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

Dev Cell. 2013 May 28;25(4):402-16. doi: 10.1016/j.devcel.2013.04.011. Epub 2013 May 16.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adipogenesis
  • Animals
  • Bone Marrow Cells / metabolism
  • Cell Cycle Proteins
  • Cell Lineage
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Cell Shape
  • Cells, Cultured
  • Chondrogenesis
  • Extracellular Matrix / genetics
  • Extracellular Matrix / metabolism
  • Gene Knock-In Techniques
  • Humans
  • Integrin beta1 / metabolism*
  • Matrix Metalloproteinase 14 / genetics
  • Matrix Metalloproteinase 14 / metabolism*
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Osteogenesis
  • Phenotype
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Proteolysis
  • Signal Transduction*
  • Stem Cell Niche
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Integrin beta1
  • Mmp14 protein, mouse
  • Phosphoproteins
  • Transcription Factors
  • Yap1 protein, mouse
  • tafazzin protein, mouse
  • MMP14 protein, human
  • Matrix Metalloproteinase 14