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Background Macrophages may be important in chronic rejection after organ transplantation. This study aimed to investigate the possibility of depleting macrophages for a certain amount of time to alleviate chronic rejection in a heart transplant model of Fischer to Lewis rats. Methods Clodronate liposome was injected abdominally to deplete macrophages for 2 time frames. The expression levels of ectodysplasin 1, arginase 1 (Arg1), chitinase-like lectin (Ym1), interferon gamma, tumor necrosis factor α (TNF-α), smooth muscle α-actin (α-SMA), monocyte chemoattractant protein 1 (MCP-1), and interleukin 10 (IL-10) were detected. Results 1. The expression levels of α-SMA, interferon gamma, TNF-α, and MCP-1 and the transformation of peripheral T cells were lower after macrophage depletion for 2 or 4 weeks. 2. The expression levels of α-SMA, TNF-α, and MCP-1 and the transformation of peripheral T cells were even lower after 4 weeks compared with 2 weeks, except for interferon gamma. 3. A higher level of expression of Arg1 and Ym1 after macrophage depletion for 2 weeks was observed. 4. A higher level of expression of IL-10 after macrophage depletion for 2 weeks, but not 4 weeks, was also observed. Conclusions Macrophage clearance after heart transplantation alleviated chronic rejection probably via M2 polarization of regenerated macrophages, reduced T-lymphocyte proliferation, and changed the expression levels of interferon gamma, TNF-α, MCP-1, and IL-10.

Lymphohematopoietic stem cells (L-HSCs) generated from self-somatic cell-derived induced pluripotent stem cells (iPSCs) are a potential source of cells for the treatment of hematological disorders. However, the generation of truly functional L-HSCs from iPSCs has yet to be achieved. Thus, whether iPSCs have the inherent potential to generate a normal differentiated phenotype and functional population of multiple lineages of terminally differentiated lymphocytes needs to be assessed. Here, we used tetraploid embryo complementation to provide a normal environment for the differentiation of hematopoietic cells from iPSCs and embryonic stem cells (ESCs). We then evaluated the characteristics, populations, and functions of lymphocytes derived from iPSCs, ESCs, and naive isogenic C57BL/6 mice. The results showed that iPSC-derived lymphocytes (iPSLs) expressed normal levels of major histocompatibility complex-I (MHC-I) and exhibited a fully pluripotent capacity to differentiate into CD4(+) T, CD8(+) T, regulatory T, B, and natural killer cells. Following in vitro stimulation with either concanavalin A or an alloantigen, iPSLs exhibited the same capacities for proliferation and cytokine secretion as ESC-derived or isogenic lymphocytes. Furthermore, iPSC-derived bone marrow cells could differentiate into multiple lymphocyte lineages that reconstituted the lymphocyte population in syngeneic lethally irradiated recipient animals. Our results demonstrated that iPSCs have the inherent potential to differentiate into multiple lineages of functional lymphocytes without bias, and further support the practical application of iPSC-based treatments to hematological disorders.

Mesenchymal stem cell (MSC) differentiation is dramatically reduced after long-term in vitro culture, which limits their application. MSCs derived from induced pluripotent stem cells (iPSCs-MSCs) represent a novel source of MSCs. In this study, we investigated the therapeutic effect of iPSC-MSCs on diabetic mice. Streptozocin-induced diabetic mice transplanted with 400 islets alone or with 1×10(6) iPSC-MSCs were examined following rapamycin injection (0.1 mg/kg/day, i.p., from days 0 to 9) after transplantation. Our results showed that iPSC-MSCs combined with rapamycin significantly prolonged islet allograft survival in the diabetic mice; 50% of recipients exhibited long-term survival (100 days). Histopathological analysis revealed that iPSC-MSCs combined with rapamycin preserved the graft effectively, inhibited inflammatory cell infiltration, and resulted in substantial release of insulin. Flow cytometry results showed that the proportion of CD4(+) and CD8(+) T cells was significantly reduced, and the number of T regulatory cells increased in the spleen and lymph nodes in the iPSC-MSCs combined with the rapamycin group compared with the rapamycin-alone group. Production of the Th1 proinflammatory cytokines interleukin-2 (IL-2) and interferon-γ was reduced, and secretion of the anti-inflammatory cytokines IL-10 and transforming growth factor-β was enhanced compared with the rapamycin group, as determined using enzyme-linked immunosorbent assays. Transwell separation significantly weakened the immunosuppressive effects of iPSC-MSCs on the proliferation of Con A-treated splenic T cells, which indicated that the combined treatment exerted immunosuppressive effects through cell-cell contact and regulation of cytokine production. Taken together, these findings highlight the potential application of iPSC-MSCs in islet transplantation.