Mesenchymal Stromal Cell (MSC)-Derived Combination of CXCL5 and Anti-CCL24 Is Synergistic and Superior to MSC and Cyclosporine for the Treatment of Graft-versus-Host Disease

The immunosuppressive properties of mesenchymal stromal cells (MSCs) have been clinically proven to be effective in treating graft-versus-host disease (GVHD). However, MSC therapy is limited by the need for laborious and expensive manufacturing processes that are fraught with batch-to-batch variability. Substitution of MSC therapy with key MSC-mediated immunomodulatory factors could be an option for GVHD treatment. Using a simulated in vitro model of the immunosuppressive effects of MSC on allogeneic graft reactions, a synergistic 2-factor combination (2FC) of CXCL5 and anti-CCL24 was identified from a panel of over 100 immunomodulatory factors as being superior to MSCs in the modulation of mixed lymphocyte reactions. This 2FC was superior to cyclosporine in ameliorating both moderate and severe GVHD while being equivalent to MSCs in moderate GVHD and superior to MSCs in severe GVHD. Its immunosuppressive efficacy could be further improved by extended treatment. Mechanistic studies revealed that in vitro the 2FC could only reduce the proliferation of Th 1 and Th 17, whereas in vivo CXCL5 acts in concert with anti-CCL24 antibody to reduce not only transplanted Th 1 and Th 17 but also cytotoxic T lymphocytes and natural killer cells to increase mouse immunosuppressive neutrophils without affecting human hematopoietic stem cell reconstitution. Concurrently, it reduced circulating human proinflammatory cytokines IFN-γ, IL-6, IL-17A, IL-8, macrophage inflammatory protein-1β, and monocyte chemoattractant protein-1. Both in vitro and in vivo data suggest that CXCL5 and anti-CCL24 antibody act in concert to ameliorate GVHD via suppression of Th 1 and Th 17 responses. We propose that this novel 2FC could substitute for MSC therapy in GVHD treatment.     

The relationship between interferon-γ gene polymorphism and acute kidney allograft rejection

Cytokine gene polymorphisms have been associated with modified gene expression and cytokine production. Gamma interferon (IFN-γ) plays an important role in the pathogenesis of kidney transplant rejection. This study evaluated the association between IFN-γ gene polymorphisms and the history of acute allograft rejection in 53 adult first-transplant recipients receiving cadaveric kidney grafts. They were followed up in a single centre until 2006, for a median time of 4 years after transplantation (1-22 years). IFN-γ gene polymorphisms +874 T/A (rs2430561) were determined by polymerase chain reaction (PCR). T/T high IFN-γ genotype was found in 12, intermediate T/A in 29 and low A/A in 12 patients. Twenty-six acute kidney rejection episodes were evidenced in 20 patients, of which none occurred in the 12 patients with low IFN-γ genotype A/A. Age, gender, number of HLA (human leukocyte antigen) mismatches, ABO blood groups, HLA, time after transplantation, creatinine clearance and immunosuppressive regimens were excluded as confounding factors associated with IFN-γ genotype distribution between rejectors and non-rejectors. IFN-γ gene polymorphisms could be an important risk factor for acute kidney transplant rejection, whereas the low A/A IFN-γ genotype could be protective against rejection.     

CD4+CD25+Foxp3+IFN-γ+ human induced T regulatory cells are induced by interferon-γ and suppress alloresponses nonspecifically

