Stem Cells International

Stem Cells International / 2019 / Article
Special Issue

Improving the Therapeutic Ability of Mesenchymal Stem/Stromal Cells for the Treatment of Conditions Influenced by Immune Cells

View this Special Issue

Review Article | Open Access

Volume 2019 |Article ID 7219297 |

Bella S. Guerrouahen, Heba Sidahmed, Asma Al Sulaiti, Moza Al Khulaifi, Chiara Cugno, "Enhancing Mesenchymal Stromal Cell Immunomodulation for Treating Conditions Influenced by the Immune System", Stem Cells International, vol. 2019, Article ID 7219297, 11 pages, 2019.

Enhancing Mesenchymal Stromal Cell Immunomodulation for Treating Conditions Influenced by the Immune System

Guest Editor: Marcela F. Bolontrade
Received31 Jan 2019
Accepted13 May 2019
Published05 Aug 2019


Mesenchymal stromal cells (MSCs), formerly known as mesenchymal stem cells, are nonhematopoietic multipotent cells and are emerging worldwide as the most clinically used and promising source for allogeneic cell therapy. MSCs, initially obtained from bone marrow, can be derived from several other tissues, such as adipose tissue, placenta, and umbilical cord. Diversity in tissue sourcing and manufacturing procedures has significant effects on MSC products. However, in 2006, a minimal set of standard criteria has been issued by the International Society of Cellular Therapy for defining derived MSCs. These include adherence to plastic in conventional culture conditions, particular phenotype, and multilineage differentiation capacity in vitro. Moreover, MSCs have trophic capabilities, a high in vitro self-renewal ability, and immunomodulatory characteristics. Thus, immunosuppressive treatment with MSCs has been proposed as a potential therapeutic alternative for conditions in which the immune system cells influence outcomes, such as inflammatory and autoimmune diseases. The precise mechanism by which MSCs affect functions of most immune effector cells is not completely understood but involves direct contact with immune cells, soluble mediators, and local microenvironmental factors. Recently, it has been shown that their homeostatic resting state requires activation, which can be achieved in vitro with various cytokines, including interferon-γ. In the present review, we focus on the suppressive effect that MSCs exert on the immune system and highlight the significance of in vitro preconditioning and its use in preclinical studies. We discuss the clinical aspects of using MSCs as an immunomodulatory treatment. Finally, we comment on the risk of interfering with the immune system in regard to cancer formation and development.

1. Background

Mesenchymal stromal cells (MSCs) are nonhematopoietic cells which possess self-renewal, proliferative, and clonogenic potential and have the ability to commit to different cell types including adipocytes, chondrocytes, and osteocytes depending on the environmental conditions [13]. They can be easily isolated from human tissues and have exceptional biological properties for advanced therapies [4]. Traditionally derived from bone marrow (BM) [5], MSC populations may also be obtained from other various tissue sources, such as maternal decidua basalis of the placenta, adipose tissue (AT), foreskin, or neonatal birth-associated tissues (fetal part of the placenta and umbilical cord (UC)) [6, 7]. In 2006, the International Society for Cellular Therapy (ISCT) established the minimum criteria for designating MSCs derived from various origins: adherence to plastic in standard culture conditions; expression of different nonspecific surface molecules such as CD105/endoglin, CD90/Thy1, and CD73/5-nucleotidase; lack of expression of CD34, CD45, CD14 or CD11b, CD79a or CD19, and HLA-DR (<2%); and trilineage differentiation potential due to the expression of several pluripotency genes. The weak expression of major histocompatibility complex (MHC) class I protects MSCs from natural killer (NK) cell-mediated killing; additionally, the lack of MHC class II expression confers to these cells the ability to evade immune recognition by CD4+ T cells. MSCs present minimal expression for HLA-DR (<2%) and do not express costimulatory proteins (CD80, CD86, and CD40), endothelial or hematopoietic surface molecule markers, such as CD31, CD45, CD34, CD14 or CD11b, and CD79a or CD19 [8]. New developments in characterization and marker profiling improve the methods of isolation, verification, and quality assessment of MSCs. In addition to hematopoietic support, tissue repair after injury, and use in regenerative medicine, the immunomodulatory properties of MSCs are attributes that represent the rationale for using MSCs as a novel therapy for many diseases, particularly disorders of the immune system [913]. Interestingly, the ISCT issued guidelines pertaining to MSC effector pathways such as immunomodulation, regeneration, and homing properties [14]. In 2002, for the first time, it was demonstrated that MSCs can modulate immunosuppression in vitro and in vivo [15]. For Caplan, the acronym MSC stands for “medicinal signaling cells,” indicating that the main attribute of MSC therapy is the secretion of bioactive molecules (extracellular vesicles (EVs), cytokines, growth factors, and chemokines) [16], and Caplan and Correa later proposed that the trophic and immunomodulatory properties of MSCs may function as site-regulated “drugstores” in vivo [17]. MSCs were also called the “guardians of inflammation” [18]. Those properties confer the clinical value of MSCs through the interaction with immune cells and the secretion of bioactive molecules leading to the suppression of lymphocyte proliferation, maturation of monocytes, and generation of regulatory T cells (Tregs) and M2 macrophages [19, 20]. In this review, we focus on the immunomodulatory effects of MSCs, the value of preconditioning, and its application in preclinical studies. We then comment on some clinical trials using MSCs and encountered hurdles. Finally, we discuss the risk of modulating the action of immune cells, which might theoretically favor the formation and development of cancer.

2. MSC-Mediated Immunomodulation of Immune Cells

MSCs were described as sensors of the inflammatory microenvironment in regard to their impact on the immune system [21]. Through cell-to-cell contact and regulatory molecule secretion which includes growth factors, chemokines, cytokines, and EVs, MSCs regulate both innate and adaptive immunity by affecting the activation, maturation, proliferation, differentiation, and effector functions of T and B lymphocytes (adaptive immune system), NK cells, neutrophils, and macrophages (innate immune system), as well as dendritic cells (DC), which link innate to adaptive immunity [22, 23].

2.1. T Lymphocytes

Activated T cells proliferate and release inflammatory cytokines and chemokines [24]. In the inflammatory environment, MSCs recruit local helper (Th) and effector T cells, via highly expressed chemokine (C-X-C motif) ligands CXCL9 and CXCL10, thus facilitating their immunomodulatory activity [25]. The intracellular enzymes indoleamine-2,3-dioxygenase (IDO) and inducible NO synthase (iNOS) produced by MSCs are some of the major mediators of T cell suppression, prompting their polarity shift from a proinflammatory Th1 state to an anti-inflammatory Th2 condition [2628]. Galectin-1, abundantly expressed in and secreted by MSCs, also acts on T lymphocyte subpopulations and influences their cytokine production and release [29]. Interleukin- (IL-) 10, transforming growth factor- (TGF-) β, and the lipid mediator prostaglandin E2 (PGE2) secretion by MSCs inhibit Th17 cell differentiation and inhibit the production of IL-17, IL-22, interferon- (IFN-) γ, and tumor necrosis factor- (TNF-) α by mature Th17 cells [3033]. In addition, TGF-β enhances T regulatory cell (Treg) function and differentiation, thus collectively modulating the Treg/Th17 balance [32]. Besides, the Notch 1 signaling pathway has been involved in MSC-mediated Treg differentiation [34], and the IL-10-dependent secretion of HLA-G5 further expands the Treg compartment [35].

