Abstract
Much of what we know about immunology suggests that little is to be gained from experiments in which human cells are administered to immunocompetent mice. Multiple reports have demonstrated that this common assumption does not hold for experiments with human mesenchymal stem/stromal cells (hMSCs). The data demonstrate that hMSCs can suppress immune responses to a variety of stimuli in immunocompetent mice by a range of different mechanisms that are similar to those employed by mouse MSCs. Therefore, further experiments with hMSCs in mice will make it possible to generate preclinical data that will improve both the efficacy and safety of the clinical trials with the cells that are now in progress.
Keywords: mesenchymal stem cells, mesenchymal stromal cells, immunomodulation, xenogeneic models
Multiple reports have demonstrated the surprising conclusion that human MSCs can suppress both inflammation and immunity in immune-competent mice. A critical question now is how can these xenogeneic models best be used to improve clinical therapies with human MSCs?
Main Text
One of the established tenets of immunity is that cells lacking the “self” markers, such as major histocompatibility complex (MHC) class I molecules, are quickly destroyed by immune responses. Therefore, there seemed to be little to be gained from experiments in which human cells were infused into immunocompetent mice. Surprisingly, an exception to this conclusion has come from experiments with human mesenchymal stem/stromal cells (hMSCs). A large series of reports have demonstrated that hMSCs can effectively suppress immune responses in immunocompetent mice (see Table 1 for examples). The hMSCs can also generate immune responses but less than other cells, and under many conditions, the immunosuppressive effects predominate.1, 2 The consequences of these observations are not trivial. A major consequence is that the xenogeneic mouse models can be used to assay the efficacy of hMSCs and thereby provide some preclinical data that are essential for well-designed trials in patients.3 Another consequence is that the use of hMSCs avoids the unfortunate tendency of mouse MSCs (mMSCs),4 like mouse fibroblasts,5 to transform spontaneously into tumorigenic cells. In addition, the xenogeneic models facilitate defining the mechanism of action of hMSCs in vivo because the hMSCs can be readily distinguished from the mouse cells they target. Furthermore, the xenogeneic models can be used in the development of allogeneic MSC therapies because the risk of host immune responses against non-self cells can be tested in xenogeneic models.
Table 1.
Efficacy of hMSCs in Mouse Models for Innate or Acquired Immunity
Disease Model | Efficacy | Mechanism of MSC Action | Comment | Source of MSCs | Animal Model | Ref. | |
---|---|---|---|---|---|---|---|
Lupus (SLE) nephritis | hMSCs | ↓disease parameters ↑survival |
↑Treg ↓Tfh and plasma cell ↓DC activation |
efficacy hMSCs > mMSCs64 |
BM, AT, ESC-MSCs | NZBxNZW | 64, 65, 66, 67 |
mMSCs | ↓disease parameters ↑survival |
↑TGF-β ↓Th1, DC, plasma cell ↓B cell activation |
BM | MRL/lpr mice | 68 | ||
Type 1 diabetes | hMSCs | ↓insulitis & delayed onset of diabetes ↑body weights, preservation of β-cell function |
hMSCs secrete TSG-6 to suppress APCs and T cells ↓Th1 cytokines and CD8+ T cells ↑IL-4, IL-10, and TGF-β1 |
no effect from hMSCs with knockdown of TSG-616 | BM | NOD/LtJ, C57BL/6 with STZ | 16 |
mMSCs | ↓insulitis & delayed onset of diabetes | mMSCs express PD-L1 to suppress T cells |
BM (Syn and Allo) | NOD/LtJ | 69 | ||
Rheumatoid arthritis | hMSCs | ↓disease severity | ↑Treg ↓ratio of pro-inflammatory to anti-inflammatory factors |
BM, AT, cord blood, ESC-MSCs | DBA/1 | 70, 71, 72, 73 | |
mMSCs | ↓disease severity | ↑Treg ↓pro-inflammatory factors ↓NF-κB pathway ↑TGF-β |
BM (Syn and Allo) | DBA/1 | 74, 75 | ||
