title: MT1-MMP plays a critical role in hematopoiesis by regulating HIF-mediated chemokine/cytokine gene transcription within niche cells.
abstract: 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.
authors.affiliation: Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Chiemi
authors.initials: C
authors.lastname: Nishida
authors.forename: Kaori
authors.initials: K
authors.lastname: Kusubata
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tashiro
authors.forename: Ismael
authors.initials: I
authors.lastname: Gritli
authors.forename: Aki
authors.initials: A
authors.lastname: Sato
authors.forename: Makiko
authors.initials: M
authors.lastname: Ohki-Koizumi
authors.forename: Yohei
authors.initials: Y
authors.lastname: Morita
authors.forename: Makoto
authors.initials: M
authors.lastname: Nagano
authors.forename: Takeharu
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Naohiko
authors.initials: N
authors.lastname: Koshikawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kuchimaru
authors.forename: Shinae
authors.initials: S
authors.lastname: Kizaka-Kondoh
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: Beate
authors.initials: B
authors.lastname: Heissig
authors.forename: Koichi
authors.initials: K
authors.lastname: Hattori
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics*; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019089:Stem Cell Factor / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D054377:Chemokine CXCL12; D018925:Chemokines; D016207:Cytokines; D051793:Hypoxia-Inducible Factor 1; D019089:Stem Cell Factor; D053511:Matrix Metalloproteinase 14