Interferon-γ (IFN-γ)-producing CD3(+)CD4(+)CD25(+)Foxp3(+) peripheral blood lymphocytes (PBL) are more frequently detectable in patients with good than in patients with impaired long-term kidney graft function, suggesting an immunoregulatory role of this induced T regulatory (iTreg) subtype. Herein, the in vitro function of separated CD3(+)CD4(+)CD25(+)Foxp3(+)IFN-γ(+) PBL that were induced by phorbol 12-myristate 13-acetate (PMA)/ionomycin or alloantigenic stimulation was investigated using cell coculture techniques and flow cytometry. CD4(+)CD25(+)Foxp3(+) PBL with intracellular IFN-γ production increased to 26% in cell cultures stimulated with PMA/ionomycin for 6 hours. Recombinant IFN-γ augmented and anti-IFN-γ monoclonal antibody blocked induction of CD4(+)CD25(+)Foxp3(+)IFN-γ(+) PBL, suggesting their IFN-γ-dependent induction. In addition, CD4(+)CD25(+)Foxp3(+)IFN-γ(+) PBL produced immunosuppressive interleukin (IL)-10, transforming growth factor-β, and IL-4 intracellularly and expressed both IFN-γ and IFN-γ receptors (CD119) on the cell surface, allowing separation of CD4(+)CD25(+)IFN-γ(+) PBL with 98% purity. Addition of enriched CD4(+)CD25(+)IFN-γ(+) PBL to autologous PMA/ionomycin stimulated PBL decreased blast formation (p < 0.05), indicating suppression of cell proliferation by CD4(+)CD25(+)IFN-γ(+) PBL. CD4(+)CD25(+)IFN-γ(+) PBL separated from primary mixed leukocyte cultures (MLC) and added to autologous or third-party secondary MLC suppressed allogeneic T-cell activation nonspecifically (p < 0.05). We conclude that CD4(+)CD25(+)Foxp3(+)IFN-γ(+) PBL are induced by IFN-γ, making them sensors for IFN-γ and initial immune responses. Circulating CD4(+)CD25(+)Foxp3(+)IFN-γ(+) PBL could suppress allogeneic T-cell responses in patients and may be involved in inhibition of the posttransplant alloresponse.     

基于细胞因子分泌对人混合淋巴细胞反应中的T淋巴细胞进行测定和纯化

目的:对同种异体外周血单个核细胞(PBMNCs)刺激后分泌细胞因子的T 淋巴细胞进行测定和纯化,为研究介导同种异体反应的T淋巴细胞提供新的途径。方法: 利用新颖的细胞因子分泌检测方法(CKSA)从单细胞水平定量测定人混合淋巴细胞反应中分泌IFN-γ,IL-4 和IL-10的T 淋巴细胞; 对分泌IFN-γ 的T细胞进行磁性纯化。结果: 同种异体PBMNCs刺激后检测到分泌IFN-γ 的T淋巴细胞水平明显升高(1.12%±0.13%),而分泌IL-4 和IL-10的T淋巴细胞则无升高(分别为0.12%±0.03%和0.10%±0.03%);分泌IFN-γ 的T淋巴细胞可以被进一步纯化(93.8±22.1)倍。结论: 利用CKSA从单细胞水平定量测定同种异体PBMNCs刺激后分泌IFN-γ 的T淋巴细胞水平显著升高,这些细胞可以被有效地纯化。     

Distinct Immunoregulatory Mechanisms in Mesenchymal Stem Cells: Role of the Cytokine Environment

Mesenchymal stem cells (MSCs) represent a population of cells which have the ability to regulate reactivity of T and B lymphocytes by multiple mechanisms. The immunoregulatory activities of MSCs are strictly influenced by the cytokine environment. Here we show that two functionally distinct cytokines, interleukin-4 (IL-4) and interferon-γ (IFN-γ), significantly potentiate the ability of MSCs to inhibit IL-10 production by activated regulatory B cells (Bregs). However, MSCs in the presence of IL-4 or IFN-γ inhibit the IL-10 production by different mechanisms. Preincubation of MSCs with IFN-γ led to the suppression, but pretreatment with IL-4 of neither MSCs nor B cells resulted in the suppression of IL-10 production. The search for candidate regulatory molecules expressed in cytokine-treated MSCs revealed different patterns of the gene expression. Pretreatment of MSCs with IFN-γ, but not with IL-4, induced expression of indoleamine-2,3-dioxygenase, cyclooxygenase-2 and programmed cell death-ligand 1. To identify the molecule(s) responsible for the suppression of IL-10 production, we used specific inhibitors of the putative regulatory molecules. We found that indomethacine, an inhibitor of cyclooxygenase-2 (Cox-2) activity, completely abrogated the inhibition of IL-10 production in cultures containing MSCs and IFN-γ, but had no effect on the suppression in cell cultures containing MSCs and IL-4. The results show that MSCs can inhibit the response of B cells to one stimulus by different mechanisms in dependence on the cytokine environment and thus support the idea of the complexity of immunoregulatory action of MSCs.     