Multiple sclerosis | hMSCs | ↓disease severity ↓pathology |
↓Th1 and Th17 ↑Breg ↓ratio of pro-inflammatory to anti-inflammatory factors |
BM, AT | C57BL/6SJL | 76, 77, 78 | |
mMSCs | ↓disease severity ↓pathology |
↓DCs and T cell function (iNOS and COX-1, COX-2) induces a Th2-type cytokine shift in T cells |
AT | C57BI/6 | 79, 80 | ||
Uveitis and retinal disruption (antigen induced) | hMSCs | complete rescue of retina | hMSCs secrete CCL2 or TSG-6 to attract MDSC or to induce Mreg | no effect from hMSCs with knockdown of TSG-6, skin fibros, apoptotic hMSCs13 | BM | C57BL/6J | 13, 17 |
mMSCs | complete rescue of retina | ↑Treg ↑TGF-β ↓Th1 and Th17 ↑IL-10 |
similar efficacy with syn-mMSCs and allo-mMSCs81 | BM (Syn and Allo) | C57BL/6J, Lewis rat |
81, 82 | |
Allergic asthma | hMSCs | ↓inflammation ↓airway hyper-reactivity |
↓serum IgE ↓Th2 cytokines |
similar efficacy with hMSCs and mMSCs; none with fibros15 | BM, AT, umbilical cord | C57/BL6 BALB/c |
15 |
mMSCs | ↓inflammation ↓airway hyper-reactivity |
↑IL-10 and IFN-γ ↑M2 suppressive phenotype ↓maturation and migration of lung DCs to the mediastinal lymph nodes |
BM, AT, umbilical cord | BALB/c | 83, 84, 85 | ||
Allogeneic corneal transplantation | hMSCs | ↓graft rejection | hMSCs express TSG-6 to suppress APC activation |
no effect from hMSCs with knock down of TSG-613, 86 | BM | C57BL/6J to BALB/c | 13, 86 |
mMSCs | ↓graft rejection | ↓APC activation ↓Th1 ↑Treg no identified molecule |
BM (Allo) | C57BL/6J Lewis rat |
87, 88 | ||
Sjögren’s syndrome-related dry eye and mouth | hMSCs | ↓disease severity ↓pathology |
↓Th1 cytokines ↓pro-inflammatory cytokines |
similar efficacy with hMSCs and mMSCs; none with fibros14 | BM | BALB/c | 14 |
mMSCs | ↓disease severity ↓pathology |
↓Th1, Th17, Tfh, B ↑Treg ↑SDF-1/CXCR4 |
BM (Allo) | NOD/Ltj NOD mice |
89, 90 | ||
Acute colitis | hMSCs | ↓disease severity | ↑Treg ↓pro-inflammatory cytokines |
AT, umbilical cord gingiva | C57/BL6 BALB/c |
91, 92, 93 | |
mMSCs | ↓disease severity | ↑Treg ↓pro-inflammatory cytokines MSCs secrete TSG-6 to dampen inflammation MSCs generate Mreg to inhibit inflammation and increase IL-10 MSCs induce T apoptosis through Fas-FasL ↑TGF-β |
BM, AT | C57BL/6, BALB/c | 44, 94, 95 | ||
Influenza virus | hMSCs | ↓pathology ↑survival |
improved protein permeability and fluid clearance | BM | BALB/c | 96 | |
Silicosis | hMSCs | ↓inflammation of lung ↓monocyte infiltration |
hMSCs secrete exosomes with miR-451 | fibros ↑fibrosis97 |
BM | C57BL/6J | 97 |
Myocardial infarction | hMSCs | ↓inflammation ↑cardiac function |
hMSCs secrete TSG-6 to suppress inflammation, ↓inflammation ↓ M1-type macrophages ↑ M2-type macrophages ↑ IL-10 |
no effect from hMSCs with knockdown of TSG-618 | BM | NOD/scid | 18, 98, 99 |
Sterile injury to cornea | hMSCs | ↓inflammation ↓opacity of cornea |
hMSCs secrete TSG-6 to suppress inflammation |
no effect from hMSCs with knockdown of TSG-619 | BM | BALB/c | 19 |
mMSCs | ↓inflammation ↓opacity of cornea |
MSCs secrete HGF to suppress inflammation ↓pro-inflammatory cytokines ↑TGF-β, IL-10 |
BM | C57BL/6, SD rat | 100, 101 | ||
Peritonitis/sepsis | hMSCs | ↓inflammation ↓monocyte and neutrophil infiltration |
hMSCs secrete TSG-6 to suppress NF-κB signaling in resident macrophage ↑phagocytic activity of monocytes ↑M2-type macrophages |
no effect from hMSCs with knockdown of TSG-651 efficacy hMSCs > mMSCs102 |
BM | C57/BL6 | 51, 102 |
mMSCs | ↓sepsis-associated organ injury, mortality rates, body temperature fluctuations | ↓ inflammatory cytokines, ↓ IL-17 and pro-inflammatory cytokines, mMSCs secrete PGE2 to induce IL-10-producing macrophages |
no effect on survival with mouse fibros, bone marrow, or heat-killed mMSCs103 | BM, AT | BALB/c C57BL/6 C57BL/6J |
103, 104, 105, 106 | |
Pancreatitis | hMSCs | ↓disease severity ↓inflammation |
