Abstract
Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults. Early stage DR involves inflammation, vascular leakage, apoptosis of vascular cells and neurodegeneration. In this study, we hypothesized that cells derived from the stromal fraction of adipose tissue (ASC) could therapeutically rescue early stage DR features. Streptozotocin (STZ) induced diabetic athymic nude rats received single intravitreal injection of human ASC into one eye and saline into the other eye. Two months post onset of diabetes, administration of ASC significantly improved “b” wave amplitude (as measured by electroretinogram) within 1–3 weeks of injection compared to saline treated diabetic eyes. Subsequently, retinal histopathological evaluation revealed a significant decrease in vascular leakage and apoptotic cells around the retinal vessels in the diabetic eyes that received ASC compared to the eyes that received saline injection. In addition, molecular analyses have shown down-regulation in inflammatory gene expression in diabetic retina that received ASC compared to eyes that received saline. Interestingly, ASC were found to be localized near retinal vessels at higher densities than seen in age matched non-diabetic retina that received ASC. In vitro, ASC displayed sustained proliferation and decreased apoptosis under hyperglycemic stress. In addition, ASC in co-culture with retinal endothelial cells enhance endothelial survival and collaborate to form vascular networks. Taken together, our findings suggest that ASC are able to rescue the neural retina from hyperglycemia-induced degeneration, resulting in importantly improved visual function. Our pre-clinical studies support the translational development of adipose stem cell-based therapy for DR to address both retinal capillary and neurodegeneration.
Highlights
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
Because adipose stem cells (ASC) are an abundant and isolated population of adult stem cells from cosmetic lipoaspirations [47], they are an excellent source for future pericyte replacement in DR as well as in other chronic wound therapies
Direct evidence that ASC play a therapeutic role in DR came from a study in which intravenously administered ASC in the STZ induced DR rat model demonstrated an improvement of blood-retinal barrier (BRB) integrity, with few donor cells differentiated into photoreceptor or astrocytes-like cells [22]
Summary
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 total number of TUNEL-positive cells in diabetic rats was normalized to total nuclear cells using MetaMorph analysis (Molecular Devices, Sunnyvale, CA) and shown as a percentage of non-diabetic animals that received saline injection. Intravitreal injection of ASC had no effect on elevated random blood glucose level after 3 weeks post transplantation, but demonstrated a slight natural expected increase in body weights in these rats (Figure S2 in File S1).
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