2.2. B Lymphocytes

B cells are indispensable for humoral immunity and secrete antibodies when stimulated by antigens and inflammatory cytokines such as IL-10. Under quiescent conditions, MSCs trigger the differentiation into regulatory B cells (Bregs) [36]; while during inflammation, MSCs inhibit B cell proliferation, dampen the production of immunoglobulins (IgA, IgG, and IgM), and lose the capacity to induce Bregs [3638]. While the potential of MSCs in B cell immunomodulation is not fully understood, it appears that inflammatory conditions are necessary for MSCs to exert their role through a combination of cell-cell contact (e.g., PD-L1 pathway) and soluble factors [39, 40].

2.3. NK Cells

Considered a subset of lymphocytes, NK cells are an important source of IFN-γ in addition to T cells [41]. MSCs are able to dampen the expansion of NK cells, effector functions, and cytotoxic production through the key mediators PGE2, IDO, and HLA-G5 [35, 42, 43].

2.4. Neutrophils

During inflammatory processes, neutrophils generate large concentrations of reactive oxygen intermediates and decrease the levels of antioxidants, which are regulators of the apoptotic cascade [44]. IL-6 produced by MSCs dampens respiratory bursts from neutrophils but does not affect phagocytic activity, matrix adhesion, and chemotaxis [45]. The suppression of their releasing destructive enzymes, such as peroxidases and proteases, rescues neutrophils from apoptosis [45, 46].

2.5. Macrophages

PGE2 secreted by MSCs influences the macrophage switch from an inflammatory M1 into an anti-inflammatory M2 state [4749]. This M2 macrophage expresses high levels of CD206 and IL-10, reduces levels of TNF-α and IL-12, and shows higher phagocytic activity [50, 51]. In addition, the shift in macrophage polarization was observed in vitro and in vivo using EVs isolated from human AT-MSCs [52]. Morrison’s group demonstrated this in an acute respiratory distress syndrome murine model using human-derived MSCs and postulated an EV-mediated mitochondrial transfer [53].

2.6. Dendritic Cells (DCs)

DCs, the most efficient antigen-presenting cells, prime naïve T cells to activate the adaptive immune cascade and interact with MSCs [54]. MSCs block the differentiation of monocytes towards DCs through a mechanism involving PGE2 [55] and prompt the differentiation of mature DCs into a regulatory subtype through cell-cell contact, involving Jagged-2 [56].

Figure 1 summarizes some of the mechanisms mediating immunomodulation.

3. Value of Preconditioning MSCs

3.1. Preconditioning MSCs to Enhance Immunomodulation

MSCs do not inherently display immunosuppressive properties at baseline. To replicate the inflammatory environment of a patient suffering from immune dysfunction, they require activation to adopt an immunosuppressive phenotype [57, 58]. In addition to the inflammatory status of the recipient, the efficacy of MSC-based therapies is influenced by differences in tissue origin, donor-to-donor heterogeneity, and dearth of standardized manufacturing practices [19, 21]. Ongoing research efforts are focused on “licensing” or “priming” MSCs to display a more homogeneous immunosuppressive phenotype. This concept refers to an in vitro exposure of MSCs to proinflammatory cytokines such as IFN-γ, TNF-α, IL-1α, or IL-1β [14]. Other preconditioning cytokines and stimuli such as hypoxia and pharmacological agents can also be used during in vitro culture to modulate the MSC secretory profile [59] and thus impact their properties [60]. Preconditioning strategies also extend to methods of triggering the expression of cytoprotective genes that aim at prolonging the longevity of MSCs introduced to an adverse inflammatory milieu and therefore extend the duration of the immunomodulatory effect exerted [61]. These stimuli appear to potentially “correct” such variation and therefore allow the use of more uniform therapeutic products with enhanced immunosuppressive potential, which may lead to higher clinical benefits in patients. Although strategies for improving MSC function are advancing at the bench, there are other factors to be considered before their implementation in the clinic. Nowadays, the assessment of functionally relevant markers reflecting the immunoregulatory properties of MSCs should become the basis for their clinical use as therapeutic cell-based products. Scientists at the U.S. Food and Drug Administration (FDA) designed an assay that identifies morphological changes associated with the immunosuppressive capacity after priming. By integrating the analysis of cellular changes with high-dimensional flow cytometry data and quantification of IFN-γ-augmented immunosuppression from multiple experimental conditions into a singular experiment, they were able to obtain a predictive measurement of the immunosuppressive capabilities of the cells [62].

3.2. Preclinical Studies Using Primed MSCs

Recent preclinical reports in the literature have demonstrated the significance of MSC priming with inflammatory cytokines for future clinical use. In addition to the aforementioned agents, others such as hyaluronan, polyinosinic acid, and polycytidylic acid have been used to prime MSCs for several forms of connective tissue repair in mice [63, 64]. These primed MSCs exhibit enhanced therapeutic properties with minimal or no significant adverse effects when compared to unprimed (naïve) counterparts [65, 66]. MSCs from multiple sources such as AT, BM, and Wharton’s Jelly (WJ) primed with IFN-γ displayed gene expression profiles consistent with an immunosuppressive potential [67]. The immunomodulatory properties of MSCs derived from UC, AT, and periodontal ligaments presented comparable immunosuppressive capacities in vitro; however, UC-MSCs had shorter expansion time, predominantly utilized HLA-G as an immunosuppressive mechanism, and upon activation with IFN-γ did not express further HLA-DR, which would lower the risk of triggering an allogeneic immune response [68]. When IFN-γ-primed BM-MSCs isolated and cultured under good manufacturing practice (GMP) conditions were infused into murine models, no adverse effects related to primed BM-MSCs administration were found. Furthermore, the comparison of phenotypic profiles between primed and unprimed MSCs from the same donor demonstrated that the changes were due to IFN-γ priming rather than genetic variability [66]. In the context of graft versus host disease (GvHD), GvHD-mice injected with IFN-γ-primed MSCs had improved survival rates when compared to the group injected with naïve cells, and this was attributed to the activation of the IFN-γ-Janus kinase- (JAK-) signal transducer and activator of transcription 1 (STAT 1) pathway, which suppressed T cell proliferation [65].

4. Clinical Applications of MSCs in Diseases Mediated by Immune Cells

Culture-expanded MSCs are classified by both the FDA and European Medicines Agency (EMA) as more than minimally manipulated cellular and gene therapy (CGT) products [69]. The earliest therapeutic attempts at using autologous MSC infusion after ex vivo culture expansion showed an acceleration of the hematopoietic reconstitution after hematopoietic stem cell transplantation [70] and high-dose chemotherapy in breast cancer [71]. In both studies, no treatment-associated adverse effects were reported, thus these results laid the foundation for ex vivo cell expansion and administration. While the majority of MSC applications so far have relied on BM being the gold standard source, other adult and fetal tissues such as AT, UC, and WJ have gained popularity because of their comparable or even superior immunomodulatory profiles and their accessibility as medical waste products [72, 73]. For early phase human clinical trials, several factors including identity, viability, and sterility are established as release criteria [8]. However, for advanced-phase clinical trials, regulatory authorities additionally required the development of potency assays as part of the release criteria [74]. Additionally, the EMA has provided multiple guidelines to ensure quality, safety, and efficacy, including the “Guideline on Human Cell-Based Medicinal Products,” “Guideline on Strategies to Identify and Mitigate Risk for First-in-Human Clinical Trials with Investigational Medicinal Products,” and “Reflection Paper on Stem Cell-Based Medicinal Products,” among others [75].

4.1. Broad Range of Applications

Most of the clinical trials performed to date have showed the feasibility and safety of the approach with however conflicting results in terms of efficacy, partially explicable with methodological biases (i.e., small cohorts, lack of control groups, variability of source, and preparation and routes of administration). Also, the use of autologous vs. allogeneic MSC is still controversial with no univocal data on the immunological properties of MSCs derived from patients suffering from autoimmune disorders compared to healthy donors [76, 77]. We provide a brief overview of clinical trials performed or ongoing in the setting of immune-related disorders. However, a more comprehensive picture is beyond the scope of the current review.