hMSCs secrete TSG-6 to reduce oxidative stress, NLRP3 inflammasome, and NF-κB signaling | no effect from hMSCs with knockdown of TSG-620 | BM | C57/BL6 | 20 |
Rat MSCs | ↑ survival rate ↓disease severity ↓inflammation |
↓TNF-α and IL-1β mRNA in lung and pancreas | BM | Sprague-Dawley rats | 107, 108 |
Syn, syngeneic; Allo, allogeneic; APC, antigen presenting cell; BM, bone marrow; AT, adipose tissue; Breg, regulatory B cell; COX, cyclooxygenase; CXCR4, C-X-C chemokine receptor type 4; DC, dendritic cell; ESC, embryonic stem cell; ESC-MSCs, ESC-derived MSCs; fibros, fibroblasts; HGF, hepatocyte growth factor; Mreg, regulatory macrophage; PD-L1, programmed death-ligand 1; PGE2, prostaglandin E2; SDF-1, stromal-cell-derived factor 1; SLE, systemic lupus erythematosus; Syn, syngeneic; Tfh, follicular helper T cells; Treg, regulatory T cell; TSG-6, TNF-stimulated gene/protein-6.
Limitations of the Obvious Experiment: mMSCs into Isogeneic Mice
Much of what we know about immunity is based on experiments in mice. Therefore, to explore the effects of MSCs6 on immunity, the obvious experiment is to administer mMSCs to isogeneic mice. Unfortunately, such experiments have encountered a series of frustrating limitations. Just as mice are not small human beings, mMSCs are not the same as hMSCs. The differences are readily apparent in attempts to isolate and culture cells from the two species (Figure 1).7, 8, 9 hMSCs are readily obtained by plating mononuclear cells from human bone marrow on standard hydrophilic tissue culture surfaces and recovering the adherent cells. After one or two passages, the cultures are free of hematopoietic cells and the hMSCs can be expanded rapidly. Moreover, the hMSCs cease proliferating after 35–55 population doublings, a clear indication that they do not undergo spontaneous transformation during expansion in culture.10 In contrast, initial cultures of adherent cells from mouse bone marrow contain mMSCs but are heavily contaminated by hematopoietic cells.4 Also, the cultures expand slowly. With time, however, the cultures undergo a “crisis”, in which most of the cells die and the only cells that survive are those that have undergone spontaneous transformation. As a result, they grow rapidly. In effect, the cells undergo the same sequence of events that was observed many decades earlier in the first attempts to culture fibroblasts from mice, a sequence that has been referred to as “multistage carcinogenesis in culture”.5 The transformed mMSCs can be cloned and serve as important tools for experimentation. However, because of their genomic instability, the phenotype may change with expansion, and, as a result, many of the experiments become non-reproducible. The molecular basis of the sequence observed with cultures of mMSCs has been explained by Phinney and associates4: mMSCs cultured under standard conditions of atmospheric air rapidly die because they are unusually sensitive to oxygen and generate reactive oxygen species. A few cells survive this catastrophic event because they acquire spontaneous mutations in p53. Because the ability of p53 to suppress mutations is lost, multiple genomic changes are generated and a few transformed cells emerge that expand rapidly in atmospheric oxygen but are tumorigenic.4, 11
Figure 1.
Summary of Major Differences between Expansion in Culture of mMSCs and hMSCs
aPhinney and associates4 developed an elegant protocol for expanding mMSCs without transformation by first immunodepleting the cultures of hematopoietic cells and then culturing them under an atmosphere of 5% oxygen. bExpansion at low density to enrich early progenitor cells defined as rapidly self-replicating MSCs or RS cells described by Lee et al.63 and in references therein. cVaries with preparations of different bone marrow aspirates taken from the same donor at the same session.
