Stromal Cell–Derived Factor-1 Effects on Ex Vivo Expanded Endothelial Progenitor Cell Recruitment for Ischemic Neovascularization

TLDR

Stromal cell‑derived factor‑1 (SDF‑1) is a chemokine that facilitates trafficking of hematopoietic stem cells. The study aimed to determine whether SDF‑1 enhances endothelial progenitor cell–mediated vasculogenesis both in vitro and in a murine hindlimb ischemia model. In vivo, SDF‑1 was locally injected into the ischemic hindlimb muscle of athymic mice together with human EPC transplantation to assess its effect on EPC recruitment and vessel formation. SDF‑1 dose‑dependently stimulated EPC migration, reduced apoptosis, increased EPC accumulation in ischemic muscle, and led to improved perfusion and capillary density, demonstrating that local SDF‑1 delivery augments EPC‑driven neovascularization.

Abstract

Stromal cell-derived factor-1 (SDF-1) is a chemokine considered to play an important role in the trafficking of hematopoietic stem cells. Given the close relationship between hematopoietic stem cells and endothelial progenitor cells (EPCs), we investigated the effect of SDF-1 on EPC-mediated vasculogenesis.Flow cytometric analysis demonstrated expression of CXCR4, the receptor of SDF-1, by 66+/-3% of EPCs after 7 days in culture. In vitro modified Boyden chamber assay showed a dose-dependent EPC migration toward SDF-1 (control versus 10 ng/mL SDF-1 versus 100 ng/mL SDF-1, 24+/-2 versus 71+/-3 versus 140+/-6 cells/mm2; P<0.0001). SDF-1 attenuated EPC apoptosis (control versus SDF-1, 27+/-1 versus 7+/-1%; P<0.0001). To investigate the effect of SDF-1 in vivo, we locally injected SDF-1 into athymic ischemic hindlimb muscle of nude mice combined with human EPC transplantation to determine whether SDF-1 augmented EPC-induced vasculogenesis. Fluorescence microscopic examination disclosed increased local accumulation of fluorescence-labeled EPCs in ischemic muscle in the SDF-1 treatment group (control versus SDF-1=241+/-25 versus 445+/-24 cells/mm2, P<0.0001). At day 28 after treatment, ischemic tissue perfusion was improved in the SDF-1 group and capillary density was also increased. (control versus SDF-1, 355+/-26 versus 551+/-30 cells/mm2; P<0.0001).These findings indicate that locally delivered SDF-1 augments vasculogenesis and subsequently contributes to ischemic neovascularization in vivo by augmenting EPC recruitment in ischemic tissues.