Treatment of autoimmune neurologic disorders
The treatment of autoimmune neurologic disorders was conducted with hMSCs in 31 (102, 121–149, 154) out of the 132 studies (33–164) selected. Among them, in 27 studies (102, 121–145, 154) hMSCs were applied for the treatment of multiple sclerosis while in three studies (146–148) they were used for the treatment of autoimmune myasthenia gravis and in only one study (149) hMSCs were used for the treatment of neuromyelitisoptica.
Multiple sclerosis is a demyelinating disease of the central nervous system of an inflammatory, chronic and progressive nature. The destruction of the myelin sheath and axonal degeneration results in scattered lesions in the central nervous system, especially in the optic nerves, brainstem, spinal cord and periventricular white matter. The dissemination of these lesions results in neurological deficits of variable course (208). The infiltration of activated T lymphocytes and the secretion of inflammatory mediators by these cells results in endothelial changes in the blood-brain barrier and stimulate the inflammatory cascade (209). The production of IFN-γ by activated TH1 lymphocytes activates macrophages that secrete proteases and TNF-α, which contribute to the destruction of oligodendrocytes. The activation of macrophages by IFN-γ also results in the production of high levels of nitric oxide. This increase in nitric oxide inhibits mitochondrial respiration and reduces the synthesis of ATP, leading to the axonal injury observed in the pathological process of the disease (210). Regarding the studies in which hMSCs were used for the treatment of multiple sclerosis (102, 121–145, 154), five studies (125, 131, 132, 134, 135) were conducted in humans, 19 (102, 121–124, 126–129, 133, 136–139, 141, 143–145, 154) were conducted in mice and three studies (130, 140, 142) used rats as the experimental model. Among these studies, 16 used hMSCs isolated from the bone marrow (102, 122, 123, 125–128, 131–137, 138, 143, 154), seven isolated hMSCs from the adipose tissue (121, 128, 130, 136, 140, 141, 145), four isolated hMSCs from the umbilical cord (124, 128, 142, 144) and two isolated hMSCs from the placenta (129, 139). In only one study (102), hMSCs were obtained from the differentiation of embryonic stem cells.
Among the animal studies, the cumulative survival rate, clinical score, disease incidence, disease onset, number of infiltrating cells, inflammation area, degree of demyelination, degree of axonal damage, death of oligodendrocytes, glial activation, number of astrocytes, total lesion area and the total distance traveled, average velocity and time spent in motion over 5 min were the outcomes used by most studies selected in this systematic review to assess the potential of hMSCs administration for the treatment of multiple sclerosis. In the human clinical trials selected, the change in the expanded disability status scale (EDSS) score was chosen as the primary endpoint that was used to assess the stabilization or improvement of general progression of the disease following hMSCs administration. However, there are many limitations associated with the used of this score. First of all, due to the subjective nature of the neurological examination, the EDSS score is composed of some variables that are subjective and therefore susceptible to observation bias. Second, the EDSS score is not appropriate to assess the rate of progression of multiple sclerosis as this score is not linear. Lastly, several aspects of the progression of the disease are not sufficiently assessed by this score. Therefore, we propose that the EDSS score should be used in conjunction with secondary endpoints that are less susceptible to bias, reflect the progression or remission of the disease and are able to assess the aspects of the progression of the disease that are not evaluated by the EDSS score. In this regard, secondary endpoints such as the size and number of plaques, the cumulative number of T2-hyperintense and gadolinium-enhancing T1 lesions, gray and white matter volume, the percentage of brain volume change, and the number of relapses should be used in conjunction with the EDSS score in order to assess the effectiveness of hMSCs administration for the treatment of multiple sclerosis in clinical trials. Exploratory endpoints such as the T and B cell population frequency in blood and the serum level of cytokines can be applied to assess additional immunomodulatory effects of the hMSCs infusion. In the majority of the studies selected the administration of hMSCs reduced the severity and clinical parameters and delayed the progression of the disease (102, 121–126, 128–139, 141–145, 154). This improvement in the clinical condition was usually accompanied by an increase in the myelin levels (121, 136, 137) and a reduction in the number of apoptotic cells (142), in vascular congestion (130), in axonal injury (124) and in the extent of the chronic demyelinated regions in the central nervous system and spinal cord (122, 124, 126, 133, 142, 154). Furthermore, an increase in the number of oligodendrocyte lineage cells (122) and NeuN-positive neurons in the gray matter and spinal cord (142) following hMSCs administration was also observed. A decrease in the number of microglia cells (142), a reduction in astrogliosis (122, 140), an inhibition in the activation of glial cells in lesion areas (126) and a decrease in the blood-brain barrier permeability (133) was also found to be associated with hMSCs administration.
