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

Seock Won Youn, Sae Won Lee, Jaewon Lee, Han Kyul Jeong, Jung Won Suh, Chang Hwan Yoon, Hyun Jae Kang, Hak Zoo Kim, Gou Young Koh, Byung Hee Oh, Young Bae Park, Hyo Soo Kim

Research output: Contribution to journalArticle

60 Citations (Scopus)

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 integrinlinked 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.

Original languageEnglish (US)
Pages (from-to)4376-4386
Number of pages11
JournalBlood
Volume117
Issue number16
DOIs
StatePublished - Apr 21 2011

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Cartilage Oligomeric Matrix Protein
Chemokine CXCL12
Bone
Stem Cells
Bone Marrow
Wounds and Injuries
Sirolimus
TIE-2 Receptor
Tissue
Hypoxia-Inducible Factor 1
Salvaging
Limb Salvage
Vascular System Injuries
Bone Marrow Cells
Small Interfering RNA
Endothelium
Repair
Phosphotransferases
Adhesion
Extremities

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

COMP-Ang1 stimulates HIF-1α-mediated SDF-1 overexpression and recovers ischemic injury through BM-derived progenitor cell recruitment. / Youn, Seock Won; Lee, Sae Won; Lee, Jaewon; Jeong, Han Kyul; Suh, Jung Won; Yoon, Chang Hwan; Kang, Hyun Jae; Kim, Hak Zoo; Koh, Gou Young; Oh, Byung Hee; Park, Young Bae; Kim, Hyo Soo.

In: Blood, Vol. 117, No. 16, 21.04.2011, p. 4376-4386.

Research output: Contribution to journalArticle

Youn, SW, Lee, SW, Lee, J, Jeong, HK, Suh, JW, Yoon, CH, Kang, HJ, Kim, HZ, Koh, GY, Oh, BH, Park, YB & Kim, HS 2011, 'COMP-Ang1 stimulates HIF-1α-mediated SDF-1 overexpression and recovers ischemic injury through BM-derived progenitor cell recruitment', Blood, vol. 117, no. 16, pp. 4376-4386. https://doi.org/10.1182/blood-2010-07-295964
Youn, Seock Won ; Lee, Sae Won ; Lee, Jaewon ; Jeong, Han Kyul ; Suh, Jung Won ; Yoon, Chang Hwan ; Kang, Hyun Jae ; Kim, Hak Zoo ; Koh, Gou Young ; Oh, Byung Hee ; Park, Young Bae ; Kim, Hyo Soo. / COMP-Ang1 stimulates HIF-1α-mediated SDF-1 overexpression and recovers ischemic injury through BM-derived progenitor cell recruitment. In: Blood. 2011 ; Vol. 117, No. 16. pp. 4376-4386.
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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 integrinlinked 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.",
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AU - Jeong, Han Kyul

AU - Suh, Jung Won

AU - Yoon, Chang Hwan

AU - Kang, Hyun Jae

AU - Kim, Hak Zoo

AU - Koh, Gou Young

AU - Oh, Byung Hee

AU - Park, Young Bae

AU - Kim, Hyo Soo

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N2 - 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 integrinlinked 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.

AB - 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 integrinlinked 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.

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