Embryonic Stem Cells Overexpressing Pitx2c Engraft in Infarcted Myocardium and Improve Cardiac Function

摘要

This study investigated the effects on cardiomyocyte differentiation of embryonic stem cells by the overexpression of the transcription factor, Pitx2c, and examined the effects of transplantation of these differentiated cells on cardiac function in a mouse model of myocardial infarction. Pitx2c overexpressing embryonic stem cells were characterized for cardiac differentiation by immunocytochemistry, RNA analysis, and electrophysiology. Differentiated cells were transplanted by directed injection into the infarcted murine myocardium and functional measurements of blood pressure, contractility, and relaxation were performed. Histochemistry and FISH analysis performed on these mice confirmed the engraftment and cardiac nature of the transplanted cells. Pitx2c overexpressing embryonic stem cells robustly differentiated into spontaneously contracting cells which acquired cardiac protein markers and exhibited action potentials resembling that of cardiomyocytes. These cells could also be synchronized to an external pacemaker. Significant improvements ( P < 0.01) in blood pressure (56%), contractility (57%), and relaxation (59%) were observed in infarcted mice with transplants of these differentiated cells but not in mice which were transplanted with control cells. The Pitx2c overexpressing cells secrete paracrine factors which when adsorbed onto a heparinated gel and injected into the infarcted myocardium produce a comparable and significant ( P < 0.01) functional recovery. Pitx2c overexpression is a valuable method for producing cardiomyocytes from embryonic stem cells, and transplantation of these cardiomyocytes into infracted myocardium restores cardiac function through multiple mechanisms.