In general, the administration of hMSCs reduced the levels of pro-inflammatory cytokines such as IFN-γ (122, 126, 128, 130, 133, 141–144), TNF-α (122, 124, 126, 128, 133, 142, 154), IL-1 (124), IL-2 (122, 128), IL-12 (122), and IL-17 (121, 122, 124, 128, 130, 138, 143, 144, 154) and increased the levels of anti-inflammatory cytokines such as IL-4 (122, 124, 126, 130, 133, 138, 140, 142, 143, 144), IL-5 (122), and IL-10 (124, 126, 128, 130, 133, 138, 139, 141–143). The level of the pro and anti-inflammatory cytokine IL-6 was found to be increased in some studies (128, 136) while in others the level of this cytokine decreased (124, 154) after the administration of hMSCs. In addition, some of the studies selected suggested that the immunomodulatory properties of hMSCs can be partially attributed to the expression of molecules with immunomodulatory functions such as LIF (136, 141), PDL-1 (102, 141), COX-2 (141), TGF-β1 (141, 143), TSG-6 (141), CD200 (141), HGF (141, 143), IDO-1 (139, 141), VEGF (143), HLA-G (130, 141), HLA-E (141), and HO-1 (141) by these cells. Furthermore, a study conducted by Tafreshi et al. (141) reported that neurotrophic factors such as BDNF, CNTF, GDNF, NGF, and NTF3 are also constitutively expressed by hMSCs, evidencing the potential of this type of stem cell for paracrine support in a neurodegenerative setting. Finally, a study conducted by Hou et al. (143) also demonstrated that hMSCs administration acted by inhibiting matrix metalloproteinase 2 and 9 activities in the spinal cord of mice with experimental autoimmune encephalomyelitis.
The proliferation and differentiation of immune cells was also significantly affected by the administration of hMSCs. In general, treatment of multiple sclerosis with hMSCs resulted in an inhibition in the proliferation of both B (102) and T (102, 131, 136, 137, 141, 145) cells and in a reduction in the infiltration of inflammatory cells into the central nervous system and spinal cord (124, 126, 130, 133, 136–139, 143, 154). Specifically, administration of hMSCs led to an inhibition in the clonal expansion and infiltration of CD4+IFN-γ+ Th1 (102, 122) and CD4+IL-17+ Th17 (102, 122, 124, 138) cells into the central nervous system. Furthermore, treatment with hMSCs resulted in a stimulation in the clonal expansion of CD4+IL-4+ Th2 (122) and CD4+CD25+FOXP3+ Treg (124, 143) cells, as reported by some studies. On the other hand, studies conducted by Llufriu et al. (134) and Guo et al. (154) reported an increase in the numbers of CD19+IL-10+ and CD19+CD5+CD1dhigh Breg cells after the administration of hMSCs. The proliferation of both CD44+ and CD45RO+memory T-lymphocytes was also found to be reduced after the administration of hMSCs, in studies conducted by Strong et al. (136) and Zafranskaya et al. (131), respectively. Cells of the innate immune system were also affected by the treatment with hMSCs, as described by some of the studies selected. For instance, a study by Bravo et al. (139) reported a reduction in the percentages of both CD11b+Ly6G+ neutrophils and CD11b+Ly6C+ inflammatory monocytes in infiltrates of mice with experimental autoimmune encephalomyelitis treated with hMSCs. In this study, lower RORγT and higher GATA-3 transcription factor expression levels in CD4+ cells were also detected in experimental autoimmune encephalomyelitis mice treated with hMSCs, which suggests that the Th17 phenotype is restrained while the Th2 subset is favored by the treatment with hMSCs. In addition, a study by Donders et al. (142) reported an inhibition in the differentiation and maturation of dendritic cells in rats with experimental autoimmune encephalomyelitis treated with hMSCs, reducing antigen presentation and, as a consequence, T-cell priming. Finally, a study by Tafreshi et al. (141) demonstrated that the loss of phosphorylated GSK3β, an enzyme known for their ability to control neuroinflammation, can be recovered in neurons of experimental autoimmune encephalomyelitis mice treated with hMSCs.
