Vascular Progenitors From Cord Blood-Derived Induced Pluripotent Stem Cells Possess Augmented Capacity for Regenerating Ischemic Retinal Vasculature

• Published in: Circulation (New York, N.Y.) Vol. 129; no. 3; pp. 359 - 372
• Main Authors: TEA SOON PARK, BHUTTO, Imran, MERGES, Carol, REIJO-PERA, Renee, FELDMAN, Ricardo A, RASSOOL, Feyruz, COOKE, John, LUTTY, Gerard, ZAMBIDIS, Elias T, ZIMMERLIN, Ludovic, HUO, Jeffrey S, NAGARIA, Pratik, MILLER, Diana, RUFAIHAH, Abdul Jalil, TALBOT, Connie, AGUILAR, Jack, GREBE, Rhonda
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 21.01.2014
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Applied cell therapy and gene therapy; Biological and medical sciences; Blood and lymphatic vessels; Capillaries - cytology; Cardiology. Vascular system; Cellular Senescence; Diabetes. Impaired glucose tolerance; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; DNA Damage; Embryonic Stem Cells - cytology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fetal Blood - cytology; Fibroblasts - cytology; Graft Survival; Humans; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Ophthalmology; Pluripotent Stem Cells - cytology; Regeneration; Reperfusion Injury - pathology; Reperfusion Injury - therapy; Retinal Diseases - pathology; Retinal Diseases - therapy; Retinopathies; Stem Cell Transplantation - methods; Transcriptome; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Endocrinopathy; Embryo; Retinopathy; Cell therapy; Regenerative medicine; Injury; Stem cell; embryonic stem cells; Cardiovascular disease; Retina; Transplantation; reperfusion injury; Homotransplantation; Blood; Vascularization; Eye; Visual system; Reperfusion; Ischemia; Capacity; Surgery; Blood vessel; Graft; Cardiology; stem cells; Diabetes mellitus; diabetic retinopathy; Trauma; nduced pluripotent stem cells; Eye disease; Blood cell; Treatment; Blood circulation; blood supply; Circulatory system; Umbilical cord; Lesion; transplantation; induced pluripotent stem cells
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.113.003000

The generation of vascular progenitors (VPs) from human induced pluripotent stem cells (hiPSCs) has great potential for treating vascular disorders such as ischemic retinopathies. However, long-term in vivo engraftment of hiPSC-derived VPs into the 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 hiPSCs for treating ischemic retinopathies, we generated VPs from a repertoire of viral-integrated and nonintegrated fibroblast and cord blood (CB)-derived hiPSC lines and tested their capacity for homing and engrafting into murine retina in an ischemia-reperfusion model. VPs from human embryonic stem cells and hiPSCs were generated with an optimized vascular differentiation system. Fluorescence-activated cell sorting purification of human embryoid body cells differentially expressing endothelial/pericytic markers identified a CD31(+)CD146(+) VP population with high vascular potency. Episomal CB-induced pluripotent stem cells (iPSCs) generated these VPs with higher efficiencies than fibroblast-iPSC. Moreover, in contrast to fibroblast-iPSC-VPs, CB-iPSC-VPs maintained expression signatures more comparable to human embryonic stem cell VPs, 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 VPs from human embryonic stem cells, CB-iPSCs, and fibroblast-iPSCs were injected systemically or directly into the vitreous of retinal ischemia-reperfusion-injured adult nonobese diabetic-severe combined immunodeficient mice. Only human embryonic stem cell- and CB-iPSC-derived VPs reliably homed and engrafted into injured retinal capillaries, with incorporation into damaged vessels for up to 45 days. VPs generated from CB-iPSCs possessed augmented capacity to home, integrate into, and repair damaged retinal vasculature.