Human Endometrial Stem Cells Confer Enhanced Myocardial Salvage And Regeneration By Paracrine Mechanisms In A Rodent Infarct Model

Background and objective: Myocardial infarction (MI) is a major cause of mortality and morbidity worldwide. Stem cell therapy holds great promise for myocardial regeneration. Autologous and allogeneic mesenchymal stem cells (MSCs) have been tested clinically, and most of the trials to date have reported safety and modest efficacy. Investigators proposed that the generation of "off the shelf" allogeneic stem cell products with selected potent may overcome limitations of autologous cells and improve the clinical outcome of stem cell therapy. Endometrial stem cells (EnSCs) with MSC characteristics are isolated from menstrual blood. A unique feature of these cells is that they can be easily obtained by noninvasive procedures from young and healthy women donors. The MSC characteristics also guarantee their immunoprevilege in allogeneic hosts. Therefore, EnSC is an ideal cell type to generate "off the shelf" cell products, but the efficacy and the mechanism of EnSCs transplantation are still unclear. Here, using an immunocompetent rat model of MI, we provide evidence that the functional benefits of EnSC transplantation is principally and possibly exclusively through paracrine effect.Methods and Results:Human EnSCs were delivered by intramyocardial injection into rats30min after coronary ligation. EnSC therapy significantly preserved viable myocardium in the infarct zone and improved cardiac function at28days. Despite increased viable myocardium and vascular density, there was scant evidence of differentiation of EnSCs into any cardiovascular cell type. Cultured human EnSCs expressed a distinctive profile of cytokines that enhanced cell survival, proliferation and function of endothelial cells in vitro. When injected into the peri-infarct zone, human EnSCs activated AKT and STAT3but inhibited p38signal pathways. EnSC therapy decreased apoptosis and promoted cell proliferation and stem cell recruitment in vivo. This is the first study to describe EnSC therapy in an immunocompetent heart, the first comparative study of cytokine production, and the first demonstration of cardioprotection by cytokine-mediated activation of survival kinases.Conclusions:Myocardial protection and enhanced post-infarction regeneration by EnSCs is mediated primarily by paracrine effects conferred by secreted cytokines that activate survival pathways and recruit endogenous progenitor stem cells. Menstrual blood provides a potentially limitless source of biologically competent "off the shelf" EnSCs for allogeneic myocardial regenerative medicine.