Together, these results indicate that the improvement in the clinical condition observed after the administration of hMSCs is a consequence of the inhibition in the proliferation and infiltration of inflammatory cells such as B, Th1 and Th17 lymphocytes, neutrophils and monocytes into the central nervous system and spinal cord promoted by these stem cells. It can be hypothesized that factors secreted by the hMSCs administered such as IL-10, IL-4, TGF-β, PGE2, HGF, and PDL-1 acts by inhibiting the activation of autoreactive CD4+ T cells and their differentiation in Th1 cells in both the periphery and central nervous system and by stimulating the differentiation of these CD4+ T cells into Th2 and Treg lymphocytes. Additionally, these factors can stimulate APCs located in both the periphery and central nervous system to differentiate into regulatory dendritic cells, further inhibiting the activation of autoreactive CD4+ T cells. The recruitment of pro-inflammatory cells such as neutrophils, basophils, monocytes, eosinophils and CD8+T lymphocytes and their infiltration into the central nervous system can also be inhibited as a result of the decrease in the secretion of pro-inflammatory cytokines and growth factors such as IFN-γ, IL-2, and TGF-β by Th1 lymphocytes and due to the secretion of anti-inflammatory factors such as GM-CSF, PGE2, and IL-6 by the hMSCs administered. The decrease in the levels of pro-inflammatory cytokines and growth factors and the secretion of anti-inflammatory factors by hMSCs can also inhibit the activation of astrocytes in the central nervous system and stimulate pro-inflammatory cells to differentiate into M2 macrophages and cells with immunomodulatory properties such and Breg cells. As a result, the secretion of TNF-α, proteases, nitric oxide and myelin-specific antibodies by pro-inflammatory cells located in the central nervous system is also inhibited, decreasing the death of oligodendrocytes and the destruction of the myelin sheath in axons. Finally, the secretion of neurotrophic factors such as BDNF, CNTF, GDNF, NGF, and NTF3 by the hMSCs administered may also act on oligodendrocytes and neurons, further inhibiting the progression of the disease. The mechanism proposed by this systematic review concerning the inhibition in the progression of the pathological process of multiple sclerosis mediated by hMSCs is represented in Figure 7.
