期刊
BLOOD
卷 119, 期 23, 页码 5405-5416出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-11-390849
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资金
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- MEXT
- Mitsubishi Pharma Research Foundation
- Program for Improvement of the Research Environment for Young Researchers
- Special Coordination Funds for Promoting Science and Technology of the MEXT, Japan
- ENSHIN Medical Research Foundation
- Kyowa Hakko Kirin Co Ltd
- Daiichi Sankyo Company Ltd
- Grants-in-Aid for Scientific Research [24591382, 23591371, 24591313, 22112009, 11J00480, 12J04973, 22112007] Funding Source: KAKEN
HSC fate decisions are regulated by cell-intrinsic and cell-extrinsic cues. The latter cues are derived from the BM niche. Membrane-type 1 matrix metalloproteinase (MT1-MMP), which is best known for its proteolytic role in pericellular matrix remodeling, is highly expressed in HSCs and stromal/niche cells. We found that, in MT1-MMP-/- mice, in addition to a stem cell defect, the transcription and release of kit ligand (KitL), stromal cell-derived factor-1 (SDF-1/CXCL12), erythropoietin (Epo), and IL-7 was impaired, resulting in a trilineage hematopoietic differentiation block, while addition of exogenous KitL and SDF-1 restored hematopoiesis. Further mechanistic studies revealed that MT1-MMP activates the hypoxia-inducible factor-1 (HIF-1) pathway via factor inhibiting HIF-1 (FIH-1) within niche cells, thereby inducing the transcription of HIF-responsive genes, which induce terminal hematopoietic differentiation. Thus, MT1-MMP in niche cells regulates postnatal hematopoiesis, by modulating hematopoietic HIF-dependent niche factors that are critical for terminal differentiation and migration. (Blood. 2012;119(23):5405-5416)
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