Background and Aims : Endothelial cells (ECs) have a crucial role in reendothelialization for repairing denuded arteries. Heme oxygenase-1 (HO-1) is a stress response protein that degrades prooxidant heme and generates molecules with antioxidative and anti-inflammatory properties. Given that redox status is critical in stem cell differentiation, our aims are to investigate the effects of HO-1 induction on human pluripotent stem cells (hPSCs) differentiation toward ECs and reendothelialization after arterial injury. Methods: We utilized a three-step protocol to differentiate hPSCs (hESCs and hiPSCs) into ECs. Cells were treated with or without hemin at different stages to induce HO-1 expression; EC characteristics and proliferative capacity were then evaluated. To examine the effect of HO-1 induction on arterial repair, we employed a mouse guide wire injury model to denude arterial endothelium. Following injury, biocompatible thermoresponsive gel embedded with vehicle or hemin was then applied around the injured artery. The arteries were harvested at different time points. Results: Compared with vehicle, hemin increased cell number of hPSCsdifferentiated ECs, concomitant with enhanced HO-1 level, expression of EC-related genes, and tube formation capacity. In vivo, hemin application increased HO-1-positive cells on the luminal surface one week after arterial denudation. Two weeks after injury, hemin-treated arteries had more CD31-positive area on the luminal surface and decreased neointima size in comparison with vehicle-treated arteries. Conclusions: Collectively, our results indicate that HO-1 induction by hemin promotes EC differentiation from hPSCs and reduces intimal hyperplasia after vascular injury, likely through enhanced reendothelization. HO-1 induction might be a therapeutic strategy following vascular injury.