Figure 7  hMSCs inhibits the pathological course of multiple sclerosis through several mechanisms. hMSC-produced IL-4, IL-10, HGF, PGE2, PDL-1, and TGF-β inhibit the activation of autoreactive CD4+T cells and their differentiation to Th1 cells and stimulate the generation of Breg, Treg, and Th2 lymphocytes. hMSCs inhibit the activation of dendritic cells and stimulate the generation of regulatory dendritic cells. hMSC-produced IL-6, PGE2, and GM-CSF suppress astrocyte activation and macrophage polarization to M1, though favors M2 polarization. hMSCs-produced neurotrophic factors BDNF, CNTF, GDNF, NGF, and NTF3 inhibit the destruction of the myelin sheath and axonal degeneration. Myasthenia gravis is an autoimmune disorder that affects the myoneural junction, resulting in weakness and fatigability of the striated skeletal muscles. Major manifestations of the disease include diploplia, ptosis, bulbar symptoms such as weakness of the muscles of the face and throat, and generalized weakness (211). The clinical manifestations of the disease results from the production of autoreactive T cells and from the secretion of IgG autoantibodies by hyperstimulated B cells. The biding of these antibodies to nicotinic acetylcholine receptors located on the skeletal muscle membrane leads to the blockade of these receptors, increases their degradation and stimulates the complement-mediated destruction of the post-synaptic cleft, compromising the neuromuscular transmission (212). In addition, the loss of the immunosuppressive activity of Treg cells, which have a decreased expression of the FoxP3 transcription factor, results in impairment of the process of immune self-tolerance and homeostasis of the immune system (213). Two (146, 147) of the three studies (146–148) in which hMSCs were used for the treatment of autoimmune myasthenia gravis were carried out in mice and only one (148) was conducted in humans. Among them, the bone marrow was chosen as the source of hMSCs in two studies (146, 148) while in one study (147) hMSCs were isolated from the dental pulp. Among the studies conducted in mice, the change in body weight, the clinical score, the inverted screen hang time, the C3 deposit level, the neuromuscular junction IgG deposit level and the serum level of both anti-acetylcholine receptor and anti-muscle-specific tyrosine kinase antibodies were the outcomes used by most studies selected in this systematic review to assess the potential of hMSCs administration for the treatment of myasthenia gravis. In the human clinical trial selected, the change in the quantitative myasthenia gravis score (QMGC) was chosen as the primary endpoint that was used to quantify the severity of the disease following hMSCs administration. It is recommended by the Myasthenia Gravis Foundation of America that the QMGS should be used in all prospective clinical trials on myasthenia gravis (214). Currently, the QMGC is composed of 13 variables that are likely to not be affected by bias. However, due to the lack of weighting of different domains, the QMGS is, sometimes, not fully representative of myasthenia gravis severity. Therefore, other clinical and laboratory parameters should be used in conjunction with QMGS to assess the efficacy of the use of hMSCs for the treatment of myasthenia gravis in clinical trials. In addition, exploratory endpoints such as the serum level of cytokines and the T and B cell population frequency in blood can be used to evaluate additional immunomodulatory effects of the hMSCs administration.
Results from the administration of hMSCs included a reduction in the severity and clinical manifestations of the disease (146–148). Furthermore, a study conducted by Ulusoy et al. (147) demonstrated that the administration of hMSCs reduced the incidence of experimental autoimmune myasthenia gravis. In this study, treatment with hMSCs also resulted in a decrease in the levels of the pro-inflammatory cytokines IL-6 and IL-12 and inhibited the proliferation of CD11b+ leukocytes in the lymph nodes. The proliferation of mononuclear cells is also inhibited by the presence of hMSCs, as described by Yu et al. (146). The levels of autoantibodies that are important for the pathogenesis autoimmune myasthenia gravis were also found to be decreased following the treatment with hMSCs in all articles selected. For instance, studies conducted by Gabr and Elkheir (148) and by Yu et al. (146) reported a decrease in the levels of the anti-acetylcholine receptor antibody in the serum of patients treated with hMSCs. In particular, Yu et al. (146) also reported an inhibition in the proliferation of acetylcholine receptor-specific lymphocytes following the treatment with hMSCs. Finally, a study conducted by Ulusoy et al. (147) reported a decrease in the serum levels of anti-muscle-specific tyrosine kinase antibodies after the treatment with hMSCs. Likewise, this study described a reduction in the percentages of neuromuscular junction IgG in the serum and complement component three deposits in the muscles of mice treated with hMSCs. It can be, therefore, speculated that the reduction in the severity and clinical manifestations of the disease observed after hMSCs administration is a direct result of the inhibitory effect of these stem cells in activation and proliferation of B cells. As a consequence, the secretion of IgG autoantibodies such as the anti-acetylcholine receptor antibody and the anti-muscle-specific tyrosine kinase antibody by hyperstimulated B-cells also decreases, culminating in the inhibition in the progression of the disease.
