Mesenchymal stem cells transfected with sFgl2 inhibit the acute rejection of heart transplantation in mice by regulating macrophage activation

Abstract

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.

Mesenchymal Stem Cell-Macrophage Crosstalk and Maintenance of Inflammatory Microenvironment Homeostasis

“…Previous studies indicated that IL-1β derived from macrophages may stimulate MSCs to secrete IL-1RA and PGE2, which leads to the polarization of Ohara et al, 2018;Kojima et al, 2019;Luo et al, 2019;Song et al, 2020 Ischemia/Reperfusion (IR)-induced sterile inflammatory liver injury MSC reprogram macrophage toward anti-inflammatory M2 phenotype Reduced hepatocellular damage; Diminished liver inflammation Li C. et al, 2019;Sheng et al, 2021 Acute liver failure MSC induced anti-inflammatory (M2) macrophages; reduced levels of macrophage Ameliorated hepatocyte death and liver inflammatory response. Li et al, 2017Li et al, , 2021Liu et al, 2018;Hwang et al, 2019;Liang et al, 2019;Shao et al, 2020;Wang et al, 2021 Ben-Mordechai et al, 2013;Xu et al, 2019;Gao et al, 2020;Liao et al, 2020 Atherosclerosis Stimulate the production of anti-inflammatory factor IL-10, and reduce the production of TNF-α by macrophage.…”

Preconditioned Mesenchymal Stromal Cells to Improve Allotransplantation Outcome

“…M2 polarization was maintained in the spleen along with elevation of Tregs. In serum, decreased IFN-γ, TNF-α, IL-1β, IL-6, and IL-12 levels and increased IL-4, IL-10, and TGF-β1 levels were observed in sFgl2-AD-MSCs-treated recipients on POD 7 and 14 [ 68 ].…”

Immunomodulatory effects of mesenchymal stem cells for the treatment of cardiac allograft rejection

“…Gao et al demonstrated the ability of MSC on macrophage polarization in vivo on a mouse heart transplantation model. 51 They suggested genemodified MSC, such as soluble fibronectin-like protein 2 (sFgl2) overexpressing MSCs, therapy had a better benefit than wild type MSCs. This is of great importance, highlighting the potential of enhancing the MSC derived therapeutic response through further genetic modifications.…”