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Imran A. Bhutto, Tea Soon Park, Carol Merges, D S. McLeod, Elias Zambidis, Gerard A. Lutty; Vascular Progenitors Derived From Human Induced Pluripotent Stem Cells Incorporate Into Mouse Retinal Vessels Injured By Transient Ischemia. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2576.
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Ischemic retinopathies are a leading cause of blindness and a potential disease target for vascular progenitor cell (VPC)-based therapy. VPCs have the potential to promote vascular repair and revascularization of ischemic retina. Induced pluripotent stem cells (iPSCs) may provide autologous, patient-specific VPCs for treatment of retinal ischemic diseases. In this study, we generated VPCs from human embryonic stem cells (hESCc) and iPSCs to examine their regenerative potential in the mouse retinal ischemia/reperfusion (I/R) injury model.
hESCs, fibroblast-iPSCs, and non-virally generated CD34+ cord blood-iPSCs were differentiated via human embryoid bodies, dissociated into small aggregates, and further differentiated into vascular lineage on fibronectin-coated plates in EGM-2. Thereafter, the monolayer included cells expressing endothelial (CD31, CD34), perivascular (CD146, α-SMA), angioblastic (KDR/VEGF-R2 and CD133) and hemangioblastic (BB9/CD143) markers. Putative VPCs were sorted for the CD31+/CD146+ populations from starting hESCs and iPSCs. CD31-/CD146- cells from each source were used as controls. 100,000 cells were injected bilaterally into the vitreous of adult NOD/Scid mice 2 days after I/R to one eye. Human cells were distinguished from mouse cells by immunostaining for luciferase. To visualize the vascular injury in flat mount retinas, we stained viable retinal blood vessels with rat anti-mouse CD31 and all retinal capillaries (viable and acellular) with anti-collagen IV. The retinas were examined and photographed using a confocal microscope at 3, 7, or 14 days after injection.
Three- to 14-day post-injection human VPCs incorporate into the damaged mouse retinal vessels, while unincorporated free cells were observed in vitreous and in retina of non-injured control eyes. These data indicate that CD31+/CD146+ cells are highly responsive to the signals from injured blood vessels, actively migrate, and incorporate in the damaged capillaries and veins. Most incorporated cells engrafted in an abluminal/pericytic position.
We have successfully derived progenitors representing angioblast/VPC population from hESCs and iPSCs that survived and integrated with blood vessels in the ischemic mouse retina. These results suggest that patient-specific human iPSCs may be used as donor cells for transplantable VPC to repair ischemic-injured retina.
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