The spontaneous transformation of mMSCs limits one of the attractive features of MSCs: the ease of generating a large number of cells required for experimentation. Two methods have been employed to minimize the problem. One is to minimally expand the cells in culture. The other is to remove macrophages from initial cultures by immune depletion and then to culture the cells under a reduced oxygen atmosphere.4 However, the mMSCs remain sensitive to exposure to atmospheric air. Also, in mMSCs prepared with either method, the presence of a small fraction of tumorigenic cells cannot be ruled out by assays such as karyotyping, chromosomal hybridization, tests of tumorigenicity in immunodeficient mice, or next-generation sequencing.10 Both methods therefore impose constraints on the experiments that can be performed with mMSCs.
Several additional differences were observed between mMSCs and hMSCs, but their relative importance is difficult to sort out. The most striking is that mMSCs can exert immunosuppressive effects through production of inducible nitric oxide synthase (iNOS), whereas human MSCs use indoleamine 2,3-dioxygenase (IDO) under similar conditions.12
Efficacy of hMSCs in Xenogeneic Mouse Models
The efficacy of hMSCs in suppressing both innate and acquired immunity in xenogeneic mouse models has now been demonstrated by extensive publications from multiple laboratories. Table 1 summarizes the results from a limited number of publications selected primarily by their efficacy in a clinically relevant model and the completeness of the data on changes in cytokines and cells involved in immunity. Several features of the data are remarkable. Immune modulation was observed by administration of hMSCs in different strains of mice, in different organs, and in response to different stimuli. In several reports, the major endpoints were obvious functional outcomes, such as the delayed onset or severity of a disease, complete rescue of antigen-induced immunopathology, or decreased rejection of an allogeneic graft.
Control Experiments Demonstrated that the Effects Were hMSC Specific
Control experiments are obviously critical in interpreting data, such as those summarized in Table 1. For example, one possible explanation for the observed effects was that hMSCs produced anergy or non-specific effects on the immune system, in part because of the relatively large number of hMSCs used in most of the experiments (about 4 × 106/kg). However, non-specific effects were ruled out in many of the reports by demonstrating that immunosuppressive effects were not duplicated by infusion of human fibroblasts or non-viable hMSCs.13, 14, 15 Also, in reports in which the effects were linked to expression of a single gene, hMSCs were ineffective after the expression of the gene was knocked down.13, 16, 17, 18, 19, 20
hMSCs and Minimally Expanded mMSCs Have Similar Effects in the Same Models
A few reports have compared the efficacy of hMSCs and mMSCs in the same models. The most informative experiments were those in which the mMSCs were expanded to a limited extent so as to minimize the possibility of transformation. As indicated in Table 1, no significant differences were noted between the efficacy of hMSCs and minimally expanded mMSCs in mouse models for silicosis, acute colitis, sepsis, allergic asthma, and Sjögren’s syndrome-related dry eye syndrome.
Why Do hMSCs and Non-transformed mMSCs Produce Similar Effects?
There are at least two reasons why hMSCs and non-transformed mMSCs produce comparable effects in immunocompetent mice. One is that MSCs are less prone to generate immune responses than other cells.2 Under resting conditions, hMSCs express low levels of HLA and co-stimulatory molecules and only express them in response to inflammatory stimuli.21 The second reason is embedded in the observation that both hMSCs and mMSCs are short-lived after infusion into mice. After intravenous administration, the usual route used, the MSCs are immediately trapped in the lung and most of the cells rapidly disappear from the lung.18, 22 Tracking of the small fraction of MSCs that escape trapping in the lung has been challenging because of the tendency of mMSCs to undergo transformation and the propensity of both mMSCs and hMSCs to undergo phagocytosis, entosis, or cannibalism, whereby they can transfer to other cells labels such as endogenous DNA sequences, GFP, and other marker genes, mitochondria, and surface epitopes.23, 24, 25, 26 One experiment to track viable hMSCs with a tissue-standardized and human-specific qRT-PCR assay indicated that the cells trapped in the lung disappeared with a half-life of about 24 hr (Figures 2A and 2C).18 Very few cells were recovered in other tissues, except for a small transient peak seen in the hearts of mice with induced myocardial infarction (Figure 2B).18 With syngeneic MSCs, quantitative data on the fate of non-transformed cells that escape trapping in the lung are difficult to extract from the literature, but most syngeneic MSCs are trapped in the lungs of an immunocompetent animal after intravenous infusion,22, 27, 28 and that only a small sub-fraction of the cells transiently appear in injured tissues.29, 30, 31, 32 The data suggest, therefore, that one of the reasons why hMSCs and mMSCs have comparable effects on immunity in mice is that both survive for only a limited time and before the species differences manifest.
