Cellular Biology Induction of Vascular Progenitor Cells From Endothelial Cells Stimulates Coronary Collateral Growth

Rationale: A well-developed coronary collateral circulation improves the morbidity and mortality of patients following an acute coronary occlusion. Although regenerative medicine has great potential in stimulating vascular growth in the heart, to date there have been mixed results, and the ideal cell type for this therapy has not been resolved. Objective: To generate induced vascular progenitor cells (iVPCs) from endothelial cells, which can differentiate into vascular smooth muscle cells (VSMCs) or endothelial cells (ECs), and test their capability to stimulate coronary collateral growth. A population of reprogrammed cells was derived that expressed pluripotent markers Oct4, SSEA-1, Rex1, and AP and hemangioblast markers CD133, Flk1, and c-kit. These cells were designated iVPCs because they remained committed to vascular lineage and could differentiate into vascular ECs and VSMCs in vitro. The iVPCs demonstrated better in vitro angiogenic potential (tube network on 2-dimensional culture, tube formation in growth factor reduced Matrigel) than native ECs. The risk of teratoma formation in iVPCs is also reduced in comparison with fully reprogrammed induced pluripotent stem cells (iPSCs). When iVPCs were implanted into myocardium, they engrafted into blood vessels and increased coronary collateral flow (microspheres) and improved cardiac function (echocardiography) better than iPSCs, mesenchymal stem cells, native ECs, and sham treatments. Conclusions: We conclude that iVPCs, generated by partially reprogramming ECs, are an ideal cell type for cell-based therapy designed to stimulate coronary collateral growth. Key Words: vascular progenitor cells Ⅲ coronary collateral growth Ⅲ coronary circulation Ⅲ induced pluripotent cells C oronary heart disease (CHD) is the leading cause of mortality and morbidity in the United States. Although there have been numerous advances in the treatment of CHD over the last many years (drug eluting stents, statins), the realization of therapeutic angiogenesis for stimulation of coronary collateral growth remains an elusive goal. Cell-based therapies for cardiovascular diseases offer a new paradigm for treatment of CHD. The outcomes of cell-based therapies in the improvement of left ventricular function and reduction of myocardial ischemia are controversial. 1–5 The challenge of growing new myocardium is enormous, involving essentials such as cardiomyocytes, conductive tissue, and a complete circulation. However, the challenge of stimulating coronary collateral growth is far less involved, and is a strategy more likely to produce an immediate benefit in the treatment of ischemic heart disease. 6,7 " Ideal " stem/iPS/ progenitor cell population for optimal coronary collateral growth (also termed arteriogenesis and collaterogenesis) in ischemic myocardium has …