Results of clinical trials in inflammatory bowel disease have been recently reviewed by Algeri et al. [76]. MSCs have been administered intravenously to control luminal inflammatory disease or locally in perianal fistulizing Crohn’s disease (CD), in cases of refractory disease or acute flares not responsive to conventional methods of treatment such as steroids and immunosuppressive drugs. The two largest studies conducted on systemic administration of allogeneic MSCs have reached conflicting conclusions: Lazebnik et al. showed clinical response in all treated patients (39 Ulcerative Colitis and 11 CD, [78]), while Pfizer did not succeed to demonstrate any clinical benefit in 48 treated Ulcerative Colitis patients compared to 40 placebo [79].

More homogenous positive results have been obtained for the treatment of fistulizing CD where MSCs promote the healing of rectal mucosa, without any observable adverse events [8082]. A phase III randomized, double blind, controlled trial with allogeneic, adipose-derived MSCs (Cx601) demonstrated a higher remission rate in 107 patients treated vs. 105 placebo [81]. Alofisel or Cx601 is going to be the first off-the-shelf MSC therapy to be approved by EMA for complex perianal fistulas in adult CD [83].

Since 2004, allogeneic MSCs have been used in the treatment of GvHD in several patients enrolled in a multitude of trials worldwide [10, 84]. Osiris sponsored a phase III trial of allogeneic BM-MSCs from random donors for the treatment of steroid-refractory GvHD (NCT00366145). Unfortunately, it was considered a failure due to a lack of positive outcomes [85]. This was due to inconsistencies in sourcing, isolation and manufacturing methods, passage numbers used, and fresh vs. thawed cells [86, 87]. Despite this, the Osiris-backed BM-MSC product has been approved in Canada, New Zealand, and Japan (on an insurance-dependent basis) for restricted use in children with GvHD [88]. Alternative sources have also been tested, and placenta-derived decidua stromal cells seem to hold promise of better response rates compared to BM-MSCs for severe acute GvHD [89].

Rheumatic disorders are also considered another potential area for MSC application. Since 2010, more than 300 patients with relapsing systemic lupus erythematosus (SLE) have been reported in the same center in Nanjing, China. However, the presence of multiple biases in the study design (i.e., lack of endpoint definition and of randomization) and in data analyses renders the study inconclusive in proving efficacy. Regardless, the use of pooled allogeneic MSCs derived from healthy donors was also shown to regulate and normalize lymphocyte counts and differentials in SLE patients [90].

Similarly, phase I/II uncontrolled clinical trials have been conducted in other inflammatory rheumatic diseases, such as systemic sclerosis, Sjögren syndrome, dermatomyositis/polymyositis, and rheumatoid arthritis with promising results, although bigger randomized prospective controlled studies are mostly warranted [91, 92]. Several ongoing clinical trials are exploring the efficacy and toxic effects of MSCs in patients with multiple sclerosis [93]; however, phase I/II studies have not brought significant positive results and further investigations are warranted [94, 95]. In a large nonrandomized comparative trial in 173 patients with active rheumatoid arthritis, the intravenous treatment with UC-MSCs succeeded in inducing a substantial remission of the disease as per the American College of Rheumatology improving standards [96]. Based on the fact that several studies in animal models of Type 1 Diabetes (T1D) have shown MSCs to ameliorate or reverse overt diabetes, also demonstrating their successful engraftment in the pancreatic islets [97, 98], Carlsson et al. performed a phase I clinical trial showing for the first time the opportunity to interfere with the progression of T1D by systemic infusion of MSCs. Autologous BM-MSCs were administered to adult patients recently diagnosed with T1D. Strikingly, during the first year postdiagnosis, no adverse events were disclosed and a conserved or improved C-peptide response to a mixed-meal tolerance test in the patient cohort was demonstrated [99].

Table 1 summarizes other clinical trials of MSCs on diseases mediated by the immune system not previously discussed (, [100106]).

Trial no.PhaseCommencement yearTargeted diseaseStatusPatient enrollment ()Country

NCT00447460I/II2007Graft vs. host disease (GvHD)Completed [100]15Spain
NCT01522716I2011Unknown (NRP)11Sweden
NCT01764100I2013Completed [101]40Italy
NCT02032446I/IIRecruiting47 (estimated)
NCT02291770III2014Unknown (NRP)130 (estimated)China
NCT02055625I/IISuspended (NRP)11Sweden
NCT02359929I2015Recruiting24 (estimated)USA
NCT01741857I/IISystemic lupus erythematosus (SLE)Completed [102]40China
NCT03171194IActive, not recruiting6 (estimated)USA
NCT03673748II2019SLE/lupus nephritisNot yet recruiting36 (estimated)Spain
NCT00781872I/II2006Multiple sclerosis (MS)Completed [103]20Israel
NCT00395200I/II2008Completed [104, 105]10UK
NCT01730547I/II2013Unknown15 (estimated)Sweden
NCT02495766I/II2015Unknown8 (estimated)Spain
NCT03799718II2019Not yet recruiting20 (estimated)USA
NCT02893306II2012Type 1 diabetes mellitus (T1DM)Unknown (NRP)10Chile
NCT02940418I2017Recruiting20 (estimated)Jordan
NCT03406585I/IIRecruiting24 (estimated)Sweden
NCT02249676II2013Devic syndrome/neuromyelitis opticaCompleted15China
NCT01659762I2012Crohn’s diseaseCompleted [106]16USA

NRP: no results posted.
4.2. Current Challenges in Clinical Use
4.2.1. Fate of the Infused MSCs

A factor that influences the future of MSC application in the clinic is that the exact fate of the cells postinfusion is yet to be completely elucidated. There are multiple reports in both human and animal models that point to sequestration of the cells in the lungs following systemic administration and their complete disappearance within 7 days of treatment [9, 107, 108]. Another study showed that allogeneic donor MSC DNA was found engrafted into the recipient’s digestive tract via chromosomal fluorescence studies [10]. This is in support of the theory that MSCs are capable of escaping sequestration and migrating to sites of inflammation, homing to released cytokines and other inflammatory molecules. If this is the case, this will facilitate the administration of MSCs to patients with multisystemic or disseminated involvement, e.g., SLE and rheumatoid arthritis, with gross effects including treating inflammation, regulating lymphocyte function, and stimulating tissue repair, including regeneration of cartilage [109]. Other theories suggest that MSCs prior to apoptosis release EVs that are capable of migrating to inflamed tissues and exerting the same anti-inflammatory effects of viable MSCs. This alternative approach highlights the potential of cell-free MSC-based therapy [52, 107].

4.2.2. Practical Decisions Impacting MSC-Based Therapy Outcome

Other dilemmas impacting the widespread clinical use of MSCs that researchers have yet to reach a consensus for are which tissue source yields the most effective product, combined with the significant impact of donor variability and continued passaging on cell growth, protein production, and EV release [85, 110]. Furthermore, there is a lack of standardized disease-specific procedures and clinical trial regulations regarding the magnitude (average of 1-2 million cells/kg body weight) and frequency of dose administration, the use of allogeneic vs. autologous MSCs, systemic vs. local administration, and primed vs. naïve cells, and the use of freshly cultured vs. frozen and thawed cells [76]. Functional differences were observed between in vivo and in vitro contexts and between species (murine vs. human) in terms of susceptibility to undergoing oncogenic transformation during expansion, and effector molecules used in T cell suppression mechanisms have to be taken into account [21]. This is highlighted by the reported discrepancies between what is described in in vitro and animal models vs. what is reported in the literature of later-phase clinical trials and by the publishing bias (few or no reports on negative outcomes and/or failed trials) [92]. Interestingly, the lack of consistent benefit seen in late phase human clinical trials may also be explained by the fact that the injected cell products were “naïve or resting” MSCs; therefore, the immunosuppressive potential of the cells is entirely depending on an individual patient’s microenvironment and immune status [19, 21, 111]. These variables collectively hinder the production of reliable “off-the-shelf” cell therapy products that produce sustainable and consistent results among patients.

