title: Regenerative therapeutic potential of adipose stromal cells in early stage diabetic retinopathy.
abstract: Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults. Early stage DR involves inflammation, vascular leakage, apoptosis of vascular cells and neurodegeneration. In this study, we hypothesized that cells derived from the stromal fraction of adipose tissue (ASC) could therapeutically rescue early stage DR features. Streptozotocin (STZ) induced diabetic athymic nude rats received single intravitreal injection of human ASC into one eye and saline into the other eye. Two months post onset of diabetes, administration of ASC significantly improved "b" wave amplitude (as measured by electroretinogram) within 1-3 weeks of injection compared to saline treated diabetic eyes. Subsequently, retinal histopathological evaluation revealed a significant decrease in vascular leakage and apoptotic cells around the retinal vessels in the diabetic eyes that received ASC compared to the eyes that received saline injection. In addition, molecular analyses have shown down-regulation in inflammatory gene expression in diabetic retina that received ASC compared to eyes that received saline. Interestingly, ASC were found to be localized near retinal vessels at higher densities than seen in age matched non-diabetic retina that received ASC. In vitro, ASC displayed sustained proliferation and decreased apoptosis under hyperglycemic stress. In addition, ASC in co-culture with retinal endothelial cells enhance endothelial survival and collaborate to form vascular networks. Taken together, our findings suggest that ASC are able to rescue the neural retina from hyperglycemia-induced degeneration, resulting in importantly improved visual function. Our pre-clinical studies support the translational development of adipose stem cell-based therapy for DR to address both retinal capillary and neurodegeneration.
authors.affiliation: Indiana Center for Vascular Biology & Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Vascular and Cardiac Center for Adult Stem Cell Therapy, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; VA Center for Regenerative Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Gangaraju
authors.initials: G
authors.lastname: Rajashekhar
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Ramadan
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Chandrika
authors.initials: C
authors.lastname: Abburi
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Breedge
authors.initials: B
authors.lastname: Callaghan
authors.affiliation: Indiana Center for Vascular Biology & Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Vascular and Cardiac Center for Adult Stem Cell Therapy, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; VA Center for Regenerative Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Dmitry O
authors.initials: DO
authors.lastname: Traktuev
authors.affiliation: Vascular and Cardiac Center for Adult Stem Cell Therapy, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Carmella
authors.initials: C
authors.lastname: Evans-Molina
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Midwest Eye Institute, Indianapolis, Indiana, United States of America.
authors.forename: Raj
authors.initials: R
authors.lastname: Maturi
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Alon
authors.initials: A
authors.lastname: Harris
authors.affiliation: Departments of Medicine and Ophthalmology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Kern
authors.affiliation: Indiana Center for Vascular Biology & Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Vascular and Cardiac Center for Adult Stem Cell Therapy, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; VA Center for Regenerative Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Keith L
authors.initials: KL
authors.lastname: March
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D017209:Apoptosis; D017690:Cell Transplantation; D003930:Diabetic Retinopathy / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D058449:Intravitreal Injections; D051381:Rats; D012171:Retinal Vessels / Q000503:physiopathology; D017154:Stromal Cells / Q000187:drug effects / Q000637:transplantation; D013997:Time Factors
chemical_list: D005947:Glucose