Chakravarthy Harshini, Beli Eleni, Navitskaya Svetlana, O'Reilly Sandra, Wang Qi, Kady Nermin, Huang Chao, Grant Maria B, Busik Julia V
Department of Physiology, Michigan State University, East Lansing, Michigan, United States of America.
Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
PLoS One. 2016 Jan 13;11(1):e0146829. doi: 10.1371/journal.pone.0146829. eCollection 2016.
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.
糖尿病视网膜病变是糖尿病一种威胁视力的并发症，患病10年后65%的患者会受其影响。糖尿病代谢损伤会导致慢性低度炎症、视网膜内皮细胞丢失以及血管修复不足。这部分归因于骨髓（BM）病变，导致源自BM的促炎单核细胞活性增加，以及源自BM的修复性循环血管生成细胞（CACs）功能受损。我们认为，糖尿病对血液中循环、定位于视网膜并归巢回其BM龛位的源自BM的细胞的性质和比例具有重大长期影响。使用带有绿色荧光蛋白（GFP）BM移植的糖尿病视网膜病变链脲佐菌素小鼠模型，我们已经证明，糖尿病状态下源自BM的循环促炎单核细胞增加，而修复性CACs被困在骨髓和脾脏中，释放到循环中的能力受损。糖尿病还会改变脾细胞和源自BM的树突状细胞对脂多糖（LPS）刺激的反应激活情况。迁移到视网膜的大多数源自BM的GFP细胞表达小胶质细胞标志物，而其他细胞表达内皮细胞、周细胞和穆勒细胞标志物。糖尿病显著增加处于激活状态的源自BM的小胶质细胞浸润，同时减少源自BM的内皮祖细胞在视网膜中的浸润。此外，注入玻璃体的对照CACs非常有效地迁移回其BM龛位，而糖尿病CACs已经丧失这种能力，这表明糖尿病CACs的体内归巢效率显著降低。此外，糖尿病导致调节CAC迁移的特定整合素表达显著降低。总体而言，这些发现表明，糖尿病中的BM病变可能在导致糖尿病视网膜病变的促炎状态增加和血管修复不足方面都发挥作用。
