Reprogrammed Endothelial Cells

Abstract

See related article, pages 241–252 Myocardial infarction, ischemic stroke, and atherosclerosis of arteries supplying the heart, brain, and lower extremities are leading causes of morbidity and mortality. The abundance of native preexisting collateral vessels in tissues, and their anatomic lumen enlargement induced by arterial obstruction (remodeling or arteriogenesis) are major determinants of the severity of ischemic tissue injury caused by these diseases. Unfortunately, findings in animal studies showing that both of these determinants vary significantly among individuals because of differences in genetic background and environmental factors (eg, cardiovascular risk factors) are beginning to find corroboration in humans.1–6 Although efforts to increase collateral growth in ischemia using small molecules, proteins, and gene therapy have shown some effectiveness in experimental animals, patient trials for therapeutic angiogenesis have been largely disappointing.7–9 Recent preclinical studies suggesting that cell-based therapies may provide a transformative approach to augment vascular growth have generated considerable excitement and have led to initial clinical trials.10–12 A key unanswered question concerns the best cell type to use.12 Since the discovery that four transcription factors, Klf-4, Sox2, Oct4, and c-Myc, could reprogram somatic cells to become induced pluripotent stem cells (iPSCs) capable of differentiating into any cell type of the body,13–15 investigation of cell reprogramming for tissue regeneration has moved forward rapidly.15–19 Although iPSCs offers great promise, their capability to form tumors presents a significant hurdle.15,20 Thus, in a sense, the greatest potential strength of iPSCs for regenerative therapies—their pluripotency—is also their greatest weakness. In this issue …