. PMID: 37072836; PMCID: PMC10114339.
  228. Aldoghachi AF, Loh JK, Wang ML, Yang YP, Chien CS, Teh HX, Omar AH, Cheong SK, Yeap SK, Ho WY, Ong AH. Current developments and therapeutic potentials of exosomes from induced pluripotent stem cells-derived mesenchymal stem cells. J Chin Med Assoc. 2023 Apr 1;86(4):356-365. doi: 10.1097/JCMA.0000000000000899. Epub 2023 Feb 10. PMID: 36762931.
  229. Dupuis V, Oltra E. Methods to produce induced pluripotent stem cell-derived mesenchymal stem cells: Mesenchymal stem cells from induced pluripotent stem cells. World J Stem Cells. 2021 Aug 26;13(8):1094-1111. doi: 10.4252/wjsc.v13.i8.1094. PMID: 34567428; PMCID: PMC8422924.
  230. Xu M, Shaw G, Murphy M, Barry F. Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells Are Functionally and Genetically Different From Bone Marrow-Derived Mesenchymal Stromal Cells. Stem Cells. 2019 Jun;37(6):754-765. doi: 10.1002/stem.2993. Epub 2019 Mar 6. PMID: 30779868; PMCID: PMC6591688.
  231. Spitzhorn LS, Megges M, Wruck W, Rahman MS, Otte J, Degistirici Ö, Meisel R, Sorg RV, Oreffo ROC, Adjaye J. Human iPSC-derived MSCs (iMSCs) from aged individuals acquire a rejuvenation signature. Stem Cell Res Ther. 2019 Mar 18;10(1):100. doi: 10.1186/s13287-019-1209-x. PMID: 30885246; PMCID: PMC6423778.
  232. Wruck W, Graffmann N, Spitzhorn LS, Adjaye J. Human Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Acquire Rejuvenation and Reduced Heterogeneity. Front Cell Dev Biol. 2021 Sep 16;9:717772. doi: 10.3389/fcell.2021.717772. PMID: 34604216; PMCID: PMC8481886.
  233. Zhang J, Chen M, Liao J, Chang C, Liu Y, Padhiar AA, Zhou Y, Zhou G. Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Hold Lower Heterogeneity and Great Promise in Biological Research and Clinical Applications. Front Cell Dev Biol. 2021 Sep 30;9:716907. doi: 10.3389/fcell.2021.716907. PMID: 34660579; PMCID: PMC8514743.
  234. Sabapathy V, Kumar S. hiPSC-derived iMSCs: NextGen MSCs as an advanced therapeutically active cell resource for regenerative medicine. J Cell Mol Med. 2016 Aug;20(8):1571-88. doi: 10.1111/jcmm.12839. Epub 2016 Apr 21. PMID: 27097531; PMCID: PMC4956943.
  235. Rajasingh S, Sigamani V, Selvam V, Gurusamy N, Kirankumar S, Vasanthan J, Rajasingh J. Comparative analysis of human induced pluripotent stem cell-derived mesenchymal stem cells and umbilical cord mesenchymal stem cells. J Cell Mol Med. 2021 Sep;25(18):8904-8919. doi: 10.1111/jcmm.16851. Epub 2021 Aug 13. PMID: 34390186; PMCID: PMC8435459.
  236. Kim S, Lee SK, Kim H, Kim TM. Exosomes Secreted from Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Accelerate Skin Cell Proliferation. Int J Mol Sci. 2018 Oct 11;19(10):3119. doi: 10.3390/ijms19103119. PMID: 30314356; PMCID: PMC6213597.
  237. Lee HR, Kim S, Shin S, Jeong SY, Lee DW, Lim SU, Kang JY, Son MY, Lee C, Yu KR, Kim M, Oh IH. iPSC-Derived MSCs Are a Distinct Entity of MSCs with Higher Therapeutic Potential than Their Donor-Matched Parental MSCs. Int J Mol Sci. 2023 Jan 3;24(1):881. doi: 10.3390/ijms24010881. PMID: 36614321; PMCID: PMC9821152.
