Abstract
Cardiac cell therapy has the potential to revolutionize treatment of heart diseases, but its success hinders on the development of a stem cell therapy capable of efficiently producing functionally differentiated cardiomyocytes. A key to unlocking the therapeutic application of stem cells lies in understanding the molecular mechanisms that govern the differentiation process. Here we report that a population of platelet-derived growth factor receptor alpha (PDGFRA) cells derived from mouse multipotent germline stem cells (mGSCs) were capable of undergoing cardiomyogenesis in vitro. Cells derived in vitro from PDGFRA positive mGSCs express significantly higher levels of cardiac marker proteins compared to PDGFRA negative mGSCs. Using Pdgfra shRNAs to investigate the dependence of Pdgfra on cardiomyocyte differentiation, we observed that Pdgfra silencing inhibited cardiac differentiation. In a rat myocardial infarction (MI) model, transplantation of a PDGFRAenriched cell population into the rat heart readily underwent functional differentiation into cardiomyocytes and reduced areas of fibrosis associated with MI injury. Together, these results suggest that mGSCs may provide a unique source of cardiac stem/progenitor cells for future regenerative therapy of damaged heart tissue.
Highlights
Current therapeutic approaches for end-stage heart failure are limited to pharmacological therapies, mechanical ventricular assist devices (VAD), and cardiac transplantation
We report that a population of plateletderived growth factor receptor alpha (PDGFRA) cells derived from mouse multipotent germline stem cells were capable of undergoing cardiomyogenesis in vitro
Using the ligand BMP4, we demonstrate that cardiomyocytes can be efficiently generated by expanding a PDGFRA expressing cell population derived from mouse multipotent germline stem cells (mGSCs)
Summary
Current therapeutic approaches for end-stage heart failure are limited to pharmacological therapies, mechanical ventricular assist devices (VAD), and cardiac transplantation. Stem cell-based therapies offer a novel approach to overcome these limitations by replacing damaged or lost myocardial tissues and restore cardiac functions. Several candidate cell types used in preclinical animal models and humans studies include, embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), neonatal cardiomyocytes, skeletal myoblasts (SKMs), endothelial progenitor cells (EPCs), and mesenchymal stem cells (MSCs) [1,2,3,4]. Among potential candidate markers for cardiac progenitors is platelet-derived growth factor receptor-alpha (Pdgfra); a cell-surface protein expressed on cardiac progenitor cells [5, 6]. Differentiation of mouse ESCs into cardiomyocyte reveals that this subpopulation co-expresses PDGFRA and another marker FLK1 [7]
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