title: Pericytes derived from adipose-derived stem cells protect against retinal vasculopathy.
abstract: BACKGROUND
  Retinal vasculopathies, including diabetic retinopathy (DR), threaten the vision of over 100 million people. Retinal pericytes are critical for microvascular control, supporting retinal endothelial cells via direct contact and paracrine mechanisms. With pericyte death or loss, endothelial dysfunction ensues, resulting in hypoxic insult, pathologic angiogenesis, and ultimately blindness. Adipose-derived stem cells (ASCs) differentiate into pericytes, suggesting they may be useful as a protective and regenerative cellular therapy for retinal vascular disease. In this study, we examine the ability of ASCs to differentiate into pericytes that can stabilize retinal vessels in multiple pre-clinical models of retinal vasculopathy.
  
  
  RESULTS
  We found that ASCs express pericyte-specific markers in vitro. When injected intravitreally into the murine eye subjected to oxygen-induced retinopathy (OIR), ASCs were capable of migrating to and integrating with the retinal vasculature. Integrated ASCs maintained marker expression and pericyte-like morphology in vivo for at least 2 months. ASCs injected after OIR vessel destabilization and ablation enhanced vessel regrowth (16% reduction in avascular area). ASCs injected intravitreally before OIR vessel destabilization prevented retinal capillary dropout (53% reduction). Treatment of ASCs with transforming growth factor beta (TGF-β1) enhanced hASC pericyte function, in a manner similar to native retinal pericytes, with increased marker expression of smooth muscle actin, cellular contractility, endothelial stabilization, and microvascular protection in OIR. Finally, injected ASCs prevented capillary loss in the diabetic retinopathic Akimba mouse (79% reduction 2 months after injection).
  
  
  CONCLUSIONS
  ASC-derived pericytes can integrate with retinal vasculature, adopting both pericyte morphology and marker expression, and provide functional vascular protection in multiple murine models of retinal vasculopathy. The pericyte phenotype demonstrated by ASCs is enhanced with TGF-β1 treatment, as seen with native retinal pericytes. ASCs may represent an innovative cellular therapy for protection against and repair of DR and other retinal vascular diseases.
authors.affiliation: Department of Ophthalmology, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Mendel
authors.forename: Erin B D
authors.initials: EB
authors.lastname: Clabough
authors.forename: David S
authors.initials: DS
authors.lastname: Kao
authors.forename: Tatiana N
authors.initials: TN
authors.lastname: Demidova-Rice
authors.forename: Jennifer T
authors.initials: JT
authors.lastname: Durham
authors.forename: Brendan C
authors.initials: BC
authors.lastname: Zotter
authors.forename: Scott A
authors.initials: SA
authors.lastname: Seaman
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Cronk
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Rakoczy
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Katz
authors.forename: Ira M
authors.initials: IM
authors.lastname: Herman
authors.forename: Shayn M
authors.initials: SM
authors.lastname: Peirce
authors.forename: Paul A
authors.initials: PA
authors.lastname: Yates
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010100:Oxygen / Q000009:adverse effects; D020286:Pericytes / Q000166:cytology / Q000378:metabolism*; D012160:Retina / Q000378:metabolism* / Q000473:pathology*; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D053773:Transforming Growth Factor beta1; D010100:Oxygen