Enhancing function of endothelial progenitors by targeting the transforming growth factor-β1/plasminogen activator inhibitor-1 system

Abstract

Purpose: To examine the impact of modulating the TGF-β/PAI-1 axis on the function of circulating CD34+ endothelial progenitor cells (EPCs) from diabetic patients and controls.

Methods: TGF-β1 and PAI-1 transcript levels were compared by gene array studies in CD34+ EPCs from diabetic patients with microvascular complications matched for age, sex, duration and degree of glycemic control, along with healthy controls. Neutralizing antibody to TGF-β1 was used to examine repopulation potential of murine hematopoietic stem cells (HSCs) in bone marrow transplantation after radiation ablation. The effects of PAI-1 inhibition on proliferation and migration of human CD34+ EPCs was studied in vitro. PAI-1 inhibition's effects on homing of CD34+ EPCs were also examined using a mouse model of ocular ischemia/reperfusion (I/R) injury.

Results: Diabetic patients, protected from microvascular complications despite suboptimal glycemic control, had reduced level of TGF-β1 and PAI-1 transcripts in their CD34+ EPCs compared to age-, sex-, duration- and degree of glycemic control-matched diabetics with microvascular complications. Treatment with neutralizing antibody to TGF-β1 enhanced in vivo repopulation potential of HSCs in bone marrow transplantation. TGF-β1 blockade also reduced the time required for cell division of single cells, increased survival of the EPCs and reduced TGF-β1 expression. Inhibition of PAI-1 promoted CD34+ EPC proliferation and migration in vitro and improved in vivo homing of diabetic CD34+ EPCs in the I/R injury model.

Conclusions: Targeting the TGF-β1/PAI-1 system offers a promising therapeutic strategy for restoring vascular reparative function in diabetic CD34+ EPCs and HSCs by enhancing key functions needed for cell therapy.

Keywords: 499 diabetic retinopathy • 700 retinal neovascularization • 543 growth factors/growth factor receptors