title: COMP-Ang1 stimulates HIF-1α-mediated SDF-1 overexpression and recovers ischemic injury through BM-derived progenitor cell recruitment.
abstract: 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-1α (HIF-1α). COMP-Ang1 increased the synthesis of HIF-1α by activating mammalian target of rapamycin (mTOR) in hypoxic endothelium. The intermediate mechanism transmitting the COMP-Ang1 signal to the downstream mTOR/HIF-1α/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-1α/SDF-1 pathway as a novel inducer of BMPC recruitment and neovasculogenesis in ischemic disease.
authors.affiliation: Department of Internal Medicine, and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea.
authors.forename: Seock-Won
authors.initials: SW
authors.lastname: Youn
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Lee
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.forename: Han-Kyul
authors.initials: HK
authors.lastname: Jeong
authors.forename: Jung-Won
authors.initials: JW
authors.lastname: Suh
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Yoon
authors.forename: Hyun-Jae
authors.initials: HJ
authors.lastname: Kang
authors.forename: Hak-Zoo
authors.initials: HZ
authors.lastname: Kim
authors.forename: Gou-Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Byung-Hee
authors.initials: BH
authors.lastname: Oh
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Park
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects*; D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000627:therapeutic use*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C515576:COMP-Ang1 fusion protein; D054377:Chemokine CXCL12; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011993:Recombinant Fusion Proteins; D058570:TOR Serine-Threonine Kinases