  238. Muthu S, Jeyaraman M, Kotner MB, Jeyaraman N, Rajendran RL, Sharma S, Khanna M, Rajendran SNS, Oh JM, Gangadaran P, Ahn BC. Evolution of Mesenchymal Stem Cell Therapy as an Advanced Therapeutic Medicinal Product (ATMP)-An Indian Perspective. Bioengineering (Basel). 2022 Mar 7;9(3):111. doi: 10.3390/bioengineering9030111. PMID: 35324800; PMCID: PMC8945480.
  239. Bellino S, La Salvia A, Cometa MF, Botta R. Cell-based medicinal products approved in the European Union: current evidence and perspectives. Front Pharmacol. 2023 Jul 31;14:1200808. doi: 10.3389/fphar.2023.1200808. PMID: 37583902; PMCID: PMC10424920.
  240. Fürst-Ladani S, Bührer A, Fürst W, Schober-Ladani N. Regulatory Aspects for Approval of Advanced Therapy Medicinal Products in the EU. Handb Exp Pharmacol. 2023 Apr 6. doi: 10.1007/164_2023_648. Epub ahead of print. PMID: 37017789.
  241. Escacena N, Quesada-Hernández E, Capilla-Gonzalez V, Soria B, Hmadcha A. Bottlenecks in the Efficient Use of Advanced Therapy Medicinal Products Based on Mesenchymal Stromal Cells. Stem Cells Int. 2015;2015:895714. doi: 10.1155/2015/895714. Epub 2015 Jul 27. PMID: 26273307; PMCID: PMC4530293.
  242. Jossen V, van den Bos C, Eibl R, Eibl D. Manufacturing human mesenchymal stem cells at clinical scale: process and regulatory challenges. Appl Microbiol Biotechnol. 2018 May;102(9):3981-3994. doi: 10.1007/s00253-018-8912-x. Epub 2018 Mar 22. PMID: 29564526; PMCID: PMC5895685.
  243. Teale MA, Schneider S, Eibl D, van den Bos C, Neubauer P, Eibl R. Mesenchymal and induced pluripotent stem cell-based therapeutics: a comparison. Appl Microbiol Biotechnol. 2023 Jul;107(14):4429-4445. doi: 10.1007/s00253-023-12583-4. Epub 2023 May 29. PMID: 37246986; PMCID: PMC10313571.
  244. Mebarki M, Abadie C, Larghero J, Cras A. Human umbilical cord-derived mesenchymal stem/stromal cells: a promising candidate for the development of advanced therapy medicinal products. Stem Cell Res Ther. 2021 Feb 26;12(1):152. doi: 10.1186/s13287-021-02222-y. PMID: 33637125; PMCID: PMC7907784.
  245. Chinnadurai R, Viswanathan S, Moll G. Editorial: Next generation MSC therapy manufacturing, potency and mechanism of action analysis. Front Immunol. 2023 Apr 21;14:1192636. doi: 10.3389/fimmu.2023.1192636. PMID: 37153609; PMCID: PMC10161792.
  246. Panés J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, Dignass A, Nachury M, Ferrante M, Kazemi-Shirazi L, Grimaud JC, de la Portilla F, Goldin E, Richard MP, Leselbaum A, Danese S; ADMIRE CD Study Group Collaborators. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016 Sep 24;388(10051):1281-90. doi: 10.1016/S0140-6736(16)31203-X. Epub 2016 Jul 29. PMID: 27477896.
  247. Gupta PK, Dutta S, Kala S, Nekkanti M, Desai SC, Mahapatra SS, Dhar A, Raju R, M R, Behera A, P S, Raviraja NS, Viswanathan P, Chandrashekar M, Thej C, K V P, Abraham J, Boggarapu H, Udaykumar K. Phase IV postmarketing surveillance study shows continued efficacy and safety of Stempeucel in patients with critical limb ischemia due to Buerger's disease. Stem Cells Transl Med. 2021 Dec;10(12):1602-1613. doi: 10.1002/sctm.21-0197. Epub 2021 Sep 13. PMID: 34519179; PMCID: PMC8641082.
  248. Hoogduijn MJ, Lombardo E. Mesenchymal Stromal Cells Anno 2019: Dawn of the Therapeutic Era? Concise Review. Stem Cells Transl Med. 2019 Nov;8(11):1126-1134. doi: 10.1002/sctm.19-0073. Epub 2019 Jul 7. PMID: 31282113; PMCID: PMC6811696.