Neuromyelitis optica is an inflammatory, demyelinating, and autoimmune disease of the central nervous system, which selectively affects the spinal cord and optic nerves, simultaneously or sequentially. Symptoms of neuromyelitis optica include loss of vision, sensitivity changes, muscle weakness, spasticity, incoordination, ataxia, urinary and fecal incontinence, and autonomic dysfunctions in parts of the trunk and limbs supplied by nerves coming out of the spine below the spinal lesion (215). Clinical and serological evidence of autoimmunity associated with B cells has been observed in patients with neuromyelitis optica, in whom demyelinating lesions exhibit perivascular immunoglobulin deposition, local activation of the complement cascade and eosinophilic infiltration (216). Other mechanisms involved in this humoral response are the secretion of IL-2, anti-myelin autoantibodies, oligodendrocyte-associated anti-glycoprotein autoantibodies, and IgG autoantibodies against the astroglial water channel aquaporin-4 (217). In general, neuromyelitis optica attacks are more severe than those of multiple sclerosis and are commonly fatal (215). The treatment of neuromyelitisoptica was carried out with hMSCs in only one study (149). This study was conducted in humans and used bone marrow-derived hMSCs for the treatment of the autoimmune disease. The study selected in this systematic review was a single case report and used the healing of pressure ulcers, the improvement of disability, the ability to walk, and the occurrence of relapse and adverse events as the primary endpoints that were used in order to assess the efficacy of hMSCs administration for the treatment of neuromyelitis optica. Because the occurrence of attacks is the main cause of neuromyelitis optica-related disability (215), we propose that the frequency and severity of attacks should be considered as the most appropriate primary endpoints in neuromyelitis optica clinical trials. In addition, exploratory endpoints such the serum levels of autoantibodies and inflammatory cytokines can be used to determinate what are the mechanisms used by the hMSCs administered to inhibit the occurrence of the pathological process. In the study selected, a reduction in both the severity and in the clinical parameters of the disease was observed following the administration of hMSCs. Table 7 summarizes the methodology employed and the results obtained in the studies selected in this systematic review regarding the effects of the administration of hMSCs for the treatment of autoimmune neurologic disorders.
Table 7  List of in vivo studies in which the therapeutic potential of the administration of hMSCs for the treatment of autoimmune neurologic disorders was evaluated.
References   Autoimmune disease   Source of hMSC   Variables   Experimental model   Clinical and laboratory effects   Mechanism proposed
(102)  Multiple sclerosis  Embryonic stem cells Bone marrow  None  Mice  ↓Clinical score↓Disease incidence↑Motor functions Effectiveness embryonic stem cells-derived MSCs > effectiveness bone marrow-derived MSCs  ↓IFN-γ+CD4+ Th1 cells into the central nervous system↓IL-17+CD4+ Th17 cells into the central nervous system↓T lymphocyte proliferation↓B lymphocyte proliferation↑PD-L1 expression