Figure 2.
Summary of Immune-Suppressive Effects of hMSCs in Mice
(A) Data from experiments, in which 2 × 106 hMSCs were infused intravenously into immune-deficient mice (NOD/scid). The hMSCs were detected in tissues by qPCR assays for human-specific Alu sequences and by qRT-PCR assays specific for human GAPDH mRNA. For the RT-PCR assays, standards curves were prepared for each tissue (with hMSCs added to tissue from control mice) to correct for variability in extraction of mRNA and the efficiency of the polymerase reaction. (B) Data on hearts from experiments, in which 1 × 106 hMSCs were infused intravenously into immune-deficient mice (NOD/scid) right after permanent ligation of the left anterior descending coronary artery. Hearts were assayed as in (A). (A and B) from Lee et al.18 Reprinted with permission from Elsevier: Lee et al., Cell Stem Cell, 2009; 5: 59, Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6 (TNF-stimulated gene/protein-6). (C) Pharmokinetic analysis of the data in (A) by Parekkadan and Milwid.109 Solid blue line, apparent activity; dashed purple line, % of total cells remaining; dashed orange line, unit activity per cell; solid red line, therapeutic activity; dotted black line, minimum effective activity. Reprinted with permission from Annu. Rev. Biomed. Eng.: Parekkadan, B., and Milwid, J.M. Annu. Rev. Biomed. Eng. 2010;12:87, Mesenchymal stem cells as therapeutics. (D) In different immune models, the major immunosuppressive factors secreted by hMSCs were observed to be TSG-6, IL-1RA (IL-1 receptor antagonist), HO-1 (heme oxygenase 1), PGE2 (prostaglandin E2), TGF-β (tumor growth factor β), CCL2, IDO1 (indoleamine-pyrrole 2,3-dioxygenase 1), FasL (Fas ligand), or PD-L1 (programmed death-ligand 1). Most of the factors primarily altered cells of the innate immune system, such as monocytes/macrophages, MDSCs, or antigen presenting dendritic cells. Subsequent waves of cytokines then suppressed inflammation and altered T cells to either increase or decrease the ratio of Th1/Th17:Th2 responses.
How Do hMSCs Alter Immunity?
The data summarized in Figure 2 and Table 1 demonstrate that hMSCs have a short window of therapeutic activity in mice but suppress immune responses, which can take weeks to develop. Therefore, as these data were being developed, they suggested the hypothesis that the MSCs primarily affect the innate immune system that controls development of acquired immunity.33, 34 The hypothesis has now been substantiated for both mMSCs and hMSCs by reports by multiple investigators.35, 36, 37, 38, 39, 40, 41, 42, 43 MSCs express multiple genes that have immunosuppressive effects that can target multiple cells of the innate immune system. The central theme emerging from the data is that the MSCs do not respond in a monolithic manner. Instead, their response varies with the nature of the immune stimulus and with the response of the immune system to the stimulus. In effect, the administered MSCs show plasticity in a response that mimics the multi-tiered plasticity of the immune system itself.
Over 12 factors that have immunosuppressive effects are expressed by hMSCs in culture38, 43, 44, 45, 46, 47, 48, 49, 50 or by hMSCs in mouse models of immune disorders (Figure 2D). In addition to factors secreted as solutes, some of the effects of hMSCs can be transmitted through cell-to-cell contacts or the secretion of extracellular vesicles.35, 36, 37, 38, 39, 40, 41, 42, 43
The cells of the innate immune system that hMSCs can target in mice include resident monocytes/macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSCs) (Figure 2D). Their effects on these cells are then transmitted to suppress inflammation or acquired immune responses through the cascades of T cells. Because a major effect of MSCs is to suppress inflammation, the results raise the possibility that they might be most effective in conditions characterized by high degrees of inflammation, such as acute respiratory distress syndrome or septic shock. As yet, there is no direct evidence to support this possibility.