  249. Mizukami A, Swiech K. Mesenchymal Stromal Cells: From Discovery to Manufacturing and Commercialization. Stem Cells Int. 2018 Apr 11;2018:4083921. doi: 10.1155/2018/4083921. PMID: 30057622; PMCID: PMC6051015.
  250. Madrigal M, Fernández PL, Lleonart R, Carreño L, Villalobos Gorday KA, Rodríguez E, de Cupeiro K, Restrepo CM, Rao KSJ, Riordan NH. Comparison of Cost and Potency of Human Mesenchymal Stromal Cell Conditioned Medium Derived from 2- and 3-Dimensional Cultures. Bioengineering (Basel). 2023 Aug 4;10(8):930. doi: 10.3390/bioengineering10080930. PMID: 37627815; PMCID: PMC10451979.
  251. Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ; Canadian Critical Care Trials Group. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One. 2012;7(10):e47559. doi: 10.1371/journal.pone.0047559. Epub 2012 Oct 25. PMID: 23133515; PMCID: PMC3485008.
  252. Wang Y, Yi H, Song Y. The safety of MSC therapy over the past 15 years: a meta-analysis. Stem Cell Res Ther. 2021 Oct 18;12(1):545. doi: 10.1186/s13287-021-02609-x. PMID: 34663461; PMCID: PMC8522073.
  253. Li DY, Li RF, Sun DX, Pu DD, Zhang YH. Mesenchymal stem cell therapy in pulmonary fibrosis: a meta-analysis of preclinical studies. Stem Cell Res Ther. 2021 Aug 18;12(1):461. doi: 10.1186/s13287-021-02496-2. PMID: 34407861; PMCID: PMC8371890.
  254. Xu P, Yang X. The Efficacy and Safety of Mesenchymal Stem Cell Transplantation for Spinal Cord Injury Patients: A Meta-Analysis and Systematic Review. Cell Transplant. 2019 Jan;28(1):36-46. doi: 10.1177/0963689718808471. Epub 2018 Oct 26. PMID: 30362373; PMCID: PMC6322141.
  255. Yao W, Dong H, Qi J, Zhang Y, Shi L. Safety and efficacy of mesenchymal stem cells in severe/critical patients with COVID-19: A systematic review and meta-analysis. EClinicalMedicine. 2022 Jul 9;51:101545. doi: 10.1016/j.eclinm.2022.101545. PMID: 35844767; PMCID: PMC9270852.
  256. Qu W, Wang Z, Engelberg-Cook E, Yan D, Siddik AB, Bu G, Allickson JG, Kubrova E, Caplan AI, Hare JM, Ricordi C, Pepine CJ, Kurtzberg J, Pascual JM, Mallea JM, Rodriguez RL, Nayfeh T, Saadi S, Durvasula RV, Richards EM, March K, Sanfilippo FP. Efficacy and Safety of MSC Cell Therapies for Hospitalized Patients with COVID-19: A Systematic Review and Meta-Analysis. Stem Cells Transl Med. 2022 Jul 20;11(7):688-703. doi: 10.1093/stcltm/szac032. PMID: 35640138; PMCID: PMC9299515.
  257. Yubo M, Yanyan L, Li L, Tao S, Bo L, Lin C. Clinical efficacy and safety of mesenchymal stem cell transplantation for osteoarthritis treatment: A meta-analysis. PLoS One. 2017 Apr 27;12(4):e0175449. doi: 10.1371/journal.pone.0175449. PMID: 28448518; PMCID: PMC5407776.
  258. Xie B, Chen S, Xu Y, Han W, Hu R, Chen M, He R, Ding S. Clinical Efficacy and Safety of Human Mesenchymal Stem Cell Therapy for Degenerative Disc Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Stem Cells Int. 2021 Sep 13;2021:9149315. doi: 10.1155/2021/9149315. PMID: 34557231; PMCID: PMC8455197.
