Abstract
Endothelial precursor cells participate in vascular repair; however in diabetes these cells can become dysfunctional. Previously, we showed that transient blockade of endogenous transforming growth factor-beta1 (TGF-beta1) by antisense phosphorodiamidate morpholino oligomers (PMOs) accelerated homing and engraftment of hematopoietic stem cells (HSC) in experimental models of bone marrow transplant. We asked whether transient blockade of TGF-beta1 could enhance mouse HCS and human CD34 + -endothelial progenitor cell (EPC) recruitment and re-endothelialization to areas of vascular injury and correct vascular reparative defects of diabetic cells. Cells were treated with either control-PMO, anti-TGF-beta-PMO, or saline. Cell proliferation in response to the above treatments was studied in the colony forming assay for 1 week. CXCR-4 expression was examined by immunostaining and migration in response to stromal derived factor-1 (SDF-1) was tested using Boyden chamber assay. Mice were injected systemically with modified HSCs and then underwent either laser rupture of Bruch’s membrane to initiate choroidal neovascularization (CNV) or modified CD34 + cells of diabetic and nondiabetic origin and then received the retinal ischemia reperfusion (I/R) injury. Neutralizing endogenous TGF-beta1 in cells sustained their survival in the absence of growth factors with no loss of proliferative potential. Pre-treatment with anti-TGF-beta-PMO increased expression of CXCR-4 in both diabetic and nondiabetic CD34 + cells and increased their migration to SDF-1. HSC treated with anti-TGF-betaPMO demonstrated increased homing to CNV lesions and increased reendothelialization of acellular capillaries in the I/R model by both diabetic and nondiabetic cells. Blocking endogenous TGF-beta1 production by PMO induced increased CXCR-4 expression in cells and increased nitric oxide generation facilitating cell migration and enhanced vascular repair. Blocking TGF-beta1 in HSC/CD34 + EPC may represent a novel therapeutic strategy in enhancing vascular repair in diabetes. This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).
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