Circulating bone marrow‐derived endothelial precursor cells contribute to neovascularization in diabetic epiretinal membranes

Abstract

Purpose Role of vasculogenesis, recruitment and differentiation of circulating bone marrow‐derived endothelial precursor cells into mature endothelium, in proliferative diabetic retinopathy (PDR) remains undefined. We investigated the presence of bone marrow‐derived endothelial precursor cells and the expression of the chemotactic pathway SDF‐1/CXCL12?CXCR4 in PDR epiretinal membranes. Methods Membranes from 8 patients with active PDR and 9 patients with inactive PDR were studied by immunohistochemistry using antibodies against CD133, vascular endothelial growth factor receptor‐2 (VEGFR‐2), CD14, SDF‐1 and CXCR4. Results Blood vessels expressed CD133, VEGFR‐2, CD14, SDF‐1 and CXCR4 in 10, 10, 10, 7 and 7 out of 17 membranes, respectively. There were significant correlations between number of blood vessels expressing CD34 and number of blood vessels expressing CD133 (rs=0.646; p=0.005), VEGFR‐2 (rs=0.704; p=0.002), CD14 (rs=0.564; p=0.018), and SDF‐1 (rs=0.577; p=0.015). Stromal cells in close association with blood vessels expressed CD133, VEGFR‐2, CD14, and CXCR4 in 10, 12, 13, and 14 membranes, respectively. Number of blood vessels expressing CD133 (p=0.013), VEGFR‐2 (p=0.005), CD14 (p=0.008) and SDF‐1 (p=0.005), and stromal cells expressing CD133 (p=0.003), VEGFR‐2 (p=0.013) and CD14 (p=0.002) was significantly higher in active membranes than in inactive membranes. Conclusion Bone marrow‐derived CD133+ endothelial progenitor cells and CD14+ monocytes may contribute to vasculogenesis in PDR.

Vasculogenesis in Diabetes-Associated Diseases: Unraveling the Diabetic Paradox

“…In T2DM patients with DR, circulating angiopoietic cells as EPCs, and mature EPCs had different regulations in PDR depending on each individual's macrovascular comorbidities (Brunner et al, 2011). Recent findings in diabetic patients have corroborated gathered experimental data, demonstrating that BMderived CD133+ EPCs, as well as, CD14+ monocytes could be mobilized to diabetic epiretinal membranes, contributing to vasculogenesis in PDR (Abu El-Asrar et al, 2011). Taken together, these data strengthen the importance of EPCs in the development of human PDR, highlighting the crucial role played by both the local retinal and the systemic environment.…”

Neural inflammation and the microglial response in diabetic retinopathy

“…The prevalence of cells staining with microglial markers near the vasculature led these authors to coin the phrase "microvascular perivasculitis." This is not unlike the perivascular CD14-positive monocyte/macrophage staining observed in ERM removed from patients with active PDR [48], in that there is no direct evidence that the cells observed by Zeng and coworkers were actually retinal microglia. Thus, we can only conclude that monocytes/macrophages are coincident with the focal pathologies that occur in DR.…”

“…Additionally, it is now known that bone marrow-derived resident monocytes/ macrophage cells, called hyalocytes, occupy the periphery of the vitreous cavity, and it was presumed that these are the cells that are present and causal in ERM formation [47]. More recently, Abu El-Asrar and colleagues studied ERM from patients with active and inactive PDR and concluded that vessel-associated cells included bone marrow-derived CD133-positive endothelial precursor cells as well as CD14-positive monocytes that may have also originated from the bone marrow [48]. These cells were more prevalent in samples from patients with active PDR.…”

Endothelial microRNA-150 is an intrinsic suppressor of pathologic ocular neovascularization

“…On the other hand, Dll4/Notch signaling controls vessel sprouting and branching, and inhibition of DLL4 showed reduced pathological neovessels in OIR (35). Moreover, CXCR4, a receptor for SDF-1 signaling, showed increased expression in diabetic epiretinal membranes (36), and inhibition of CXCR4 reduces the laser-induced CNV lesion sizes and leakage in rats (37). Together these findings are consistent with our data of miR-150, a suppressor of Fzd4, Dll4, and Cxcr4, protecting against OIR.…”