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⁺ and CD8⁺ ) 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^low dendritic cells, CD68⁺ CD206⁺ macrophages, CD4⁺ CD25⁺ Foxp3⁺ 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;6:1997-2008.

Keywords: Allograft tolerance; Cardiac transplantation; Human endometrial regenerative cells; Mice; Stromal cell-derived factor-1.