Seock-Won Youn, MS1*, Sae-Won Lee, PhD1,2*, Jaewon Lee, BS1, Han-Kyul Jeong, BS1, Jung-Won Suh, MD1, Chang-Hwan Yoon, MD1, Hyun-Jae Kang, MD1, Hak-Zoo Kim, PhD3, Gou-Young Koh, MD3, Byung-Hee Oh, MD1, Young-Bae Park1 and Hyo-Soo Kim, MD1,2,4#
1 Department of Internal Medicine, and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea, Republic of; 2 Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea, Republic of; 3 Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon, Korea, Republic of
* S-W.Y. and S-W.L. contributed equally to this work
# Corresponding author
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 (SDF-1), the principal regulator of BM-cells trafficking. Furthermore, SDF-1 stimulation by COMP-Ang1 was blocked by siRNA against hypoxia-inducible factor-1α (HIF-1α). COMP-Ang1 increased the synthesis of HIF-1 by activating mammalian target of rapamycin (mTOR) in hypoxic endothelium. The intermediate mechanism transmitting COMP-Ang1 signal to downstream mTOR/HIF1α/SDF-1 pathway was the enhanced binding of Tie2 receptor with integrin-linked kinase (ILK), an upstream activator of mTOR. In mouse ischemic model, local injection of COMP-Ang1 stimulated the incorporation of BMPCs into ischemic limb, thereby enhanced neovasculogenesis and limb salvage. Collectively, our findings identify COMP-Ang1/HIF-1α/SDF-1 pathway as a novel inducer of BMPCs recruitment and neovasculogenesis in ischemic disease.