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.

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