  259. Fan M, Huang Y, Chen Z, Xia Y, Chen A, Lu D, Wu Y, Zhang N, Qian J. Efficacy of mesenchymal stem cell therapy in systolic heart failure: a systematic review and meta-analysis. Stem Cell Res Ther. 2019 May 31;10(1):150. doi: 10.1186/s13287-019-1258-1. Erratum in: Stem Cell Res Ther. 2019 Jul 15;10(1):206. PMID: 31151406; PMCID: PMC6544951.
  260. Chen X, Wang C, Yin J, Xu J, Wei J, Zhang Y. Efficacy of Mesenchymal Stem Cell Therapy for Steroid-Refractory Acute Graft-Versus-Host Disease following Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis. PLoS One. 2015 Aug 31;10(8):e0136991. doi: 10.1371/journal.pone.0136991. PMID: 26323092; PMCID: PMC4554731.
  261. Kim G, Eom YW, Baik SK, Shin Y, Lim YL, Kim MY, Kwon SO, Chang SJ. Therapeutic Effects of Mesenchymal Stem Cells for Patients with Chronic Liver Diseases: Systematic Review and Meta-analysis. J Korean Med Sci. 2015 Oct;30(10):1405-15. doi: 10.3346/jkms.2015.30.10.1405. Epub 2015 Sep 12. PMID: 26425036; PMCID: PMC4575928.
  262. Liu Y, Dong Y, Wu X, Xu X, Niu J. The assessment of mesenchymal stem cells therapy in acute on chronic liver failure and chronic liver disease: a systematic review and meta-analysis of randomized controlled clinical trials. Stem Cell Res Ther. 2022 May 16;13(1):204. doi: 10.1186/s13287-022-02882-4. PMID: 35578365; PMCID: PMC9109309.
  263. Long Z, Zhang M, Zhang T, Zeng L, Yang K, Yang T, Yu G, Li J, Wu Y, Chen H. The Effectiveness and Safety of Mesenchymal Stem Cells in the Treatment of Osteoarthritis: A Systematic Review and Meta-analysis of 28 Randomized Controlled Trials. Stem Cells Int. 2022 Oct 12;2022:6151866. doi: 10.1155/2022/6151866. PMID: 36277037; PMCID: PMC9581629.
  264. Cao JX, You J, Wu LH, Luo K, Wang ZX. Clinical efficacy analysis of mesenchymal stem cell therapy in patients with COVID-19: A systematic review. World J Clin Cases. 2022 Sep 26;10(27):9714-9726. doi: 10.12998/wjcc.v10.i27.9714. PMID: 36186213; PMCID: PMC9516915.
  265. Luk F, de Witte SF, Bramer WM, Baan CC, Hoogduijn MJ. Efficacy of immunotherapy with mesenchymal stem cells in man: a systematic review. Expert Rev Clin Immunol. 2015 May;11(5):617-36. doi: 10.1586/1744666X.2015.1029458. Epub 2015 Mar 27. PMID: 25817052.
  266. Hoque F, Akther S, Islam S. Review on therapeutic efficacy of mesenchymal stem cell (MSC) therapy for treating different disease. Int J Clin Exp Med. 2021, 5(2), 96-100. doi: 10.26855/ijcemr.2021.04.001
  267. Egido-Moreno S, Valls-Roca-Umbert J, Céspedes-Sánchez JM, López-López J, Velasco-Ortega E. Clinical Efficacy of Mesenchymal Stem Cells in Bone Regeneration in Oral Implantology. Systematic Review and Meta-Analysis. Int J Environ Res Public Health. 2021 Jan 21;18(3):894. doi: 10.3390/ijerph18030894. PMID: 33494139; PMCID: PMC7908266.
  268. Kvistad CE, Kråkenes T, Gjerde C, Mustafa K, Rekand T, Bø L. Safety and Clinical Efficacy of Mesenchymal Stem Cell Treatment in Traumatic Spinal Cord Injury, Multiple Sclerosis and Ischemic Stroke - A Systematic Review and Meta-Analysis. Front Neurol. 2022 May 30;13:891514. doi: 10.3389/fneur.2022.891514. PMID: 35711260; PMCID: PMC9196044.