Use of Mesenchymal Stem Cells (MSC) in Chronic Inflammatory Fistulizing and Fibrotic Diseases: a Comprehensive Review

Mesenchymal stem cells (MSC), multipotent adult stem cells, feature the potential to regenerate tissue damage and, in parallel, inhibit inflammation and fibrosis. MSC can be safely transplanted in autologous and allogeneic ways as they are non-immunogenic, and consequently represent a therapeutic option for refractory connective tissue diseases, fibrosing diseases like scleroderma and fistulizing colitis like in Crohn’s disease. Actually, there are more than 200 registered clinical trial sites for evaluating MSC therapy, and 22 are on autoimmune diseases. In irradiation-induced colitis, MSC accelerate functional recovery of the intestine and dampen the systemic inflammatory response. In order to provide rescue therapy for accidentally over-irradiated prostate cancer patients who underwent radiotherapy, allogeneic bone marrow-derived MSC from family donors were intravenously infused to three patients with refractory and fistulizing colitis resembling fistulizing Crohn’s disease. Systemic MSC therapy of refractory irradiation-induced colitis was safe and effective on pain, diarrhoea, hemorrhage, inflammation and fistulization accompanied by modulation of the lymphocyte subsets towards an increase of T regulatory cells and a decrease of activated effector T cells. The current data indicate that MSC represent a promising alternative strategy in the treatment of various immune-mediated diseases. Encouraging results have already been obtained from clinical trials in Crohn’s disease and SLE as well as from case series in systemic sclerosis. MSC represent a safe therapeutic measure for patients who suffer from chronic and fistulizing colitis. These findings are instructional for the management of refractory inflammatory bowel diseases that are characterized by similar clinical and immunopathological features.     

γ干扰素联合脂多糖诱导人脐带间充质干细胞向MSC2极化

文题释义： γ干扰素联合脂多糖模拟炎症微环境：间充质干细胞的免疫抑制能力不是内在的,而是由促炎细胞因子诱导的。间充质干细胞暴露于炎症信号可显著增强其对T细胞、单核细胞/巨噬细胞和树突状细胞的免疫抑制作用。γ干扰素由活化T细胞和NK细胞产生,激活抗原提呈细胞,上调转录因子T-bet 而促进Th1细胞分化;脂多糖是革兰阴性细菌细胞壁外壁的组成成分,是免疫反应的强烈刺激剂,具有通过信号转导途径促进各种炎性细胞因子分泌的作用。 间充质干细胞可极化为MSC1和MSC2两种类型：间充质干细胞既可以抑制免疫应答,也可以促进免疫应答,不同的炎症递质会诱导间充质干细胞极化分型并表现出截然相反的免疫调节作用,这一特性称为间充质干细胞免疫调节的可塑性。间充质干细胞可以通过下游Toll样受体信号极化成2种类型：MSC1和MSC2。文献报道Toll样受体4引发的MSC1主要发挥促炎功能,而Toll样受体3引发的MSC2主要发挥免疫抑制功能。 背景：间充质干细胞的免疫调节特性已被临床广泛应用于自身免疫性疾病和移植物抗宿主病,但是其免疫调节的可塑性导致间充质干细胞临床治疗效果出现异质性和不稳定性。 目的：探索γ干扰素联合脂多糖模拟炎症微环境诱导人脐带间充质干细胞向MSC2极化的作用。 方法：体外分离培养人脐带间充质干细胞,进行形态学、表面标志物、成脂及成骨诱导分化能力鉴定。分别用γ干扰素(10 μg/L)、脂多糖(100 μg/L)及二者联合刺激人脐带间充质干细胞24 h,与植物凝集素刺激的外周血单个核细胞直接共培养或Transwell间接共培养5 d。流式细胞术检测共培养不同时间点调节性T细胞和Th1细胞比例,荧光定量PCR检测人脐带间充质干细胞的Toll样受体2,3,4 mRNA表达水平。 结果与结论：①人脐带间充质干细胞呈梭形或成纤维形,高表达CD73、CD90、CD105,低表达CD34、CD45、HLA-DR;②在直接与间接共培养条件下,γ干扰素联合脂多糖刺激人脐带间充质干细胞均可增加调节性T细胞的比例,优于γ干扰素或脂多糖单独刺激组、未刺激组及外周血单个核细胞对照组(P < 0.05);③Th1细胞比例随共培养时间的延长呈逐渐下降的趋势;④在间接共培养的条件下,γ干扰素联合脂多糖刺激人脐带间充质干细胞更早向免疫抑制型MSC2极化,Toll样受体3表达显著增高(P < 0.05);⑤以上结果表明间接共培养体系下γ干扰素(10 μg/L)联合脂多糖(100 μg/L)是诱导人脐带间充质干细胞向MSC2极化的高效组合,并且MSC2的免疫抑制作用不依赖于细胞间的直接接触,为MSC2来源外泌体将来应用于临床研究奠定实验基础。 ORCID: 0000-0001-7335-2558(黄恬) 中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程     

