Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration

TLDR

Cardiac regeneration with hiPSCs requires exploration of cell preparation, tissue engineering, and transplantation strategies. The study reports a new protocol to simultaneously induce cardiomyocytes and vascular cells and generate hiPSC‑engineered cardiovascular cell sheets for therapeutic use in infarcted hearts. The protocol extends a cardiomyocyte differentiation scheme by adding stage‑specific vascular endothelial growth factor to induce vascular cells. The hiPSC‑engineered cardiac tissue sheets integrated physically, improved cardiac function in rat infarcted hearts, and retained over 40 % cardiomyocytes after four weeks, indicating therapeutic promise.

Abstract

To realize cardiac regeneration using human induced pluripotent stem cells (hiPSCs), strategies for cell preparation, tissue engineering and transplantation must be explored. Here we report a new protocol for the simultaneous induction of cardiomyocytes (CMs) and vascular cells [endothelial cells (ECs)/vascular mural cells (MCs)] and generate entirely hiPSC-engineered cardiovascular cell sheets, which showed advantageous therapeutic effects in infarcted hearts. The protocol adds to a previous differentiation protocol of CMs by using stage-specific supplementation of vascular endothelial cell growth factor for the additional induction of vascular cells. Using this cell sheet technology, we successfully generated physically integrated cardiac tissue sheets (hiPSC-CTSs). HiPSC-CTS transplantation to rat infarcted hearts significantly improved cardiac function. In addition to neovascularization, we confirmed that engrafted human cells mainly consisted of CMs in >40% of transplanted rats four weeks after transplantation. Thus, our HiPSC-CTSs show promise for cardiac regenerative therapy.