title: Vascular progenitors from cord blood-derived induced pluripotent stem cells possess augmented capacity for regenerating ischemic retinal vasculature.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  VPs generated from CB-iPSCs possessed augmented capacity to home, integrate into, and repair damaged retinal vasculature.
authors.affiliation: Institute for Cell Engineering, and Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD (T.S.P., L.Z., J.S.H., J.A., E.T.Z.); Wilmer Ophthalmological Institute, Johns Hopkins University School of Medicine, Baltimore, MD (I.B., R.G., C.M., G.L.); Department of Radiation Oncology (P.N., F.R.) and Department of Microbiology/Immunology (D.M., R.A.F.), University of Maryland School of Medicine, Baltimore, MD; Department of Cardiovascular Medicine (A.J.R., J.C.) and Institute for Stem Cell Biology and Regenerative Medicine (A.J.R., R.R.-P., J.C.), Stanford University, Palo Alto, CA; and Institute for Basic Biomedical Science at Johns Hopkins School of Medicine, Baltimore, MD (C.T.).
authors.forename: Tea Soon
authors.initials: TS
authors.lastname: Park
authors.forename: Imran
authors.initials: I
authors.lastname: Bhutto
authors.forename: Ludovic
authors.initials: L
authors.lastname: Zimmerlin
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Huo
authors.forename: Pratik
authors.initials: P
authors.lastname: Nagaria
authors.forename: Diana
authors.initials: D
authors.lastname: Miller
authors.forename: Abdul Jalil
authors.initials: AJ
authors.lastname: Rufaihah
authors.forename: Connie
authors.initials: C
authors.lastname: Talbot
authors.forename: Jack
authors.initials: J
authors.lastname: Aguilar
authors.forename: Rhonda
authors.initials: R
authors.lastname: Grebe
authors.forename: Carol
authors.initials: C
authors.lastname: Merges
authors.forename: Renee
authors.initials: R
authors.lastname: Reijo-Pera
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Feldman
authors.forename: Feyruz
authors.initials: F
authors.lastname: Rassool
authors.forename: John
authors.initials: J
authors.lastname: Cooke
authors.forename: Gerard
authors.initials: G
authors.lastname: Lutty
authors.forename: Elias T
authors.initials: ET
authors.lastname: Zambidis
mesh_terms: D000818:Animals; D002196:Capillaries / Q000166:cytology; D016922:Cellular Senescence; D004249:DNA Damage; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology*; D005312:Fetal Blood / Q000166:cytology*; D005347:Fibroblasts / Q000166:cytology; D006085:Graft Survival; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D039904:Pluripotent Stem Cells / Q000166:cytology*; D012038:Regeneration; D015427:Reperfusion Injury / Q000473:pathology / Q000628:therapy*; D012164:Retinal Diseases / Q000473:pathology / Q000628:therapy*; D033581:Stem Cell Transplantation / Q000379:methods*; D059467:Transcriptome
keywords: blood supply; diabetic retinopathy; embryonic stem cells; induced pluripotent stem cells; reperfusion injury; stem cells; transplantation