Hierarchical immunogenicity of donor MHC class I peptides in allotransplantation

The recognition of major histocompatibility complex (MHC) allopeptides by recipient MHC class II-restricted CD4(+) T cells via indirect pathway is a prerequisite for the generation of an immune response to the allograft. We tested 13-mer to 24-mer peptides from the MHC class I molecule for their possible immunogenicity in a fully MHC-mismatched rat strain combination. Our results confirm the hierarchical distribution of the immunogenicity of donor MHC class I peptides in the T cell alloactivation via indirect pathway. In addition, we show that allopeptide-induced immune response is critical for acute rejection of heart allografts. Among the seven allopeptides tested, peptide P1 was identified as immunodominant; it induced the greatest T cell proliferation and cytokine production in vitro as well as a significant reduction in allograft survival time. The TCR repertoire of T cells involved in the in vitro and in vivo responses induced by the dominant allopeptide P1 was found to be limited to the Vbeta10 and Vbeta 19 gene families. The identification of dominant allopeptides should greatly facilitate characterization of the specific T cell population responsible for allograft rejection and may be used to modulate the alloimmune response through antigen-specific therapy.     

Mesenchymal Stem Cell-Mediated Immature Dendritic Cells Induce Regulatory T Cell-Based Immunosuppressive Effect

Immature dendritic cells (imDCs) are increasingly viewed as mediators of T-cell tolerance. We investigated factors enabling induction of regulatory T (Treg) cells through syngeneic imDC/mesenchymal stem cell (MSC) co-cultures in vitro and immunosuppressive effects of MSC-mediated imDCs (MSCs were excluded after 72 h co-culture) in vivo. In these experiments, we found that Foxp3⁺ Treg cell population remarkably increased after the T cell priming phase when splenocytes were co-cultured with both imDCs and MSCs, presumably inducing naïve T cells into Treg cells by MSCs and imDCs. In parallel, TGF-β secretion was markedly induced from the imDC+MSC+splenocyte culture supernatant to a significant level at 72-h co-culture, compared to the MSC or imDC+splenocyte co-culture. Based on these results, using a murine melanoma tumor model, we confirmed that the subcutaneous injection of B16 cells induced a perfect tumor incidence in allogeneic recipients when MSC-mediated DCs were coinjected. Consequently, these results suggested that immune tolerance with MSC-mediated DCs leads to immunosuppression induced by at least Foxp3-specific Treg cells. This tool may be useful in clinical trials due to the yet unknown side effects of stem cell therapy.     

