Imbalances in Mobilization and Activation of Pro-Inflammatory and Vascular Reparative Bone Marrow-Derived Cells in Diabetic Retinopathy

• Published in: PloS one Vol. 11; no. 1; p. e0146829
• Main Authors: Chakravarthy, Harshini, Beli, Eleni, Navitskaya, Svetlana, O'Reilly, Sandra, Wang, Qi, Kady, Nermin, Huang, Chao, Grant, Maria B, Busik, Julia V
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13-01-2016; Public Library of Science (PLoS)
• Subjects: Activation; Angiogenesis; Animals; Biology; Bone marrow; Bone Marrow Cells - cytology; Bone Marrow Transplantation; Cell activation; Cell Count; Cell migration; Cells (biology); Chimera; Complications and side effects; Dendritic cells; Dendritic Cells - pathology; Development and progression; Diabetes; Diabetes mellitus; Diabetic retinopathy; Diabetic Retinopathy - immunology; Diabetic Retinopathy - pathology; Drug dosages; Endothelial cells; Endothelial Cells - pathology; Green Fluorescent Proteins - metabolism; Health aspects; Homing; Homing behavior; Infiltration; Inflammation; Inflammation - pathology; Integrins; Laboratories; Leukocyte migration; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Male; Markers; Mice, Inbred C57BL; Microglia; Microglia - pathology; Microvessels - drug effects; Microvessels - pathology; Monocytes; Monocytes - pathology; Neurosciences; Pathology; Physiology; Progenitor cells; Repair; Retina; Retina - pathology; Retinopathy; Rodents; Spleen; Spleen - pathology; Splenocytes; Stem cells; Streptozocin; Transplantation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0146829

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.