Diabetic retinopathy (DR) is the most common vascular complication in patients with long-standing diabetes, and is the leading cause of blindness in working-age adults. The estimated prevalence in the USA is 3.4% (nearly 4.1 million individuals) and about 40% of individuals with diabetes develop vision threating retinopathy. Future projections suggest that DR will become a larger public health problem, with an increase in the aging population as well as an increased prevalence of diabetes. In the early stages of DR, pericyte loss, basement membrane thickening, and endothelial dysfunction results in loss of blood-retinal barrier integrity leading to severe macular edema. In the subsequent stages, progressive capillary and neurodegeneration results in significant loss of vision. In recent years, the concept of repairing terminally differentiated organs with a cell base therapy has evolved. Cells derived from the stromal fraction of human adipose tissue (ASC, adipose stem/stromal cells) could potentially be used as a therapeutic strategy in DR. In this study we hypothesized that adipose tissue may provide a novel autologous source of putative stem cells with significant potential for tissue repair and rescue from diabetic injury. Preliminar data generated in a rat model of streptozotocin (STZ)-induced diabetes and a ischemia-reperfusion (I/R) injury model, ASC treatment significantly improved the vascular pathology and enhanced visual function. Based on these preliminary data, the major goal of this project is to investigate the hypothesis that treatment with ASC will rescue the vascular and neuronal damage induced in diabetes by decreasing ischemia/inflammation-induced cell death and stabilizing the vasculature by forming perivascular pericytes. We propose to investigate our hypothesis through the following specific aims:
Specific aim 1 : To evaluate the potential mechanisms by which ASC resist hyperglycemic stress to protect retinal cells and contribute to enhanced vascular integrity as pericytes in vitro.
Specific aim 2 : To determine the therapeutic efficacy of ASC transplanted into the vitreous humor of an STZ-induced diabetic and I/R injury rat models. Overall, we anticipate the findings through the specific aims will characterize 1) the specific intracellular pathways through which ASC produce beneficial effects on retinal neuronal and endothelial cells, 2) mechanisms by which ASC differentiate into pericytes to form stable vascular networks, 3) time course of ASC integration into host vasculature and repair of retinal damage and improvements in retinal function, and 4) efficacy and safety of ASC therapeutics. The long-term goal of this project is to establish a readily available novel adult stem cell sourc from fat tissue that can be employed to limit the diabetic retinal damage. Thus, this proposal wil address beneficial aspects of autologous therapy of ASC in diabetic vascular complications. It is expected that our results will pave the way for Phase I human clinical trials of ASC-based therapeutics.
We hypothesize in this project that adult stem cells isolated from fat tissue will decrease cell death and stabilize the vasculature in models of DR, thus leading to clinical studies on its use in patients with DR. Our work is expected to provide critica preclinical data for a novel therapeutic strategy involving the use of ethically acceptable and easily obtainable stem cells to treat the ocular complications of DR in the growing diabetic and aging patient populations.
|Bhattacharya, Sujoy; Gangaraju, Rajashekhar; Chaum, Edward (2017) Recent Advances in Retinal Stem Cell Therapy. Curr Mol Biol Rep 3:172-182|
|Rajashekhar, Gangaraju (2014) Mesenchymal stem cells: new players in retinopathy therapy. Front Endocrinol (Lausanne) 5:59|
|Rajashekhar, Gangaraju; Ramadan, Ahmed; Abburi, Chandrika et al. (2014) Regenerative therapeutic potential of adipose stromal cells in early stage diabetic retinopathy. PLoS One 9:e84671|