5. Risk of Modulating the Action of Immune Cells and the Dilemma of Cancer Formation and Development

One of the main concerns in MSC-based therapy is that tumorigenicity could result from MSC malignant transformation during in vitro culture expansion or following infusion, or the immunosuppressive effects exerted by MSCs could allow tumor formation and development of already existing malignant cells in the host/recipient [112]. Similarly to murine MSCs readily undergoing spontaneous transformation in vitro [113], Rosland et al. demonstrated spontaneous malignant transformation of BM-derived human MSCs after in vitro cultures leading to an aggressively metastatic disease in immunodeficient mice [114]. However, the impaired immunological status of the recipient was likely more prone to initiate or develop cancer [115]. In humans, MSCs are minimally susceptible to oncogenic transformation in vivo, and long-term culture either does not affect MSC morphology or cause chromosomal alterations [116]. Furthermore, continued passaging leads to loss of already existing aneuploidy, or any resulting aneuploidy leads to senescence, negating the risk of cancer formation [117]. The Committee for Advanced Therapies and the Cell Product Working Party organized a meeting to discuss the risk of tumor formation following MSC-based therapies, with a focus on regulatory and scientific aspects. When discussing the influence of the manufacturing process on inducing cytogenetic abnormalities, it was highlighted that culture duration and conditions present critical risk factors for producing chromosomal aberrations. The committee also suggested that long-term expansion could mostly cause chromosomal aberrations rather than donor-derived factors [112]. However, in a study by Tarte et al., aneuploidy without risk of transformation occurring in a long-term culture of clinical grade MSCs was most likely donor dependent (3 out of 5 aberrations were derived from the same donor) [118]. Thus, donor screening and monitoring of the long-term expansion and integrity of the cells are a requirement [119].

MSCs exhibit a tropism for the tumor microenvironment niche [120], and selective homing into inflammatory tumor sites has been established in various types of cancer [121]. Even if MSCs have intrinsic antitumor properties, they can potentially alter their phenotype towards a protumorigenic role including proangiogenic and immunosuppressive capabilities. Thus, the presence of MSCs within the cancerous stroma has been a matter of contradictory reports [122]. There is no official statement on the potential of tumorigenicity in MSC-based therapies, and no observation of tumor formation of MSC origin in patients given cellular therapy. Despite these facts, one cannot rule out the possibility of MSC-derived tumors developing in vivo. Interestingly, there are reports of spontaneous MSC transformation resulting from MSC culture cross-contamination with malignant cells emphasizing the importance of maintaining good manufactory practice conditions in the production of cell therapy products [123, 124]. While MSC therapy has been qualified as safe by both FDA and EMA, the potential long-term risks still have to be considered.

6. Conclusion

In the last 10 years, MSCs have been a promising treatment for a plethora of immune-related conditions, through the regulation of inflammation and the support of tissue homeostasis. Despite having been unanimously deemed safe, clinical trials report conflicting data in terms of efficacy in several clinical settings. Inconsistencies can be ascribed to limitations in the design of clinical trials and translation of successful preclinical models, discrepancies in the source, preparation and handling of the MSC product, route of administration, and type of donor (autologous vs. allogeneic).

Moreover, the lack of in vitro biomarkers correlating with the in vivo activity of MSCs has so far hindered the progress towards uniformly potent cell products. MSC priming or licensing, before administration, might offer the possibility to enhance their effectiveness in vivo, limiting the variability inherent to the inflammatory status of the patients.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.


The authors wish to thank the Qatar National Library for funding the publication of this article.