(121)  Multiple sclerosis  Adipose tissue  Administration of MSCs from older donors  Mice  None
Administration of MSCs from younger donors   ↓Clinical score↑Activity and utilization of the arena space↑Distance traveled↑Moving velocity↑Myelin levels Effectiveness MSCs from younger donors > effectiveness MSCs from older donors  ↓Infiltrating cells in the spinal cord↓Splenocyte proliferation↑IL-17 in the serum↑IL-12 in the serum↑IFN-γ in the serum
(122)  Multiple sclerosis  Bone marrow  None  Mice  ↓Clinical score↓Disease progression  ↑Oligodendrocyte lineage cells in lesion areas↓IFN-γ+CD4+ Th1 cells↓IL-17+CD4+ Th17 cells↑IL-4+Th2 cells↓Infiltrating cells in the central nervous system↓Extent of the chronic demyelinated regions↑Oligodendrogenesis↓Astrogliosis↓Myelin-specific memory splenocytes↓IFN-γ↓TNF-α↓IL-17↓IL-2↓IL-12↑IL-4↑IL-5
(154)  Multiple sclerosis  Bone marrow  None  Mice  ↓Clinical scores↓Demyelination in the spinal cord  ↓Infiltration of inflammatory cells↓IL-6 in the serum↓TNF-α in the serum↓IL-17 in the serum↓Splenic cell production and secretion of IL-6, TNF-α and IL-17↑Splenic production of IL-10↓Splenic Th17 cells↑CD19+CD5+CD1dhigh Breg cells
(123)  Multiple sclerosis  Bone marrow  None  Mice  ↓Disease progression↑Survival rates↑Motor function  ↓Spleen cells proliferation
(124)  Multiple sclerosis  Umbilical cord stroma  None  Mice  ↓Histopathologic scores↓Clinical score↓Demyelination in the spinal cord↓Axonal injury in the spinal cord  ↓Perivascular immune cell infiltration↓IL-17+CD4+ Th17 cells↓IFN-γ/IL-4 ratio↑CD4+CD25+FOXP3+ Treg cells↑IL-4↑IL-10↓IL-17↓TNF-α↓IL-1 in the spinal cord↓IL-6 in the spinal cord
(126)  Multiple sclerosis  Bone marrow  None  Mice  ↓Average clinical score↓Maximum clinical score↓Demyelination of the spinal cord  ↓Inflammatory cell infiltration into the central nervous system↓Inflammatory mononuclear cell infiltration in the white matter of the spinal cord↓CD4+ cells in the spinal cord↓Activation of glial cells↓IFN-γ in the serum↓TNF-α in the serum↑IL-4 in the serum↑IL-10 in the serum↓MMP-2 activity in the spinal cord↓MMP-9 activity in the spinal cord
(127)  Multiple sclerosis  Bone marrow  None  Mice  None  None
(128)  Multiple sclerosis  Bone marrow  None  Mice  ↓Daily mean clinical score↓Daily mean clinical score↓Maximal disease score↓Cumulative disease score  ↓Proliferation of mitogen or antigen-stimulated T-cells↓IFN- γ↓IL-2
Adipose tissue    Effectiveness adipose tissue and umbilical cord-derived MSCs > effectiveness bone marrow-derived MSCs  ↓IL-17 (Ad-MSCs and BMSCs only)↓TNF-α (Ad-MSCs and UC-MSCs only)↑IL-6 (BMSCs only)
Umbilical cord stroma    ↓Daily mean clinical score↓Maximal disease score↓Cumulative disease score  ↑IL-10 (BMSCs only)
(129)  Multiple sclerosis  Placenta  Intramuscular implantation of MSCs  Mice  ↓Disease progression  None
Direct injection of MSCs into the central nervous system   ↓Clinical score
(133)  Multiple sclerosis  Bone marrow  None  Mice  ↓Disease progression↓Average clinical score↓Maximum clinical score↓Demyelination of the lumbar spinal cord↓Blood-brain barrier permeability  ↓Immune cell infiltration in the lumbar spinal cord↓IFN-γ in the serum↓TNF-α in the serum↑IL-4 in the serum↑IL-10 in the serum
