Transplanted allogeneic cardiac progenitor cells secrete GDF-15 and stimulate an active immune remodeling process in the ischemic myocardium

Abstract

Background Despite promising results in clinical studies, the mechanism for the beneficial effects of allogenic cell-based therapies remains unclear. Macrophages are not only critical mediators of inflammation but also critical players in cardiac remodeling. We hypothesized that transplanted allogenic rat cardiac progenitor cells (rCPCs) augment T-regulatory cells which ultimately promote proliferation of M2 like macrophages by an as-yet undefined mechanism. Methods and results To test this hypothesis, we used crossover rat strains for exploring the mechanism of myocardial repair by allogenic CPCs. Human CPCs (hCPCs) were isolated from adult patients undergoing coronary artery bypass grafting, and rat CPCs (rCPCs) were isolated from male Wistar-Kyoto (WKY) rat hearts. Allogenic rCPCs suppressed the proliferation of T-cells observed in mixed lymphocyte reactions in vitro. Transplanted syngeneic or allogeneic rCPCs significantly increased cardiac function in a rat myocardial infarct (MI) model, whereas xenogeneic CPCs did not. Allogeneic rCPCs stimulated immunomodulatory responses by specifically increasing T-regulatory cells and M2 polarization, while maintaining their cardiac recovery potential and safety profile. Mechanistically, we confirmed the inactivation of NF-kB in Treg cells and increased M2 macrophages in the myocardium after MI by transplanted CPCs derived GDF15 and it’s uptake by CD48 receptor on immune cells. Conclusion Collectively, these findings strongly support the active immunomodulatory properties and robust therapeutic potential of allogenic CPCs in post-MI cardiac dysfunction.

Identification of a distinct cluster of GDF15highmacrophages exhibiting anti-inflammatory activities

“…In Kupffer cells, Li et al have demonstrated that GDF15 treatment attenuated LPS- induced expressions of inflammatory cytokines and inducible nitric oxide synthase 38 . Interestingly, GDF15, being a paracrine anti-inflammatory factor, has also been observed in rat cardiac progenitor cells, of which allogeneic transplantation in the myocardium represses T cell-mediated inflammation and promotes M2 macrophage polarization 20 . In addition, GDF-15 was also shown to inhibit the recruitment of polymorphonuclear cells following ischemic tissue injuries 19 .…”

“…non-alcoholic fatty liver disease and type 2 diabetes mellitus) 16 17 and cardiovascular diseases (e.g. myocardial infarction and atherosclerosis) [18][19][20] . Traditionally, monocytederived macrophages are classified into M1 (pro-inflammatory) and M2 (anti-inflammatory and regenerative) phenotypes.…”

“…Traditionally, monocyte-derived macrophages are classified into M1 (pro-inflammatory) and M2 (anti-inflammatory and regenerative) phenotypes. It has been observed that GDF15 may facilitate the differentiation of macrophages toward the anti-inflammatory M2 phenotype 20,21 . In previous studies, researchers identified some macrophage cells in human lung tissues from both healthy subjects and patients with PAH, which exhibited a high level of GDF15 expression 22,23 .…”

Identification of a distinct cluster of GDF15high macrophages induced by in vitro differentiation exhibiting anti-inflammatory activities

“…non-alcoholic fatty liver disease and type 2 diabetes mellitus) ( 16 ) ( 17 ) and cardiovascular diseases ( e.g. myocardial infarction and atherosclerosis) ( 18 – 20 ). Traditionally, monocyte-derived macrophages are classified into M1 (pro-inflammatory) and M2 (anti-inflammatory and regenerative) phenotypes.…”

Correction: Transplanted allogeneic cardiac progenitor cells secrete GDF-15 and stimulate an active immune remodeling process in the ischemic myocardium

“…Following publication of the original article [1], we have been notified that one of the authors' names was spelled incorrectly. It should be as follows: First name-Xuebin, last name-Fu.…”