Vascular Progenitors from Cord Blood-Derived iPSC Possess Augmented Capacity for Regenerating Ischemic Retinal Vasculature

Background —The generation of vascular progenitors (VP) from human induced pluripotent stem cells (hiPSC) has great potential for treating vascular disorders such as ischemic retinopathies. However, long-term in vivo engraftment of hiPSC-derived VP into retina has not yet been reported. This goal may be limited by the low differentiation yield, greater senescence, and poor proliferation of hiPSC-derived vascular cells. To evaluate the potential of hiPSC for treating ischemic retinopathies, we generated VP from a repertoire of viral-integrated and non-integrated fibroblast and cord blood (CB)-derived hiPSC lines, and tested their capacity for homing and engrafting into murine retina in an ischemia-reperfusion (I/R) model. Methods and Results —VP from human embryonic stem cells (hESC) and hiPSC were generated with an optimized hemato-vascular differentiation system. FACS-purification of human embryoid body (hEB) cells differentially expressing endothelial/pericytic markers identified a CD31+CD146+ VP population with high vascular potency. Episomal CB-iPSC generated these VP with higher efficiencies than fibroblast-iPSC. Moreover, in contrast to fibroblast-iPSC-VP, CB-iPSC-VP maintained expression signatures more comparable to hESC-VP, expressed higher levels of immature vascular markers, demonstrated less culture senescence and sensitivity to DNA damage, and possessed fewer transmitted reprogramming errors. Luciferase transgene-marked VP from hESC, CB-iPSC, and fibroblast-iPSC were injected systemically or directly into the vitreous of retinal I/R-injured adult NOD-SCID mice. Only hESC- and CB-iPSC-derived VP reliably homed and engrafted into injured retinal capillaries, with incorporation into damaged vessels for up to 45 days. Conclusions —VP generated from CB-iPSC possessed augmented capacity to home, integrate into, and repair damaged retinal vasculature.