(136)  Multiple sclerosis  Adipose tissue  Administration of MSCs isolated from lean subjects  Mice  ↓Disease progression↓Clinical score↑Total distance traveled↑Moving duration↑Total velocity↑Myelin content in the central nervous system Effectiveness MSCs from lean subjects > effectiveness MSCs from obese subjects  ↓Cell infiltration into the central nervous system↓Proliferation of T cells↓Proliferation of memory CD44+ T cells
Administration of MSCs isolated from obese subjects   ↓Myelin content in the central nervous system  ↑Cell infiltration into the central nervous system↓Overall size of the lymph nodes↑Size of the spleen↑Proliferation of T cells↑Differentiation of T cells into mature CD4+ and CD8+ T cells↑IL-1 gene expression (MSCs from lean subjects)↑IL-6 gene expression (MSCs from lean subjects)↑IL-12 gene expression (MSCs from lean subjects)↑PDGF gene expression (MSCs from lean subjects)↑TNF-α gene expression (MSCs from lean subjects)↑LIF gene expression (MSCs from lean subjects)↑ICAM-1 gene expression (MSCs from lean subjects)↑G-CSF gene expression (MSCs from lean subjects)
(137)  Multiple sclerosis  Bone marrow  None  Mice  ↓Disease progression  ↓T lymphocytes proliferation
(138)  Multiple sclerosis  Bone marrow  Administration of PSGL-1/SLeX mRNA-transfected MSCsAdministration of MSCs alone  Mice  ↓Clinical score↑Neurological function↑ Myelination Effectiveness PSGL-1/SLeX mRNA-transfected MSCs > effectiveness MSCs alone  ↑Percentage of rolling and adherent cells↓Proliferation of CD4+ T lymphocytes↓Lymphocytes infiltration into the white matter of the spinal cord
(139)  Multiple sclerosis  Placenta  None  Mice  ↓Disease progression↓Clinical score  ↓Inflammatory cell infiltration↓CD4+IL17+ Th17 cells↓CD11b+Ly6G+ neutrophils↓CD11b+Ly6C+ inflammatory monocytes↓Spleen cells proliferation↓IL-17↑IL-4↑IL-10↓RORγT gene↑GATA-3 gene
(141)  Multiple sclerosis  Adipose tissue  None  Mice  ↓Astrogliosis  ↑GSK3β+ neurons in the spinal cord↑IL-4
(143)  Multiple sclerosis  Bone marrow  None  Mice  ↓Clinical score↓Demyelination in the spinal cord↓Astrocytes Treatment with hBM-MSCs and minocycline > treatment with hBM-MSCs or minocycline alone  ↓Microglia cells↑NeuN-positive neurons in the gray matter and spinal cord↓Apoptotic cells↓IFN-γ↓TNF-α↑IL-4↑IL-10
(144)  Multiple sclerosis  Umbilical cord stroma  Administration of umbilical cord derived-MSCs previously treated with IFN-γAbsence of stimulation of MSCs with IFN-γ prior to administration  Mice  ↓Clinical scores↓Disease progression Effectiveness MSCs + IFN-γ > effectiveness MSCs alone  ↓Leukocyte infiltration in the spinal cord white matter↑CD4+CD25+Foxp3+CD127low/neg Treg cells in cervical lymph nodes cells and splenocytes↓PBMCs proliferation (in vitro)↑IL-10↑IL-4↑HGF↑VEGF↑TGF-β↓IFN-γ↓IL-17
(145)  Multiple sclerosis  Adipose tissue  None  Mice  ↓Clinical scores↑Survival rates  ↓Peripheral MOG-specific T-cell responses↓IFN-γ↓IL-17A↓IL-6↑IL-4
(130)  Multiple sclerosis  Adipose tissue  None  Rats  ↓Disease progression↓Mean clinical scores↓Histopathologic score↓Vascular congestion↓Axonal loss of the gray and white matters of cerebral cortex  ↓Immune cell infiltration↑HLA-G gene expression in lymph nodes and brains↓CD3 mRNA expression expression in the brain↓CD19 mRNA expression expression in the brain↓CD11b mRNA expression expression in the brain↓IFN-γ in the serum↓IL-17 in the serum↑IL-4 in the serum↑IL-10 in the serum