Recombinant IFN-γ abrogates allograft tolerance induced by donor-specific blood transfusion by restoring alloantibody production

Donor-specific tolerance to heart allograft was induced in adult Lewis rats by pregraft donor-specific blood transfusion (DST). We previously showed that this tolerant state is characterized by a dramatic inhibition of T cell and macrophage activation. In addition, tolerant animals could not mount an efficient anti-donor humoral response whereas transfer of sera from rejecting animals triggered rejection in tolerant animals. This tolerance can be abrogated by daily post-graft administration of recombinant IFN-γ (rIFN-γ). To elucidate the mechanisms of action of rIFN-γ, T cell, macrophage and B cell functions were assessed in allograft recipients. IFN-γ did not restore the expression of Th1-related cytokine mRNA or the activated macrophage product inducible nitric oxide synthase in allografts. Importantly, rIFN-γ treatment promptly restored the anti-donor humoral response in DST-treated recipients. We conclude that rIFN-γ treatment in DST-treated allograft recipients cannot reverse the unresponsive state of Th1 cells and macrophages infiltrating the graft, but can provide B cell help for IgG alloantibody production which is lacking in these animals.     

IL-12hi Rapamycin-Conditioned Dendritic Cells Mediate IFN-γ–Dependent Apoptosis of Alloreactive CD4+ T Cells In Vitro and Reduce Lethal Graft-Versus-Host Disease

Rapamycin (RAPA) inhibits the mechanistic target of rapamycin (mTOR), a crucial immune system regulator. Dendritic cells (DC) generated in RAPA (RAPA-DC) enrich for CD4⁺ forkhead box p3 (FoxP3⁺) regulatory T cells and induce T cell apoptosis by an unknown mechanism. RAPA-DC also promote experimental allograft survival, yet paradoxically secrete increased IL-12, crucial for the generation of IFN-γ⁺ CD4⁺ T cells. However, IFN-γ is pro-apoptotic and IL-12-driven IFN-γ inhibits experimental graft-versus-host disease (GVHD). We hypothesized that IL-12^hi RAPA-DC would facilitate IFN-γ-mediated apoptosis of alloreactive T cells and, unlike control (CTR)-DC, would reduce lethal GVHD. Following LPS stimulation, RAPA-DC exhibited decreased MHCII and co-stimulatory molecules and contained a significant population of CD86^lo IL-12^hi cells. Consistent with our hypothesis, both unstimulated and LPS-stimulated RAPA-DC enhanced alloreactive CD4⁺ T cell apoptosis in culture. Augmented T cell apoptosis was ablated by IFN-γ neutralization or using T cells lacking the IFN-γ receptor, and it was associated with increased expression of Fas and cleaved caspase 8. DC production or responses to IFN-γ were not important to increased apoptotic functions of RAPA-DC. LPS-stimulated IL-12p40^−/− RAPA-DC induced lower levels of T cell apoptosis in culture, which was further decreased with addition of anti-IFN-γ. Finally, whereas CTR-DC accelerated mortality from GVHD, LPS-treated RAPA-DC significantly prolonged host survival. In conclusion, increased apoptosis of allogeneic CD4⁺ T cells induced by LPS-stimulated IL-12^hi RAPA-DC is mediated in vitro through IFN-γ and in part by increased IL-12 expression. Enhanced production of IL-12, the predominant inducer of IFN-γ by immune cells, is a probable mechanism underlying the capacity of LPS-treated RAPA-DC to reduce GVHD.     