  269. Ranjbaran H, Mohammadi Jobani B, Amirfakhrian E, Alizadeh-Navaei R. Efficacy of mesenchymal stem cell therapy on glucose levels in type 2 diabetes mellitus: A systematic review and meta-analysis. J Diabetes Investig. 2021 May;12(5):803-810. doi: 10.1111/jdi.13404. Epub 2020 Oct 22. PMID: 32926576; PMCID: PMC8089007.
  270. Farini A, Sitzia C, Erratico S, Meregalli M, Torrente Y. Clinical applications of mesenchymal stem cells in chronic diseases. Stem Cells Int. 2014;2014:306573. doi: 10.1155/2014/306573. Epub 2014 Apr 30. PMID: 24876848; PMCID: PMC4021690.
  271. García-Bernal D, García-Arranz M, Yáñez RM, Hervás-Salcedo R, Cortés A, Fernández-García M, Hernando-Rodríguez M, Quintana-Bustamante Ó, Bueren JA, García-Olmo D, Moraleda JM, Segovia JC, Zapata AG. The Current Status of Mesenchymal Stromal Cells: Controversies, Unresolved Issues and Some Promising Solutions to Improve Their Therapeutic Efficacy. Front Cell Dev Biol. 2021 Mar 16;9:650664. doi: 10.3389/fcell.2021.650664. PMID: 33796536; PMCID: PMC8007911.
  272. Eiro N, Fraile M, González-Jubete A, González LO, Vizoso FJ. Mesenchymal (Stem) Stromal Cells Based as New Therapeutic Alternative in Inflammatory Bowel Disease: Basic Mechanisms, Experimental and Clinical Evidence, and Challenges. Int J Mol Sci. 2022 Aug 10;23(16):8905. doi: 10.3390/ijms23168905. PMID: 36012170; PMCID: PMC9408403.
  273. Mastrolia I, Foppiani EM, Murgia A, Candini O, Samarelli AV, Grisendi G, Veronesi E, Horwitz EM, Dominici M. Challenges in Clinical Development of Mesenchymal Stromal/Stem Cells: Concise Review. Stem Cells Transl Med. 2019 Nov;8(11):1135-1148. doi: 10.1002/sctm.19-0044. Epub 2019 Jul 16. PMID: 31313507; PMCID: PMC6811694.
  274. Sensebé L, Krampera M, Schrezenmeier H, Bourin P, Giordano R. Mesenchymal stem cells for clinical application. Vox Sang. 2010 Feb;98(2):93-107. doi: 10.1111/j.1423-0410.2009.01227.x. Epub 2009 Aug 3. PMID: 19663934.
  275. Baldari S, Di Rocco G, Piccoli M, Pozzobon M, Muraca M, Toietta G. Challenges and Strategies for Improving the Regenerative Effects of Mesenchymal Stromal Cell-Based Therapies. Int J Mol Sci. 2017 Oct 2;18(10):2087. doi: 10.3390/ijms18102087. PMID: 28974046; PMCID: PMC5666769.
  276. Rady D, Abbass MMS, El-Rashidy AA, El Moshy S, Radwan IA, Dörfer CE, Fawzy El-Sayed KM. Mesenchymal Stem/Progenitor Cells: The Prospect of Human Clinical Translation. Stem Cells Int. 2020 Aug 11;2020:8837654. doi: 10.1155/2020/8837654. PMID: 33953753; PMCID: PMC8063852.
  277. Gemayel J, Chaker D, El Hachem G, Mhanna M, Salemeh R, Hanna C, Harb F, Ibrahim A, Chebly A, Khalil C. Mesenchymal stem cells-derived secretome and extracellular vesicles: perspective and challenges in cancer therapy and clinical applications. Clin Transl Oncol. 2023 Jul;25(7):2056-2068. doi: 10.1007/s12094-023-03115-7. Epub 2023 Feb 17. PMID: 36808392.
  278. Lukomska B, Stanaszek L, Zuba-Surma E, Legosz P, Sarzynska S, Drela K. Challenges and Controversies in Human Mesenchymal Stem Cell Therapy. Stem Cells Int. 2019 Apr 9;2019:9628536. doi: 10.1155/2019/9628536. PMID: 31093291; PMCID: PMC6481040.