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

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-beta, a key factor that modulates stem cell quiescence, is increased in the serum of type 2 diabetic patients We asked whether transient TGF-beta 1 inhibition in CD34(+) cells would improve their reparative ability. RESEARCH DESIGN AND METHODS-To inhibit TGF-beta 1 protein expression, CD34(+) cells were treated ex vivo with antisense phosphorodiamidate morpholino oligomers (TGF-beta 1-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-beta 1-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-beta 1-PMO treatment compared with control PMO-treated cells. CONCLUSIONS-Transient inhibition of TGF-beta 1 may represent a promising therapeutic strategy for restoring the reparative capacity of dysfunctional diabetic CD34(+) cells. Diabetes 59:2010-2019, 2010