Abstract 222: Implantation of Adipose Tissue-Derived Stromal Cells Induces Angiogenesis in Ischemic Tissue. Role of SDF-1-mediated Endothelial Progenitor Cell Mobilization.
Background. Therapeutic angiogenesis using autologous bone marrow mononuclear cells (BM-MNCs) may represent a novel approach for attenuating tissue damage and preserving function in ischemic tissues. However, recent data indicate that patients with the most severe vascular disease may have insufficient or deficient endothelial progenitor cells (EPCs) and the poorest response to angiogenic therapy. Accordingly, we examined whether implantation of adipose tissue-derived stromal cells (ADSCs) might augment angiogenesis in a mouse model of hindlimb ischemia.
Method and Results. C57BL/6J mouse inguinal fat pad-derived stromal cells were cultured in standard medium. Fluorescence-activated cell sorter (FACS) analysis of cultured ADSCs indicated that Sca-1 antigen, but not CD31, CD34, c-kit, Lin, CXCR4 and flk-1 was expressed. These cells expressed vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1 (SDF-1) mRNA if compared with mature adipocytes. Hindlimb ischemia was surgically induced in mice and cultured ADSCs (1.0x106 cells/animal), or PBS (control) were injected into the ischemic tissues at postoperative day 1. Implantation of ADSCs induced significant increases in circulating EPCs 3 and 7 days after cell implantation. This phenomenon was further supported by FACS analysis, which disclosed a significant increase in Sca-1/Flk-1 positive cells in the ADSCs group vs. the control group (0.37 ± 0.04% vs. 0.25 ± 0.02% p < 0.05). Three weeks after cell implantation, the ADSCs-implanted group had a greater laser Doppler blood perfusion index (0.93 ± 0.03 vs. 0.79 ± 0.05 p < 0.05), and a higher capillary density (p < 0.05) compared to the control group. Both SDF-1 expression at the ischemic muscles and secretion of SDF-1 into the peripheral blood were augmented in the ADSCs group compared to the control group. To block SDF-1, intraperitoneal injections of anti-SDF-1 neutralizing antibody reduced therapeutic effect of ADSCs implantation.
Conclusions. Adipose tissue is a valuable source of cells for therapeutic angiogenesis and implantation of ADSCs can salvage tissues from critical ischemia. Moreover, SDF-1 may play an important role in mediating therapeutic angiogenesis for ischemic disease by mobilization of BM-derived EPCs.