Reprogrammed endothelial cells: cell therapy for coronary collateral growth?

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 of Circulation Research, Yin et al21 utilized a different strategy for cell reprogramming aimed at stimulating growth of vascular tissue. These investigators used the same four transcription factors originally described by Yamanaka and et al,14 but forced their expression in early passage rat aorta endothelial cells (ECs) using a tetracyclineinducible system. Possibly because of the induction system or characteristics of cultured ECs (as opposed to fibroblasts) that prevent the former from being reprogrammed to full pluripotency, the reprogrammed ECs had a phenotype more consistent with a vascular progenitor cell.21 For example, these induced vascular progenitor cells (iVPCs) expressed in vitro both pluripotent markers (eg, Oct4, SSEA-1, Rex1, AP) and hemangioblast markers (eg, CD133, Flk1, c-kit). They also had a unique DNA methylation pattern, compared to iPSCs, causing the authors to suggest that they retain some “epigenetic memory” of their EC lineage. Furthermore, they do not form teratomas or embryoid bodies, can differentiate into ECs and smooth muscle cells but not myocardial cells, and have greater angiogenic potential than ECs.21 When Yin et al injected these iVPCs into the myocardium in a rat model of chronic repetitive ischemia-reperfusion, collateral-dependent blood flow and recovery of pump function were significantly improved compared to iPSCs and pluripotent cells derived from fibroblasts, bone marrow-derived mesenchymal stem cells, or native ECs (Figure). Moreover, in contrast to iPSCs, no teratomas were evident even 3 months after implantation. These exciting findings are a major conceptual advance that could ultimately lead to an effective cell therapy for revascularization in obstructive disease.