Journal
BLOOD
Volume 117, Issue 16, Pages 4376-4386Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-07-295964
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Funding
- Innovative Research Institute for Cell Therapy [A062260]
- Korea government (MEST) [2010-0020257]
- Ministry of Education and Science, Korea
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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-1 alpha(HIF-1 alpha). COMP-Ang1 increased the synthesis of HIF-1 alpha by activating mammalian target of rapamycin (mTOR) in hypoxic endothelium. The intermediate mechanism transmitting the COMP-Ang1 signal to the downstream mTOR/HIF-1 alpha/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-1 alpha/SDF-1 pathway as a novel inducer of BMPC recruitment and neovasculogenesis in ischemic disease. (Blood. 2011; 117(16):4376-4386)
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