  1. X. Wei, X. Yang, Z. P. Han, F. F. Qu, L. Shao, and Y. F. Shi, “Mesenchymal stem cells: a new trend for cell therapy,” Acta Pharmacologica Sinica, vol. 34, no. 6, pp. 747–754, 2013. View at: Publisher Site | Google Scholar
  2. M. C. Ciuffreda, G. Malpasso, P. Musarò, V. Turco, and M. Gnecchi, “Protocols for in vitro differentiation of human mesenchymal stem cells into osteogenic, chondrogenic and adipogenic lineages,” in Mesenchymal Stem Cells, M. Gnecchi, Ed., vol. 1416 of Methods in Molecular Biology, pp. 149–158, Humana Press, New York, NY, USA, 2016. View at: Publisher Site | Google Scholar
  3. E. M. Horwitz, K. le Blanc, M. Dominici et al., “Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement,” Cytotherapy, vol. 7, no. 5, pp. 393–395, 2005. View at: Publisher Site | Google Scholar
  4. S. Deola, B. S. Guerrouahen, H. Sidahmed et al., “Tailoring cells for clinical needs: meeting report from the advanced therapy in healthcare symposium (October 28–29 2017, Doha, Qatar),” Journal of Translational Medicine, vol. 16, no. 1, article 276, 2018. View at: Publisher Site | Google Scholar
  5. M. F. Pittenger, A. M. Mackay, S. C. Beck et al., “Multilineage potential of adult human mesenchymal stem cells,” Science, vol. 284, no. 5411, pp. 143–147, 1999. View at: Publisher Site | Google Scholar
  6. L. A. Marquez-Curtis, A. Janowska-Wieczorek, L. E. McGann, and J. A. W. Elliott, “Mesenchymal stromal cells derived from various tissues: biological, clinical and cryopreservation aspects,” Cryobiology, vol. 71, no. 2, pp. 181–197, 2015. View at: Publisher Site | Google Scholar
  7. R. Hass, C. Kasper, S. Böhm, and R. Jacobs, “Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC,” Cell Communication and Signaling, vol. 9, no. 1, article 12, 2011. View at: Publisher Site | Google Scholar
  8. M. Dominici, K. le Blanc, I. Mueller et al., “Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement,” Cytotherapy, vol. 8, no. 4, pp. 315–317, 2006. View at: Publisher Site | Google Scholar
  9. J. A. Ankrum, J. F. Ong, and J. M. Karp, “Mesenchymal stem cells: immune evasive, not immune privileged,” Nature Biotechnology, vol. 32, no. 3, pp. 252–260, 2014. View at: Publisher Site | Google Scholar
  10. K. Le Blanc, I. Rasmusson, B. Sundberg et al., “Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells,” The Lancet, vol. 363, no. 9419, pp. 1439–1441, 2004. View at: Publisher Site | Google Scholar
  11. K. Le Blanc, F. Frassoni, L. Ball et al., “Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study,” The Lancet, vol. 371, no. 9624, pp. 1579–1586, 2008. View at: Publisher Site | Google Scholar
  12. R. Jitschin, D. Mougiakakos, L. Von Bahr et al., “Alterations in the cellular immune compartment of patients treated with third-party mesenchymal stromal cells following allogeneic hematopoietic stem cell transplantation,” Stem Cells, vol. 31, no. 8, pp. 1715–1725, 2013. View at: Publisher Site | Google Scholar
  13. X. Chen, Y. Gan, W. Li et al., “The interaction between mesenchymal stem cells and steroids during inflammation,” Cell Death & Disease, vol. 5, no. 1, article e1009, 2014. View at: Publisher Site | Google Scholar
  14. J. Galipeau, M. Krampera, J. Barrett et al., “International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials,” Cytotherapy, vol. 18, no. 2, pp. 151–159, 2016. View at: Publisher Site | Google Scholar
  15. A. Bartholomew, C. Sturgeon, M. Siatskas et al., “Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo,” Experimental Hematology, vol. 30, no. 1, pp. 42–48, 2002. View at: Publisher Site | Google Scholar
  16. A. I. Caplan, “What's in a name?” Tissue Engineering. Part A, vol. 16, no. 8, pp. 2415–2417, 2010. View at: Publisher Site | Google Scholar
  17. A. I. Caplan and D. Correa, “The MSC: an injury drugstore,” Cell Stem Cell, vol. 9, no. 1, pp. 11–15, 2011. View at: Publisher Site | Google Scholar
  18. D. J. Prockop and J. Youn Oh, “Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation,” Molecular Therapy, vol. 20, no. 1, pp. 14–20, 2012. View at: Publisher Site | Google Scholar
  19. A. Keating, “Mesenchymal stromal cells: new directions,” Cell Stem Cell, vol. 10, no. 6, pp. 709–716, 2012. View at: Publisher Site | Google Scholar
  20. M. Wang, Q. Yuan, and L. Xie, “Mesenchymal stem cell-based immunomodulation: properties and clinical application,” Stem Cells International, vol. 2018, Article ID 3057624, 12 pages, 2018. View at: Publisher Site | Google Scholar
  21. M. E. Bernardo and W. E. Fibbe, “Mesenchymal stromal cells: sensors and switchers of inflammation,” Cell Stem Cell, vol. 13, no. 4, pp. 392–402, 2013. View at: Publisher Site | Google Scholar
  22. Y. Wang, X. Chen, W. Cao, and Y. Shi, “Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications,” Nature Immunology, vol. 15, no. 11, pp. 1009–1016, 2014. View at: Publisher Site | Google Scholar
  23. L. Lin and L. Du, “The role of secreted factors in stem cells-mediated immune regulation,” Cellular Immunology, vol. 326, pp. 24–32, 2018. View at: Publisher Site | Google Scholar
  24. S. Dimeloe, A. V. Burgener, J. Grählert, and C. Hess, “T-cell metabolism governing activation, proliferation and differentiation; a modular view,” Immunology, vol. 150, no. 1, pp. 35–44, 2017. View at: Publisher Site | Google Scholar
  25. J. Zhuang, Z. Shan, T. Ma et al., “CXCL9 and CXCL10 accelerate acute transplant rejection mediated by alloreactive memory T cells in a mouse retransplantation model,” Experimental and Therapeutic Medicine, vol. 8, no. 1, pp. 237–242, 2014. View at: Publisher Site | Google Scholar
  26. A. Keating, “How do mesenchymal stromal cells suppress T cells?” Cell Stem Cell, vol. 2, no. 2, pp. 106–108, 2008. View at: Publisher Site | Google Scholar
  27. J. Su, X. Chen, Y. Huang et al., “Phylogenetic distinction of iNOS and IDO function in mesenchymal stem cell-mediated immunosuppression in mammalian species,” Cell Death and Differentiation, vol. 21, no. 3, pp. 388–396, 2014. View at: Publisher Site | Google Scholar
  28. K. Sato, K. Ozaki, I. Oh et al., “Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells,” Blood, vol. 109, no. 1, pp. 228–234, 2007. View at: Publisher Site | Google Scholar
  29. F. Gieseke, J. Bohringer, R. Bussolari, M. Dominici, R. Handgretinger, and I. Muller, “Human multipotent mesenchymal stromal cells use galectin-1 to inhibit immune effector cells,” Blood, vol. 116, no. 19, pp. 3770–3779, 2010. View at: Publisher Site | Google Scholar
  30. X. Qu, X. Liu, K. Cheng, R. Yang, and R. C. H. Zhao, “Mesenchymal stem cells inhibit Th17 cell differentiation by IL-10 secretion,” Experimental Hematology, vol. 40, no. 9, pp. 761–770, 2012. View at: Publisher Site | Google Scholar
  31. S. Ghannam, J. Pène, G. Torcy-Moquet, C. Jorgensen, and H. Yssel, “Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype,” Journal of Immunology, vol. 185, no. 1, pp. 302–312, 2010. View at: Publisher Site | Google Scholar
  32. D. Wang, S. Huang, X. Yuan et al., “The regulation of the Treg/Th17 balance by mesenchymal stem cells in human systemic lupus erythematosus,” Cellular & Molecular Immunology, vol. 14, no. 5, pp. 423–431, 2017. View at: Publisher Site | Google Scholar
  33. F. Baratelli, Y. Lin, L. Zhu et al., “Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells,” The Journal of Immunology, vol. 175, no. 3, pp. 1483–1490, 2005. View at: Publisher Site | Google Scholar
  34. B. Del Papa, P. Sportoletti, D. Cecchini et al., “Notch1 modulates mesenchymal stem cells mediated regulatory T‐cell induction,” European Journal of Immunology, vol. 43, no. 1, pp. 182–187, 2013. View at: Publisher Site | Google Scholar
