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MT1-MMP-dependent control of skeletal stem cell commitment via a β1-integrin/YAP/TAZ signaling axis.

  • Author(s): Tang, Yi
  • Rowe, R Grant
  • Botvinick, Elliot L
  • Kurup, Abhishek
  • Putnam, Andrew J
  • Seiki, Motoharu
  • Weaver, Valerie M
  • Keller, Evan T
  • Goldstein, Steven
  • Dai, Jinlu
  • Begun, Dana
  • Saunders, Thomas
  • Weiss, Stephen J
  • et al.
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.

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