title: MT1-MMP-dependent control of skeletal stem cell commitment via a β1-integrin/YAP/TAZ signaling axis.
abstract: In vitro, topographical and biophysical cues arising from the extracellular matrix (ECM) direct skeletal stem cell (SSC) commitment and differentiation. However, the mechanisms by which the SSC-ECM interface is regulated and the outcome of such interactions on stem cell fate in vivo remain unknown. Here we demonstrate that conditional deletion of the membrane-anchored metalloproteinase MT1-MMP (Mmp14) in mesenchymal progenitors, but not in committed osteoblasts, redirects SSC fate decisions from osteogenesis to adipo- and chondrogenesis. By effecting ECM remodeling, MT1-MMP regulates stem cell shape, thereby activating a β1-integrin/RhoGTPase signaling cascade and triggering the nuclear localization of the transcriptional coactivators YAP and TAZ, which serve to control SSC lineage commitment. These data identify a critical MT1-MMP/integrin/YAP/TAZ axis operative in the stem cell niche that oversees SSC fate determination.
authors.affiliation: Division of Molecular Medicine & Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tang
authors.forename: R Grant
authors.initials: RG
authors.lastname: Rowe
authors.forename: Elliot L
authors.initials: EL
authors.lastname: Botvinick
authors.forename: Abhishek
authors.initials: A
authors.lastname: Kurup
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Putnam
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
authors.forename: Evan T
authors.initials: ET
authors.lastname: Keller
authors.forename: Steven
authors.initials: S
authors.lastname: Goldstein
authors.forename: Jinlu
authors.initials: J
authors.lastname: Dai
authors.forename: Dana
authors.initials: D
authors.lastname: Begun
authors.forename: Thomas
authors.initials: T
authors.lastname: Saunders
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Weiss
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D050156:Adipogenesis; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D018797:Cell Cycle Proteins; D019070:Cell Lineage; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D048430:Cell Shape; D002478:Cells, Cultured; D020219:Chondrogenesis; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D055879:Gene Knock-In Techniques; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010012:Osteogenesis; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D015398:Signal Transduction; D055153:Stem Cell Niche; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D019012:Integrin beta1; C507096:Mmp14 protein, mouse; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000217:Acyltransferases; C486363:tafazzin protein, mouse; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14