  35. Z. Selmani, A. Naji, I. Zidi et al., “Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells,” Stem Cells, vol. 26, no. 1, pp. 212–222, 2008. View at: Publisher Site | Google Scholar
  36. F. Luk, L. Carreras-Planella, S. S. Korevaar et al., “Inflammatory conditions dictate the effect of mesenchymal stem or stromal cells on B cell function,” Frontiers in Immunology, vol. 8, p. 1042, 2017. View at: Publisher Site | Google Scholar
  37. A. Corcione, F. Benvenuto, E. Ferretti et al., “Human mesenchymal stem cells modulate B-cell functions,” Blood, vol. 107, no. 1, pp. 367–372, 2006. View at: Publisher Site | Google Scholar
  38. M. Franquesa, F. K. Mensah, R. Huizinga et al., “Human adipose tissue-derived mesenchymal stem cells abrogate plasmablast formation and induce regulatory B cells independently of T helper cells,” Stem Cells, vol. 33, no. 3, pp. 880–891, 2015. View at: Publisher Site | Google Scholar
  39. H. Wang, F. Qi, X. Dai et al., “Requirement of B7-H1 in mesenchymal stem cells for immune tolerance to cardiac allografts in combination therapy with rapamycin,” Transplant Immunology, vol. 31, no. 2, pp. 65–74, 2014. View at: Publisher Site | Google Scholar
  40. L. Fan, C. Hu, J. Chen, P. Cen, J. Wang, and L. Li, “Interaction between mesenchymal stem cells and B-cells,” International Journal of Molecular Sciences, vol. 17, no. 5, p. 650, 2016. View at: Publisher Site | Google Scholar
  41. E. Vivier, E. Tomasello, M. Baratin, T. Walzer, and S. Ugolini, “Functions of natural killer cells,” Nature Immunology, vol. 9, no. 5, pp. 503–510, 2008. View at: Publisher Site | Google Scholar
  42. G. M. Spaggiari, A. Capobianco, S. Becchetti, M. C. Mingari, and L. Moretta, “Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation,” Blood, vol. 107, no. 4, pp. 1484–1490, 2006. View at: Publisher Site | Google Scholar
  43. G. M. Spaggiari, A. Capobianco, H. Abdelrazik, F. Becchetti, M. C. Mingari, and L. Moretta, “Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2,” Blood, vol. 111, no. 3, pp. 1327–1333, 2008. View at: Publisher Site | Google Scholar
  44. R. W. G. Watson, “Redox regulation of neutrophil apoptosis,” Antioxidants & Redox Signaling, vol. 4, no. 1, pp. 97–104, 2002. View at: Publisher Site | Google Scholar
  45. L. Raffaghello, G. Bianchi, M. Bertolotto et al., “Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche,” Stem Cells, vol. 26, no. 1, pp. 151–162, 2008. View at: Publisher Site | Google Scholar
  46. D. Jiang, J. Muschhammer, Y. Qi et al., “Suppression of neutrophil-mediated tissue damage—a novel skill of mesenchymal stem cells,” Stem Cells, vol. 34, no. 9, pp. 2393–2406, 2016. View at: Publisher Site | Google Scholar
  47. A. B. Vasandan, S. Jahnavi, C. Shashank, P. Prasad, A. Kumar, and S. J. Prasanna, “Human mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE2-dependent mechanism,” Scientific Reports, vol. 6, no. 1, article 38308, 2016. View at: Publisher Site | Google Scholar
  48. L. Chiossone, R. Conte, G. M. Spaggiari et al., “Mesenchymal stromal cells induce peculiar alternatively activated macrophages capable of dampening both innate and adaptive immune responses,” Stem Cells, vol. 34, no. 7, pp. 1909–1921, 2016. View at: Publisher Site | Google Scholar
  49. C. Manferdini, F. Paolella, E. Gabusi et al., “Adipose stromal cells mediated switching of the pro-inflammatory profile of M1-like macrophages is facilitated by PGE2: in vitro evaluation,” Osteoarthritis and Cartilage, vol. 25, no. 7, pp. 1161–1171, 2017. View at: Publisher Site | Google Scholar
  50. J. Kim and P. Hematti, “Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages,” Experimental Hematology, vol. 37, no. 12, pp. 1445–1453, 2009. View at: Publisher Site | Google Scholar
  51. M. Magatti, E. Vertua, S. De Munari et al., “Human amnion favours tissue repair by inducing the M1-to-M2 switch and enhancing M2 macrophage features,” Journal of Tissue Engineering and Regenerative Medicine, vol. 11, no. 10, pp. 2895–2911, 2017. View at: Publisher Site | Google Scholar
  52. C. Lo Sicco, D. Reverberi, C. Balbi et al., “Mesenchymal stem cell-derived extracellular vesicles as mediators of anti-inflammatory effects: endorsement of macrophage polarization,” Stem Cells Translational Medicine, vol. 6, no. 3, pp. 1018–1028, 2017. View at: Publisher Site | Google Scholar
  53. T. J. Morrison, M. V. Jackson, E. K. Cunningham et al., “Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer,” American Journal of Respiratory and Critical Care Medicine, vol. 196, no. 10, pp. 1275–1286, 2017. View at: Publisher Site | Google Scholar
  54. G. M. Spaggiari and L. Moretta, “Interactions between mesenchymal stem cells and dendritic cells,” in Mesenchymal Stem Cells - Basics and Clinical Application II, B. Weyand, M. Dominici, R. Hass, R. Jacobs, and C. Kasper, Eds., vol. 130 of Advances in Biochemical Engineering/Biotechnology, pp. 199–208, Springer, Berlin, Heidelberg, 2012. View at: Publisher Site | Google Scholar
  55. G. M. Spaggiari, H. Abdelrazik, F. Becchetti, and L. Moretta, “MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2,” Blood, vol. 113, no. 26, pp. 6576–6583, 2009. View at: Publisher Site | Google Scholar
  56. B. Zhang, R. Liu, D. Shi et al., “Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2-dependent regulatory dendritic cell population,” Blood, vol. 113, no. 1, pp. 46–57, 2009. View at: Publisher Site | Google Scholar
  57. M. Krampera, J. Galipeau, Y. Shi, K. Tarte, and L. Sensebe, “Immunological characterization of multipotent mesenchymal stromal cells--the International Society for Cellular Therapy (ISCT) working proposal,” Cytotherapy, vol. 15, no. 9, pp. 1054–1061, 2013. View at: Publisher Site | Google Scholar
  58. M. Krampera, “Mesenchymal stromal cell ‘licensing’: a multistep process,” Leukemia, vol. 25, no. 9, pp. 1408–1414, 2011. View at: Publisher Site | Google Scholar
  59. J. R. Ferreira, G. Q. Teixeira, S. G. Santos, M. A. Barbosa, G. Almeida-Porada, and R. M. Gonçalves, “Mesenchymal stromal cell secretome: influencing therapeutic potential by cellular pre-conditioning,” Frontiers in Immunology, vol. 9, p. 2837, 2018. View at: Publisher Site | Google Scholar
  60. C. Hu and L. Li, “Preconditioning influences mesenchymal stem cell properties in vitro and in vivo,” Journal of Cellular and Molecular Medicine, vol. 22, no. 3, pp. 1428–1442, 2018. View at: Publisher Site | Google Scholar
  61. L. H. A. Silva, M. A. Antunes, C. C. Dos Santos, D. J. Weiss, F. F. Cruz, and P. R. M. Rocco, “Strategies to improve the therapeutic effects of mesenchymal stromal cells in respiratory diseases,” Stem Cell Research & Therapy, vol. 9, no. 1, article 45, 2018. View at: Publisher Site | Google Scholar
  62. M. W. Klinker, R. A. Marklein, J. L. Lo Surdo, C. H. Wei, and S. R. Bauer, “Morphological features of IFN-γ–stimulated mesenchymal stromal cells predict overall immunosuppressive capacity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 13, pp. E2598–E2607, 2017. View at: Publisher Site | Google Scholar
  63. P. Succar, M. Medynskyj, E. J. Breen, T. Batterham, M. P. Molloy, and B. R. Herbert, “Priming adipose-derived mesenchymal stem cells with hyaluronan alters growth kinetics and increases attachment to articular cartilage,” Stem Cells International, vol. 2016, Article ID 9364213, 13 pages, 2016. View at: Publisher Site | Google Scholar
