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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Acyltransferases
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Adipogenesis
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Animals
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Bone Marrow Cells / metabolism
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Cell Cycle Proteins
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Cell Lineage
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Cell Nucleus / genetics
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Cell Nucleus / metabolism
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Cell Shape
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Cells, Cultured
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Chondrogenesis
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Extracellular Matrix / genetics
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Extracellular Matrix / metabolism
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Gene Knock-In Techniques
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Humans
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Integrin beta1 / metabolism*
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Matrix Metalloproteinase 14 / genetics
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Matrix Metalloproteinase 14 / metabolism*
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Mesenchymal Stem Cells / cytology
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Mesenchymal Stem Cells / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Osteogenesis
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Phenotype
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Proteolysis
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Signal Transduction*
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Stem Cell Niche
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcriptional Activation
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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Integrin beta1
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Mmp14 protein, mouse
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Phosphoproteins
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Transcription Factors
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YAP-Signaling Proteins
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Yap1 protein, mouse
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Acyltransferases
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tafazzin protein, mouse
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MMP14 protein, human
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Matrix Metalloproteinase 14