title: Imbalances in Mobilization and Activation of Pro-Inflammatory and Vascular Reparative Bone Marrow-Derived Cells in Diabetic Retinopathy.
abstract: Diabetic retinopathy is a sight-threatening complication of diabetes, affecting 65% of patients after 10 years of the disease. Diabetic metabolic insult leads to chronic low-grade inflammation, retinal endothelial cell loss and inadequate vascular repair. This is partly due to bone marrow (BM) pathology leading to increased activity of BM-derived pro-inflammatory monocytes and impaired function of BM-derived reparative circulating angiogenic cells (CACs). We propose that diabetes has a significant long-term effect on the nature and proportion of BM-derived cells that circulate in the blood, localize to the retina and home back to their BM niche. Using a streptozotocin mouse model of diabetic retinopathy with GFP BM-transplantation, we have demonstrated that BM-derived circulating pro-inflammatory monocytes are increased in diabetes while reparative CACs are trapped in the BM and spleen, with impaired release into circulation. Diabetes also alters activation of splenocytes and BM-derived dendritic cells in response to LPS stimulation. A majority of the BM-derived GFP cells that migrate to the retina express microglial markers, while others express endothelial, pericyte and Müller cell markers. Diabetes significantly increases infiltration of BM-derived microglia in an activated state, while reducing infiltration of BM-derived endothelial progenitor cells in the retina. Further, control CACs injected into the vitreous are very efficient at migrating back to their BM niche, whereas diabetic CACs have lost this ability, indicating that the in vivo homing efficiency of diabetic CACs is dramatically decreased. Moreover, diabetes causes a significant reduction in expression of specific integrins regulating CAC migration. Collectively, these findings indicate that BM pathology in diabetes could play a role in both increased pro-inflammatory state and inadequate vascular repair contributing to diabetic retinopathy.
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Harshini
authors.initials: H
authors.lastname: Chakravarthy
authors.affiliation: Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Eleni
authors.initials: E
authors.lastname: Beli
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Navitskaya
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Sandra
authors.initials: S
authors.lastname: O'Reilly
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Nermin
authors.initials: N
authors.lastname: Kady
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Chao
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Julia V
authors.initials: JV
authors.lastname: Busik
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D016026:Bone Marrow Transplantation; D002452:Cell Count; D002678:Chimera; D003713:Dendritic Cells / Q000473:pathology; D003930:Diabetic Retinopathy / Q000276:immunology / Q000473:pathology*; D042783:Endothelial Cells / Q000473:pathology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000473:pathology; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D009000:Monocytes / Q000473:pathology; D012160:Retina / Q000473:pathology; D013154:Spleen / Q000473:pathology
chemical_list: D008070:Lipopolysaccharides; D049452:Green Fluorescent Proteins