(140)  Multiple sclerosis  Adipose tissue  None  Rats  ↓Duration of paralysis↓Disease progression↓Clinical score  ↓Inflammatory cell infiltration in the spinal cord↑IL-10 gene expression in the lymph node↑IDO gene expression in the lymph node↑IFN-γ gene expression in the lymph node
(142)  Multiple sclerosis  Umbilical cord stroma  None  Rats  ↓Clinical score  ↓Proliferation of activated T cells↓Autoantigen-induced T-cell proliferation↓Dendritic cell differentiation and maturation↑IDO-1↓IFN-γ↑IL-10↑LIF gene↑PD-L1 gene↑COX-2 gene↑TGF- β1 gene↑TSG-6 gene↑CD200 gene↑HGF gene↑HLA-E gene↑HLA-G gene↑HO-1 gene↑BDNF gene↑CNTF gene↑GDNF gene↑NGF gene↑NTF3 gene
(125)  Multiple sclerosis  Bone marrow  None  Humans  ↓Expanded disability status scale score  None
(131)  Multiple sclerosis  Bone marrow  None  Humans  ↓Expanded disability status scale score  ↓CD45RO+ memory T-lymphocytes↓Myelin-stimulated T cells proliferation
(132)  Multiple sclerosis  Bone marrow  None  Humans  ↓Expanded disability status scale score  None
(134)  Multiple sclerosis  Bone marrow  None  Humans  ↓Mean cumulative number of gadolinium-enhancing lesions↓Expanded disability status scale score  ↑ CD19+IL-10+ Breg cells frequency↓Breg/CD19+ cells ratio↓Th1/Th17 cells ratio
(135)  Multiple sclerosis  Bone marrow  None  Humans  ↓Expanded disability status scale score↑Sensory function↑Pyramidal function↑Cerebellar function  None
(146)  Autoimmune myasthenia gravis  Bone marrow  None  Mice  ↓Mean clinical score  ↓Anti-acetylcholine receptor antibody levels (in the serum)↓AchR-specific lymphocyte proliferation (in the serum)↓Mononuclear cells proliferation
(147)  Autoimmune myasthenia gravis  Dental pulp  None  Mice  ↓Clinical score↑Inverted screen hang time↓Disease incidence↓Complement component three deposits in the muscle  ↓Anti-muscle-specific tyrosine kinase antibody levels (in the serum)↓Neuromuscular junction IgG levels (in the serum)↓CD11b+ leukocytes in lymph nodes↓IL-6↓IL-12
(148)  Autoimmune myasthenia gravis  Bone marrow  None  Humans  ↓Quantitative myasthenia gravis score  ↓Anti-acetylcholine receptor antibody levels (in the serum)
(149)  Neuromyelitis optica  Bone marrow  None  Humans  ↑Healing of pressure ulcers↑Improvement of disability↑Ability to walk  None
Both the methodology employed and the results obtained by each article are represented in this table. MMP-2, matrix metalloproteinase-2; MMP-9, matrix metalloproteinase-9; Ad-MSCs, adipose tissue-derived mesenchymal stem cells; Uc-MSCs, umbilical cord-derived mesenchymal stem cells; BMSCs, bone marrow-derived mesenchymal stem cells; PDGF, platelet-derived growth factor; G-CSF, granulocyte-colony stimulating factor; RORγT, RAR-related orphan receptor gamma T; GSK3β, glycogen synthase kinase 3 beta; TSG-6, tumor necrosis factor-inducible gene 6 protein; HLA-E, human leukocyte antigen E; HLA-G, human leukocyte antigen G; HO-1, heme oxygenase 1; BDNF, brain-derived neurotrophic factor; CNTF, Ciliary neurotrophic factor; GDNF, glial cell-derived neurotrophic factor; NTF3, neurotrophin-3; MOG, myelin oligodendrocyte glycoprotein; AchR, acetylcholine receptor.