Background: Mesenchymal stem cells (MSCs) have become a promising candidate for cell-based immune therapy for acute rejection (AR) after heart transplantation due to possessing immunomodulatory properties. In this study, we evaluated the efficacy of soluble fibronectin-like protein 2 (sFgl2) overexpressing mesenchymal stem cells (sFgl2-MSCs) in inhibiting AR of heart transplantation in mice by regulating immune tolerance through inducing M2 phenotype macrophage polarization.
Methods and results: The sFgl2, a novel immunomodulatory factor secreted by regulatory T cells, was transfected into MSCs to enhance their immunosuppressive functions. After being co-cultured for 72 h, the sFgl2-MSCs inhibited M1 polarization whereas promoted M2 of polarization macrophages through STAT1 and NF-κB pathways in vitro. Besides, the sFgl2-MSCs significantly enhanced the migration and phagocytosis ability of macrophages stimulated with interferon-γ (IFN-γ) and lipopolysaccharide (LPS). Further, the application potential of sFgl2-MSCs in AR treatment was demonstrated by heterotopic cardiac transplantation in mice. The tissue damage and macrophage infiltration were evaluated by H&E and immunohistochemistry staining, and the secretion of inflammatory cytokines was analyzed by ELISA. The results showed that sFgl2-MSCs injected intravenously were able to locate in the graft, promote the M2 polarization of macrophages in vivo, regulate the local and systemic immune response, significantly protect tissues from damaging, and finally prolonged the survival time of mice heart grafts.
Conclusion: sFgl2-MSCs ameliorate AR of heart transplantation by regulating macrophages, which provides a new idea for the development of anti-AR treatment methods after heart transplantation.
Keywords: Acute rejection; Heart transplantation; MSC-based therapy; Macrophage; Soluble fibrinogen-like protein 2.