COMP-Ang1 stimulates HIF-1a-mediated SDF-1 overexpression and recovers ischemic injury through BM-derived progenitor cell recruitment.

Youn SW, Lee SW, Lee J, Jeong HK, Suh JW, Yoon CH, Kang HJ, Kim HZ, Koh GY, Oh BH, Park YB, Kim HS.
Source: Blood
Publication Date: (2011)
Issue: 117(16): 4376-86
Research Area:
Stem Cells
Basic Research
Cells used in publication:
Endothelial, umbilical vein, human (HUVEC)
Species: human
Tissue Origin: vein
Mononuclear, peripheral blood, human
Species: human
Tissue Origin: blood
Recruitment and adhesion of bone marrow (BM)-derived circulating progenitor cells to ischemic tissue are important for vasculogenesis and tissue repair. Recently, we found cartilage oligomeric matrix protein (COMP)-Ang1 is a useful cell-priming agent to improve the therapeutic efficacy of progenitor cells. However, the effect and the underlying mechanisms of COMP-Ang1 on recruitment of BM-derived progenitor cells (BMPCs) to foci of vascular injury have not been well defined. Here, we found that COMP-Ang1 is a critical stimulator of stromal cell-derived factor 1 (SDF-1), the principal regulator of BM-cell trafficking. Furthermore, SDF-1 stimulation by COMP-Ang1 was blocked by small-interfering RNA (siRNA) against hypoxia-inducible factor-1a (HIF-1a). COMP-Ang1 increased the synthesis of HIF-1a by activating mammalian target of rapamycin (mTOR) in hypoxic endothelium. The intermediate mechanism transmitting the COMP-Ang1 signal to the downstream mTOR/HIF-1a/SDF-1 pathway was the enhanced binding of the Tie2 receptor with integrin-linked kinase (ILK), an upstream activator of mTOR. In the mouse ischemic model, local injection of COMP-Ang1 stimulated the incorporation of BMPCs into ischemic limb, thereby enhancing neovasculogenesis and limb salvage. Collectively, our findings identify the COMP-Ang1/HIF-1a/SDF-1 pathway as a novel inducer of BMPC recruitment and neovasculogenesis in ischemic disease.