Stromal Cell-Derived Factor-1 Mediates Cardiac Allograft Tolerance Induced by Human Endometrial Regenerative Cell-Based Therapy

Abstract

Endometrial regenerative cells (ERCs) are mesenchymal-like stromal cells, and their therapeutic potential has been tested in the prevention of renal ischemic reperfusion injury, acute liver injury, ulcerative colitis, and immunosuppression. However, their potential in the induction of transplant tolerance has not been investigated. The present study was undertaken to investigate the efficacy of ERCs in inducing cardiac allograft tolerance and the function of stromal cell-derived factor-1 (SDF-1) in the ERC-mediated immunoregulation. The inhibitory efficacy of human ERCs in the presence or absence of rapamycin was examined in both mouse cardiac allograft models between BALB/c (H-2 d ) donors and C57BL/6 (H-2 b ) recipients and in vitro cocultured splenocytes. AMD3100 was used to inhibit the function of SDF-1. Intragraft antibody (IgG and IgM) deposition and immune cell (CD4 1 and CD8 1 ) infiltration were measured by immunohistochemical staining, and splenocyte phenotypes were determined by fluorescence-activated cell sorting analysis. The results showed that ERC-based therapy induced donor-specific allograft tolerance, and functionally inhibiting SDF-1 resulted in severe allograft rejection. The negative effects of inhibiting SDF-1 on allograft survival were correlated with increased levels of intragraft antibodies and infiltrating immune cells, and also with reduced levels of regulatory immune cells including MHC class II low CD86 low CD40 lowdendritic cells, CD68 1 CD206 1 macrophages, CD4 1 CD25 1 Foxp3 1 T cells, and CD1d high CD5 high CD83 low IL-10 high B cells both in vivo and in vitro. These data showed that human ERC-based therapy induces cardiac allograft tolerance in mice, which is associated with SDF-1 activity, suggesting that SDF-1 mediates the immunosuppression of ERC-based therapy for the induction of transplant tolerance. STEM CELLS TRANSLATIONAL MEDICINE 2017;6:1997 SIGNIFICANCE STATEMENTEndometrial regenerative cells (ERCs) are newly identified stromal cells with advantages of noninvasively obtained method, abundant resources, highly proliferative rate, immunoregulatory function, and absence of tumorigenesis. Stromal cell-derived factor-1 (SDF-1) is involved in many different physiological and pathological processes. This study demonstrates that human ERC-based therapy can effectively suppress immune response and further induce allograft tolerance in a mouse cardiac transplantation model, and SDF-1 secreted by ERCs plays an essential role in ERC-mediated graft protection. Simultaneously, as xenograft, human ERCs are proven to be safe and effective in mice, which hold significant promise for therapeutic use in future clinical transplantation.

Stromal Cell-Derived Factor-1 Enhances the Therapeutic Effects of Human Endometrial Regenerative Cells in a Mouse Sepsis Model

“…Furthermore, ERCs do not express MHC class I molecules and only express low levels of MHC class II molecules [10], which enables ERCs with low immunogenicity to function smoothly in mice without rejection. Our research group has validated the therapeutic effects of ERCs in a variety of experimental disease models, such as promoting immune tolerance in cardiac allograft [11], relieving ulcerative colitis injury [12], alleviating acute liver injury [13], mitigating pulmonary fibrosis [14], and lightening renal ischemia-reperfusion injury [15]. However, up to now, we and other groups have not found and reported any case of ERCs rejected by mice.…”

“…In addition, CXCR4 is highly conserved during evolution [17]. The conservation of SDF-1/CXCR4 in different species can ensure that human endometrial regenerative cells can function properly in mice [11]. Furthermore, studies have shown that AMD3100, a potent antagonist of CXCR4 receptor, can effectively block the function of SDF-1/CXCR4 signaling pathway [18].…”

“…SDF-1/CXCR4 signaling pathway plays an important role in mediating cells chemotaxis and metastasis [19], inducing angiogenesis [20], and promoting immunoregulation [21]. Studies have shown that ERCs can also secrete high levels of SDF-1, which is 9824 ± 1700 pg/ml in culture supernatant measured by ELISA [11]. Meanwhile, it has been demonstrated that ERCs with high SDF-1 secretion play a positive role in promoting immune tolerance in cardiac allograft [11].…”

The Role of Macrophages in Oocyte Donation Pregnancy: A Systematic Review

“…The relation of SDF1α to macrophages is described in other research [78]. A renal study in mice showed that the timing in upregulation and the location of infiltration of macrophages is similar to those of SDF1α, suggesting there might be an interaction between macrophages and SDF1α [79].…”

Downregulation of Dickkopf-1 Augments the Therapeutic Effects of Endometrial Regenerative Cells on Experimental Colitis

“…ERCs possess the similar phenotypic markers with MSCs (high expression of CD29, CD44 and CD90 molecules, but low of CD45), but surmount the limits of traditional MSCs. Compared with MSCs, ERCs were with more outstanding advantages, including diverse differentiation potentials, immunomodulatory properties, non-invasive obtaining process and high proliferative capacity without karyotypic abnormality [18]. We and others have previously reported the forcible therapeutic effects of ERC for immune-related diseases such as ulcerative colitis, acute liver injury, critical limb ischemia, renal ischemia reperfusion injury, pulmonary brosis, myocardial infarction, and so on [19][20][21][22][23][24].…”