  64. E. E. Saether, C. S. Chamberlain, E. Aktas, E. M. Leiferman, S. L. Brickson, and R. Vanderby, “Primed mesenchymal stem cells alter and improve rat medial collateral ligament healing,” Stem Cell Reviews, vol. 12, no. 1, pp. 42–53, 2016. View at: Publisher Site | Google Scholar
  65. D. S. Kim, I. K. Jang, M. W. Lee et al., “Enhanced immunosuppressive properties of human mesenchymal stem cells primed by interferon-γ,” EBioMedicine, vol. 28, pp. 261–273, 2018. View at: Publisher Site | Google Scholar
  66. A. J. Guess, B. Daneault, R. Wang et al., “Safety profile of good manufacturing practice manufactured interferon γ-primed mesenchymal stem/stromal cells for clinical trials,” Stem Cells Translational Medicine, vol. 6, no. 10, pp. 1868–1879, 2017. View at: Publisher Site | Google Scholar
  67. Q. Wang, Q. Yang, Z. Wang et al., “Comparative analysis of human mesenchymal stem cells from fetal-bone marrow, adipose tissue, and Warton’s jelly as sources of cell immunomodulatory therapy,” Human Vaccines & Immunotherapeutics, vol. 12, no. 1, pp. 85–96, 2016. View at: Publisher Site | Google Scholar
  68. J. H. Kim, C. H. Jo, H. R. Kim, and Y. I. Hwang, “Comparison of immunological characteristics of mesenchymal stem cells from the periodontal ligament, umbilical cord, and adipose tissue,” Stem Cells International, vol. 2018, Article ID 8429042, 12 pages, 2018. View at: Publisher Site | Google Scholar
  69. M. Mendicino, A. M. Bailey, K. Wonnacott, R. K. Puri, and S. R. Bauer, “MSC-based product characterization for clinical trials: an FDA perspective,” Cell Stem Cell, vol. 14, no. 2, pp. 141–145, 2014. View at: Publisher Site | Google Scholar
  70. H. M. Lazarus, S. E. Haynesworth, S. L. Gerson, N. S. Rosenthal, and A. I. Caplan, “Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use,” Bone Marrow Transplantation, vol. 16, no. 4, pp. 557–564, 1995. View at: Google Scholar
  71. O. N. Koç, S. L. Gerson, B. W. Cooper et al., “Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy,” Journal of Clinical Oncology, vol. 18, no. 2, pp. 307–316, 2000. View at: Publisher Site | Google Scholar
  72. K. H. Yoo, I. K. Jang, M. W. Lee et al., “Comparison of immunomodulatory properties of mesenchymal stem cells derived from adult human tissues,” Cellular Immunology, vol. 259, no. 2, pp. 150–156, 2009. View at: Publisher Site | Google Scholar
  73. S. M. Melief, J. J. Zwaginga, W. E. Fibbe, and H. Roelofs, “Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts,” Stem Cells Translational Medicine, vol. 2, no. 6, pp. 455–463, 2013. View at: Publisher Site | Google Scholar
  74. C. de Wolf, M. van de Bovenkamp, and M. Hoefnagel, “Regulatory perspective on in vitro potency assays for human mesenchymal stromal cells used in immunotherapy,” Cytotherapy, vol. 19, no. 7, pp. 784–797, 2017. View at: Publisher Site | Google Scholar
  75. J. Ancans, “Cell therapy medicinal product regulatory framework in Europe and its application for MSC-based therapy development,” Frontiers in Immunology, vol. 3, p. 253, 2012. View at: Publisher Site | Google Scholar
  76. M. Algeri, A. Conforti, A. Pitisci et al., “Mesenchymal stromal cells and chronic inflammatory bowel disease,” Immunology Letters, vol. 168, no. 2, pp. 191–200, 2015. View at: Publisher Site | Google Scholar
  77. C. Serena, N. Keiran, A. Madeira et al., “Crohn’s disease disturbs the immune properties of human adipose-derived stem cells related to inflammasome activation,” Stem Cell Reports, vol. 9, no. 4, pp. 1109–1123, 2017. View at: Publisher Site | Google Scholar
  78. L. B. Lazebnik, A. G. Konopliannikov, O. V. Kniazev et al., “Use of allogeneic mesenchymal stem cells in the treatment of intestinal inflammatory diseases,” Terapevticheskiĭ Arkhiv, vol. 82, no. 2, pp. 38–43, 2010. View at: Google Scholar
  79. A. I. Pfizer, “A study to investigate the safety and possible clinical benefit of Multistem(r) in patients with moderate to severe ulcerative colitis,” 2014, View at: Google Scholar
  80. R. Ciccocioppo, M. E. Bernardo, A. Sgarella et al., “Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease,” Gut, vol. 60, no. 6, pp. 788–798, 2011. View at: Publisher Site | Google Scholar
  81. J. Panés, D. García-Olmo, G. van Assche et al., “Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial,” The Lancet, vol. 388, no. 10051, pp. 1281–1290, 2016. View at: Publisher Site | Google Scholar
  82. F. de la Portilla, F. Alba, D. García-Olmo, J. M. Herrerías, F. X. González, and A. Galindo, “Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn’s disease: results from a multicenter phase I/IIa clinical trial,” International Journal of Colorectal Disease, vol. 28, no. 3, pp. 313–323, 2013. View at: Publisher Site | Google Scholar
  83. C. Sheridan, “First off-the-shelf mesenchymal stem cell therapy nears European approval,” Nature Biotechnology, vol. 36, no. 3, pp. 212–214, 2018. View at: Publisher Site | Google Scholar
  84. N. Dunavin, A. Dias, M. Li, and J. McGuirk, “Mesenchymal stromal cells: what is the mechanism in acute graft-versus-host disease?” Biomedicines, vol. 5, no. 4, p. 39, 2017. View at: Publisher Site | Google Scholar
  85. J. Galipeau, “The mesenchymal stromal cells dilemma--does a negative phase III trial of random donor mesenchymal stromal cells in steroid-resistant graft-versus-host disease represent a death knell or a bump in the road?” Cytotherapy, vol. 15, no. 1, pp. 2–8, 2013. View at: Publisher Site | Google Scholar
  86. J. Galipeau, “Concerns arising from MSC retrieval from cryostorage and effect on immune suppressive function and pharmaceutical usage in clinical trials,” ISBT Science Series, vol. 8, no. 1, pp. 100-101, 2013. View at: Publisher Site | Google Scholar
  87. G. Moll, J. J. Alm, L. C. Davies et al., “Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties?” Stem Cells, vol. 32, no. 9, pp. 2430–2442, 2014. View at: Publisher Site | Google Scholar
  88. J. Galipeau and L. Sensebe, “Mesenchymal stromal cells: clinical challenges and therapeutic opportunities,” Cell Stem Cell, vol. 22, no. 6, pp. 824–833, 2018. View at: Publisher Site | Google Scholar
  89. O. Ringden, A. Baygan, M. Remberger et al., “Placenta-derived decidua stromal cells for treatment of severe acute graft-versus-host disease,” Stem Cells Translational Medicine, vol. 7, no. 4, pp. 325–331, 2018. View at: Publisher Site | Google Scholar
  90. A. Cras, D. Farge, T. Carmoi, J. J. Lataillade, D. D. Wang, and L. Sun, “Update on mesenchymal stem cell-based therapy in lupus and scleroderma,” Arthritis Research & Therapy, vol. 17, no. 1, article 301, 2015. View at: Publisher Site | Google Scholar
  91. A. Tyndall, “Mesenchymal stem cell treatments in rheumatology: a glass half full?” Nature Reviews Rheumatology, vol. 10, no. 2, pp. 117–124, 2014. View at: Publisher Site | Google Scholar
  92. A. Tyndall, “Mesenchymal stromal cells and rheumatic disorders,” Immunology Letters, vol. 168, no. 2, pp. 201–207, 2015. View at: Publisher Site | Google Scholar
  93. N. Joyce, G. Annett, L. Wirthlin, S. Olson, G. Bauer, and J. A. Nolta, “Mesenchymal stem cells for the treatment of neurodegenerative disease,” Regenerative Medicine, vol. 5, no. 6, pp. 933–946, 2010. View at: Publisher Site | Google Scholar
  94. T. K. Ng, V. R. Fortino, D. Pelaez, and H. S. Cheung, “Progress of mesenchymal stem cell therapy for neural and retinal diseases,” World Journal of Stem Cells, vol. 6, no. 2, pp. 111–119, 2014. View at: Publisher Site | Google Scholar