The variability with which hMSCs respond is illustrated by some of the examples cited in Table 1. For example, hMSCs suppressed Th1/Th17 responses in models in which inflammation is a prominent feature of the innate immune response and autoimmunity, e.g., models for rheumatoid arthritis, multiple sclerosis, Sjögren’s syndrome, and acute colitis. In models for allergic asthma, hMSCs suppressed both Th2 or mixed Th2/Th17 inflammation. In several models e.g., peritonitis,51 hMSCs suppressed inflammation by being activated to secrete the anti-inflammatory protein TSG-6 (tumor necrosis factor-inducible gene 6) that blunted nuclear factor κB (NF-κB) signaling. In other models, MSCs suppressed inflammation by secreting keratinocyte growth factor or lipoxin 4B.52, 53 In a model for antigen-induced uveitis, a small number of intravenously administered hMSCs reached lymph nodes draining the site of antigen injection, where they secreted chemokine (C-C motif) ligand 2 (CCL2).17 The CCL2 then attracted murine MDSCs that aborted development of acquired immunity and completely rescued the retina. In several models, the primary effect of the hMSCs was to increase the number of regulatory macrophages or regulatory T cells through secretion of TSG-6 or some other mechanisms. In still others, the primary effect was to suppress the activity of antigen presenting cells. Some of the differences are probably explained by “donor-to-donor” variability in the bioactivity of preparations of hMSCs that is reflected in different levels of biomarkers, such as TSG-654 and TWIST.55
In effect, the data demonstrate that hMSCs suppress immunity in immunocompetent mice through a plethora of different mechanisms that are employed in different settings. At the same time, it must be recognized that many of the details may need to be re-examined because additional data are generated with the new technologies for the analysis of cells. For example, extensive transcriptome assays of macrophages, the cells that are a primary target of MSCs, have demonstrated that macrophages are more complex than previously recognized.56 Instead of just two phenotypes (M1 and M2), they have a “color wheel” of phenotypes,57 many of which are reversibly inter-changed by signals that identify tissue of origin and responses that reflect functional demands on the cells.58 Moreover, the transcriptome profiles of macrophages do not correlate with standard markers for the cells. Therefore, attempts are being made to classify macrophages on the basis of networks of genes that are activated by specific agonists or signals, such as Toll-like receptor 4/lipopolysaccharide responses.56 These and similar data on other cells are likely to alter the current paradigms for immunology and therefore our understanding of the effects of hMSCs.
Discussion
Trials in animal models of human diseases are an essential first step in the development of most therapies. Mice, and to a lesser extent rats, are the most attractive sources of such models but clearly are not true cognates of human diseases. The limitations are particularly apparent in trying to develop therapies for immune disorders because, by one estimate,59 there are over 80 major differences between the mouse and human immune systems. The differences help explain the slow progress in developing therapies for human immune disorders, which have prompted attempts to produce mice and other species with humanized immune systems. Until the humanized systems become generally available, the development of potential therapies for human immune diseases depends on data developed in wild-type mice and therefore requires large extrapolations of the data to provide the translational therapeutic indices essential for well-designed trials in patients.3
Developing preclinical data for cell therapies for immune diseases presents a special challenge because the cells administered to patients will usually be human cells. The first suggestion that hMSCs were immunosuppressive came not from preclinical observations but from a clinical trial in which a young child with near terminal graft-versus-host disease was improved by administration of MSCs from his mother.60 The development of preclinical data was delayed because of the belief that hMSCs should be immunogenic in immunocompetent mice. However, the opposite is true, as indicated by the publications cited here and others that are too numerous to include in a short review.
The question now is not, “Can hMSCs suppress inflammation and immunity in immune competent mice”? That question has been answered. The questions that remain are, “What are the mechanisms of their actions in response to different immune stimuli”? and “How can these xenogeneic systems best be used to develop translational therapeutic indices that can serve as a guide to the efficacy and safety of hMSCs as therapies for patients?” It will be important to resolve issues such as the effects of differences between mMSCs and hMSCs in HLA/MHC types, co-stimulatory molecules, paracrine factors, and species-specific cytokines, chemokines, and receptors. For therapeutic applications of the cells, however, a critical question is whether the xenogeneic models provide a means of selecting preparations of hMSCs that are most effective in treating specific immune disorders and thereby overcome some of the variability encountered in clinical trials with hMSCs.54, 61, 62, 63
Conflicts of Interest
D.J.P. is chair of the Scientific Advisory Committee and has a small equity share (<5%) in a start-up biotech (Temple Therapeutics, LLC), with an interest in MSCs. The other authors have no potential conflicts of interest.
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