Building functional vascular grafts from human pluripotent stem cells-derived endothelial cells

Abstract

Background & Aim Stem cell therapy may transform the treatment of cardiovascular disease, with an anticipated impact rivalling the results of revascularization and device therapies. Human pluripotent stem cells are currently developed as sources of tissue-specific cells for organ repair and regeneration. In clinically relevant small and large animal studies, we sought to investigate the feasibility of human embryonic and induced pluripotent stem cell-derived endothelial cell (hESC-EC, hiPSC-EC) engraftments. Methods, Results & Conclusion To generate endothelial cells, human pluripotent stem cells were treated with endothelial growth factors and CD31+ cell population was isolated from differentiating cultures. We obtained highly expandable populations of hESC-EC and hiPSC-EC which expressed mature endothelial cell markers. We implanted cell-laden hydrogel Matrigel subcutaneously into athymic nude rats. We studied angiogenesis in a small animal imaging system equipped with a high-resolution SPECT/CT and PET/MRI to acquire whole-body images. At two weeks after axillary or inguinal implantation in rats, a robust increase in local perfusion was detected by radiolabeled albumin at the engraftment sites, suggesting the functional incorporation of human hPSC-EC into the host microvasculature. Histology confirmed survival, successful engraftment, and formation of capillary-like structures. In a canine model, hiPSC-EC-seeded onto decellularised vascular segments were functional as infrarenal aortic interposition grafts. As assessed by quantitative PCR during follow-up, the expression of human angiogenic factors was induced, suggesting that endothelial cells may undergo maturation in vivo. Similar to the rodent model, we showed retention of hiPSC-EC and dynamic remodelling of the vessel wall with good maintenance of vascular patency in dogs. Combination of pluripotent stem cell-derived endothelial cells and biomatrices may be a promising tissue engineering approach to repair ischemic tissues and induce the formation of blood vessel networks.