固相MHC Ⅰ类相关抗原A刺激的NK细胞对树突状细胞活性的影响

目的:观察固相MHC I类相关抗原A(iMICA)刺激的NK细胞对树突状细胞(DCs)活性的影响。方法:首先取新鲜分离及受固相MICA刺激的异体NK细胞,或IL-2、及IL-2联合iMICA刺激的自体NK细胞与未成熟DCs(iDCs)按5∶1比例孵育24 h后,用流式细胞术(FCM)分析HLA-DR+或CD86+频率的DCs。然后取自体NK细胞以iMICA刺激后,按1∶5的比例与iDCs孵育24 h后,FCM检测DCs上HLA-DR、CD86的表达。最后在NK细胞与DCs的共培养体系中加入抗IFN-γ抗体,观察DCs上HLA-DR、CD86表达的变化。结果:当NK细胞与iDCs孵育比例为5∶1时,异体新鲜分离的与自体活化的NK细胞均能杀伤iDCs;而iMICA无协同作用。当NK细胞与iDCs孵育的比例为1∶5时,iMICA刺激的NK细胞可促进DCs表达HLA-DR和CD86;而加入抗IFN-γ抗体可抑制NK细胞诱导DCs表面HLA-DR和CD86表达的上调。结论:异体新鲜分离的或自体活化的NK细胞杀伤iDCs时,无需iMICA的刺激;但当NK细胞的数目明显低于iDCs时,iMICA可刺激NK细胞分泌IFN-γ促进DCs成熟。     

Defective lymphokine production by most CD8+ and CD4+ tumor-specific T cell clones derived from human melanoma-infiltrating lymphocytes in response to autologous tumor cells in vitro

Human melanomas are infiltrated by tumor-reactive T lymphocytes. However, the ability of these cells to elicit a specific anti-tumor response in vivo remains to be established. Because lymphokine production is critical for T cell functions, we have analyzed the capacity of melanoma-specific tumor-infiltrating lymphocyte (TIL) clones to produce major lymphokines: interleukin-2 (IL-2), interferon-γ (IFN-γ) and interleukin-4 (IL-4), as well as tumor necrosis factor (TNF), in response to direct antigen presentation by autologous and allogeneic tumor cells. We report here that, upon stimulation by autologous melanoma cells, all TIL clones secreted TNF but only a few of them produced significant amounts of IL-2, IL-4 or IFN-γ. Nonetheless, all these clones consistently produced two or three of these last lymphokines upon stimulation with phorbol myristate acetate and calcium ionophore, as well as IL-2 upon CD3 stimulation, showing the existence of three lymphokine profiles among them: Th1, Th0 and a profile characterized by IL-2 and IL-4, but not IFN-γ secretion. Stimulation of TIL clones by allogeneic melanoma lines sharing the appropriate HLA-peptide complexes revealed that defective IL-2 production seemed to be a constant feature for some clones, while it was, for other clones, dependent on the antigen-presenting tumor cells. For this last type of clone, we further showed that defective IL-2 induction resulted from an LFA-3 defect of some melanoma cells or from distinct yet undefined defects of other melanoma lines. Our data suggest that defective lymphokine secretion may be an essential component of the in vivo failure of melanoma-reactive TIL to control tumor development. Interestingly both CD4⁺ and CD8⁺ TIL clones from one patient were fully activated by the autologous melanoma cells in vitro, supporting a potential role of such TIL in spontaneous or induced tumor rejection.     

Immune modulation and safety profile of adoptive immunotherapy using expanded autologous activated lymphocytes against advanced cancer

Expanded activated autologous lymphocyte (EAAL) therapy with CD3(+)CD8(+) cytotoxic T lymphocyte and CD3(-)56(+) natural killer cell as the major effector cells is a type of adoptive cell therapy. In this study, 19 patients with metastatic tumors received EAAL therapy. Two to four weeks after the administration of EAAL cells, the subsets of CD3(+)CD8(+) T lymphocytes and CD3(-)CD56(+) natural killer cells in the peripheral blood were increased significantly in comparison with those before the therapy. The number of IFN-γ secreting cells also significantly increased after the EAAL infusion (p=0.002) and the p values for the counts of CD3(+)IFN-γ(+) lymphocytes and CD3(-)IFN-γ(+) lymphocytes were 0.006 and 0.015, respectively. Moreover, the percentage of IFN-γ producing cells of the CD3(+), CD8(+) and CD3(-) subsets after infusion were all increased significantly, which indicated that EAAL therapy was able to enrich the potentially anti-tumor cytotoxic peripheral blood lymphocytes.     

