Transient Inhibition of Transforming Growth Factor-β1 in Human Diabetic CD34+ Cells Enhances Vascular Reparative Functions

Abstract

OBJECTIVE Peripheral blood CD34+ cells from diabetic patients demonstrate reduced vascular reparative function due to decreased proliferation and diminished migratory prowess, largely resulting from decreased nitric oxide (NO) bioavailability. The level of TGF-β, a key factor that modulates stem cell quiescence, is increased in the serum of type 2 diabetic patients. We asked whether transient TGF-β1 inhibition in CD34+ cells would improve their reparative ability. RESEARCH DESIGN AND METHODS To inhibit TGF-β1 protein expression, CD34+ cells were treated ex vivo with antisense phosphorodiamidate morpholino oligomers (TGF-β1-PMOs) and analyzed for cell surface CXCR4 expression, cell survival in the absence of added growth factors, SDF-1-induced migration, NO release, and in vivo retinal vascular reparative ability. RESULTS TGF-β1-PMO treatment of diabetic CD34+ cells resulted in increased expression of CXCR4, enhanced survival in the absence of growth factors, and increased migration and NO release as compared with cells treated with control PMO. Using a retinal ischemia reperfusion injury model in mice, we observed that recruitment of diabetic CD34+ cells to injured acellular retinal capillaries was greater after TGF-β1-PMO treatment compared with control PMO–treated cells. CONCLUSIONS Transient inhibition of TGF-β1 may represent a promising therapeutic strategy for restoring the reparative capacity of dysfunctional diabetic CD34+ cells.