  95. T. Gharibi, M. Ahmadi, N. Seyfizadeh, F. Jadidi-Niaragh, and M. Yousefi, “Immunomodulatory characteristics of mesenchymal stem cells and their role in the treatment of multiple sclerosis,” Cellular Immunology, vol. 293, no. 2, pp. 113–121, 2015. View at: Publisher Site | Google Scholar
  96. L. Wang, L. Wang, X. Cong et al., “Human umbilical cord mesenchymal stem cell therapy for patients with active rheumatoid arthritis: safety and efficacy,” Stem Cells and Development, vol. 22, no. 24, pp. 3192–3202, 2013. View at: Publisher Site | Google Scholar
  97. R. H. Lee, M. J. Seo, R. L. Reger et al., “Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 46, pp. 17438–17443, 2006. View at: Publisher Site | Google Scholar
  98. M. Jurewicz, S. Yang, A. Augello et al., “Congenic mesenchymal stem cell therapy reverses hyperglycemia in experimental type 1 diabetes,” Diabetes, vol. 59, no. 12, pp. 3139–3147, 2010. View at: Publisher Site | Google Scholar
  99. P. O. Carlsson, E. Schwarcz, O. Korsgren, and K. le Blanc, “Preserved β-cell function in type 1 diabetes by mesenchymal stromal cells,” Diabetes, vol. 64, no. 2, pp. 587–592, 2015. View at: Publisher Site | Google Scholar
  100. J. A. Perez-Simon, O. Lopez-Villar, E. J. Andreu et al., “Mesenchymal stem cells expanded in vitro with human serum for the treatment of acute and chronic graft-versus-host disease: results of a phase I/II clinical trial,” Haematologica, vol. 96, no. 7, pp. 1072–1076, 2011. View at: Publisher Site | Google Scholar
  101. M. Introna, G. Lucchini, E. Dander et al., “Treatment of graft versus host disease with mesenchymal stromal cells: a phase I study on 40 adult and pediatric patients,” Biology of Blood and Marrow Transplantation, vol. 20, no. 3, pp. 375–381, 2014. View at: Publisher Site | Google Scholar
  102. D. Wang, J. Li, Y. Zhang et al., “Umbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: a multicenter clinical study,” Arthritis Research & Therapy, vol. 16, no. 2, p. R79, 2014. View at: Publisher Site | Google Scholar
  103. D. Karussis, C. Karageorgiou, A. Vaknin-Dembinsky et al., “Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis,” Archives of Neurology, vol. 67, no. 10, pp. 1187–1194, 2010. View at: Publisher Site | Google Scholar
  104. P. Connick, M. Kolappan, R. Patani et al., “The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments,” Trials, vol. 12, no. 1, article 62, 2011. View at: Publisher Site | Google Scholar
  105. P. Connick, M. Kolappan, C. Crawley et al., “Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study,” The Lancet Neurology, vol. 11, no. 2, pp. 150–156, 2012. View at: Publisher Site | Google Scholar
  106. T. Dhere, I. Copland, M. Garcia et al., “The safety of autologous and metabolically fit bone marrow mesenchymal stromal cells in medically refractory Crohn's disease - a phase 1 trial with three doses,” Alimentary Pharmacology & Therapeutics, vol. 44, no. 5, pp. 471–481, 2016. View at: Publisher Site | Google Scholar
  107. A. Galleu, Y. Riffo-Vasquez, C. Trento et al., “Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation,” Science Translational Medicine, vol. 9, no. 416, article eaam7828, 2017. View at: Publisher Site | Google Scholar
  108. R. H. Lee, A. A. Pulin, M. J. Seo et al., “Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6,” Cell Stem Cell, vol. 5, no. 1, pp. 54–63, 2009. View at: Publisher Site | Google Scholar
  109. A. Kurtz, “Mesenchymal stem cell delivery routes and fate,” International Journal of Stem Cells, vol. 1, no. 1, pp. 1–7, 2008. View at: Publisher Site | Google Scholar
  110. R. T. Maziarz, “Mesenchymal stromal cells: potential roles in graft-versus-host disease prophylaxis and treatment,” Transfusion, vol. 56, no. 4, pp. 9S–14S, 2016. View at: Publisher Site | Google Scholar
  111. Y. Shi, P. Kirwan, and F. J. Livesey, “Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks,” Nature Protocols, vol. 7, no. 10, pp. 1836–1846, 2012. View at: Publisher Site | Google Scholar
  112. L. Barkholt, E. Flory, V. Jekerle et al., “Risk of tumorigenicity in mesenchymal stromal cell–based therapies—bridging scientific observations and regulatory viewpoints,” Cytotherapy, vol. 15, no. 7, pp. 753–759, 2013. View at: Publisher Site | Google Scholar
  113. L. He, F. Zhao, Y. Zheng, Y. Wan, and J. Song, “Loss of interactions between p53 and survivin gene in mesenchymal stem cells after spontaneous transformation in vitro,” The International Journal of Biochemistry & Cell Biology, vol. 75, pp. 74–84, 2016. View at: Publisher Site | Google Scholar
  114. G. V. Røsland, A. Svendsen, A. Torsvik et al., “Long-term cultures of bone marrow–derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation,” Cancer Research, vol. 69, no. 13, pp. 5331–5339, 2009. View at: Publisher Site | Google Scholar
  115. H. Y. Lee and I. S. Hong, “Double-edged sword of mesenchymal stem cells: cancer-promoting versus therapeutic potential,” Cancer Science, vol. 108, no. 10, pp. 1939–1946, 2017. View at: Publisher Site | Google Scholar
  116. K. Mareschi, I. Ferrero, D. Rustichelli et al., “Expansion of mesenchymal stem cells isolated from pediatric and adult donor bone marrow,” Journal of Cellular Biochemistry, vol. 97, no. 4, pp. 744–754, 2006. View at: Publisher Site | Google Scholar
  117. B. G. Stultz, K. McGinnis, E. E. Thompson, J. L. Lo Surdo, S. R. Bauer, and D. A. Hursh, “Chromosomal stability of mesenchymal stromal cells during in vitro culture,” Cytotherapy, vol. 18, no. 3, pp. 336–343, 2016. View at: Publisher Site | Google Scholar
  118. K. Tarte, J. Gaillard, J. J. Lataillade et al., “Clinical-grade production of human mesenchymal stromal cells: occurrence of aneuploidy without transformation,” Blood, vol. 115, no. 8, pp. 1549–1553, 2010. View at: Publisher Site | Google Scholar
  119. D. A. Cornélio and S. R. B. de Medeiros, “Genetic evaluation of mesenchymal stem cells,” Revista Brasileira de Hematologia e Hemoterapia, vol. 36, no. 4, pp. 238–240, 2014. View at: Publisher Site | Google Scholar
  120. S. Kidd, E. Spaeth, J. L. Dembinski et al., “Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging,” Stem Cells, vol. 27, no. 10, pp. 2614–2623, 2009. View at: Publisher Site | Google Scholar
  121. B. M. Beckermann, G. Kallifatidis, A. Groth et al., “VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma,” British Journal of Cancer, vol. 99, no. 4, pp. 622–631, 2008. View at: Publisher Site | Google Scholar
  122. R. S. Waterman, S. L. Henkle, and A. M. Betancourt, “Mesenchymal stem cell 1 (MSC1)-based therapy attenuates tumor growth whereas MSC2-treatment promotes tumor growth and metastasis,” PLoS One, vol. 7, no. 9, article e45590, 2012. View at: Publisher Site | Google Scholar
  123. R. de la Fuente, A. Bernad, J. Garcia-Castro, M. C. Martin, and J. C. Cigudosa, “Retraction: spontaneous human adult stem cell transformation,” Cancer Research, vol. 70, no. 16, article 6682, 2010. View at: Publisher Site | Google Scholar
  124. A. Torsvik, G. V. Rosland, A. Svendsen et al., “Spontaneous malignant transformation of human mesenchymal stem cells reflects cross-contamination: putting the research field on track - letter,” Cancer Research, vol. 70, no. 15, pp. 6393–6396, 2010. View at: Publisher Site | Google Scholar

Copyright © 2019 Bella S. Guerrouahen et al. 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. The publication of this article was funded by Qatar National Library.

More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

Article of the Year Award: Outstanding research contributions of 2020, as selected by our Chief Editors. Read the winning articles.