Alloreactivity but Failure to Reject Human Islet Transplants by Humanized Balb/c/Rag2−/−gc−/− Mice

A human islet transplant can cure patients with type 1 diabetes. A drawback of islet transplantation is the life‐long immunosuppressive medication, often associated with severe side effects. Moreover, in spite of the immunosuppressive therapy, islets are lost in the majority of transplanted patients over time. An improved small animal model for studies on human islet allograft rejection mechanisms and the development of new measures for its prevention is clearly warranted. Here, we evaluated the potential of Balb/cRag2^?/?γc^?/? mice carrying a human‐like immune system (so‐called humanized mice) as a tool for studies on the rejection of transplanted human islets. Human T cells from Balb/cRag2^?/?γc^?/? mice, which as neonates had been transplanted with CD34⁺ human cord blood haematopoietic stem cells (HIS mice), proliferated in response to allogeneic human dendritic cells, but failed to reject a human islet allograft transplanted to the renal subcapsular space as assessed by immunohistochemistry and analysis of human serum C‐peptide levels. Histological analysis revealed that few if any T cells had migrated to the grafted tissue. These observations question the usefulness of the HIS mouse model for studies on human islet allograft rejection mechanisms and highlight the need for further improvements.     

Dysfunction of Mesenchymal Stem Cells Isolated from Metabolic Syndrome and Type 2 Diabetic Patients as Result of Oxidative Stress and Autophagy may Limit Their Potential Therapeutic Use

Mesenchymal stem cells (MSC) have become a promising tool for therapeutic intervention. Their unique features, including self-renewal, multipotency and immunomodulatory properties draw the worldwide attention of researchers and physicians with respect to their application in disease treatment. However, the environment (so-called niche) from which MSCs are isolated may determine their usefulness. Many studies indicated the involvement of MSCs in ageing and disease. In this review, we have focused on how type 2 diabetes (T2D) and metabolic syndrome (MS) affect MSC properties, and thus limit their therapeutic potential. Herein, we mainly focus on apoptosis, autophagy and mitochondria deterioration processes that indirectly affect MSC fate. Based on the data presented, special attention should be paid when considering autologous MSC therapy in T2D or MS treatments, as their therapeutic potential may be restricted.     

Mesenchymal stromal cells for tolerance induction in organ transplantation

The primary challenge in organ transplantation continues to be the need to suppress the host immune system long-term to ensure prolonged allograft survival. Long-term non-specific immunosuppression can, however, result in life-threatening complications. Thus, efforts have been pursued to explore novel strategies that would allow minimization of maintenance immunosuppression, eventually leading to transplant tolerance. In this scenario, bone marrow-derived mesenchymal stromal cells (MSC), given their unique immunomodulatory properties to skew the balance between regulatory and memory T cells, have emerged as potential candidates for cell-based therapy to promote immune tolerance. Here, we review our initial clinical experience with bone marrow-derived MSC in living-donor kidney transplant recipients and provide an overview of the available results of other clinical programs with MSC in kidney and liver transplantation, highlighting hurdles and success of this innovative cell-based therapy.     

Mesenchymal stem cells might be used to induce tolerance in heart transplantation

Heart transplantation is the last treatment selection for end-stage heart diseases, but the side-effects of immunosuppressive agents and morbidity brought by lifelong immunosuppression still remains unavoidable. Mesenchymal stem cell (MSC) is one kind of adult pluripotent cell that not only can differentiate into cardiomyocytes but also maintain some unique immunomodulatory function. There were reports that MSCs could both in vitro and in vivo suppress alloreactive CD4(+) T cell which is mainly responsible for chronic rejection that leads to progressive graft vascular stenosis. We based our hypothesis on that MSC could escape recognition of alloreactive cells and would interact with important immune cells such as T cells, dendritic cells after cardiac transplantation to induce a cytokine profile shift in the Th1/Th2 balance toward the anti-inflammatory phenotype Th2. And then tolerance may be induced. Also it is conceivable that MSCs may differentiate toward cardiomyocyte in the specific microenvironment. Further work are necessary to verify if MSCs can protect heart graft from chronic rejection and its potential to be used as substitutes for classic immunosuppressants.