Prevalence estimates suggest that 23.6 million US residents have diabetes, and this number is predicted to double over the next thirty years. Diabetic retinopathy is the leading cause of blindness, and occurs in 100% of Type 1 and 60% of Type 2 diabetic patients within 20 years of diagnosis, and more than 12,000 patients become blind each year due to ocular complications from this disease. The underlying cause of diabetic retinopathy is damage to the retinal microvasculature from chronic hyperglycemia leading to increased vascular permeability and vascular occlusion. Recent evidence has shown that all of these events follow from the initial loss of pericytes on microvessels in the retina, which makes endothelial cells susceptible to diabetic conditions that result in the microaneurysms, venous changes, retinal capillary loss, and retinal ischemia. We propose to target the aberrant loss of pericytes by developing and evaluating a novel adult stem cell therapy that, we hypothesize, will supplement the native pericyte population and maintain microvessel homeostasis, thereby preventing the downstream effects that ultimately lead to macular edema. We have recently shown that a sub-population of adult human adipose-derived stem cells (hASCs) spontaneously differentiates into pericytes when injected in vivo, and in so doing, stabilizes the microvascular endothelium. We will test the hypothesis that cultured ASCs contain a sub-population of pericytes (or, pericyte precursors) that exhibits the intracellular signaling machinery, contractil properties, and functional abilities to diminish microvascular leakage, reduce capillary dropout, and prevent pathologic angiogenic induction and/or EC hyper-proliferation in three relevant murine models: oxygen-induced retinopathy (OIR), streptozocin induced diabetes (STZ), and Akimba whose pathological outcomes are related to early non-proliferative and late proliferative aspects of human DR. Our strategy is to supplement the endogenous pericyte population in order to enhance endothelial stability and prevent vessel loss. Therefore, we have designed three aims to evaluate the putative pericyte capacity of hASCs in the retina.
Aim 1 : Identify the hASC subpopulation(s) capable of becoming functional pericytes in vitro;
Aim 2 : Determine the capacity of hASCs to stabilize retinal vessels against acute (OIR) and chronic (STZ &Akimba) vascular insults;
Aim 3 : Determine the capacity of hASCs to enhance retinal revascularization and stabilize aberrant neovascularization following acute (OIR) and chronic (STZ &Akimba) vascular insults.
Prevalence estimates suggest that 23.6 million US residents have diabetes, and this number is predicted to double over the next thirty years. Diabetic retinopathy is the leading cause of blindness, and occurs in 100% of Type 1 and 60% of Type 2 diabetic patients within 20 years of diagnosis. Current treatments are only able to treat the symptoms (not the cause) of the disease, are inefficient (require repeated application) and, over the long-term, ineffective (recurrent macular edema is a common outcome). We will develop and evaluate an adult stem cell based approach for treating diabetes that is aimed at supplementing and replacing diseased retinal perivascular cells with healthy adult progenitor cells, thereby preventing and mitigating the abnormal vascular responses that occur during diabetic retinopathy.
|Geevarghese, Anita; Herman, Ira M (2014) Pericyte-endothelial crosstalk: implications and opportunities for advanced cellular therapies. Transl Res 163:296-306|
|Durham, Jennifer T; Surks, Howard K; Dulmovits, Brian M et al. (2014) Pericyte contractility controls endothelial cell cycle progression and sprouting: insights into angiogenic switch mechanics. Am J Physiol Cell Physiol 307:C878-92|