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Proteolytic Remodeling of the 3D Extracellular Matrix Controls the Nuclear Regulation of Mesenchymal Stem Cell Fate and Function

In vitro, topographical and biophysical cues arising from the extracellular matrix (ECM) direct mesenchymal stem cell (MSC) commitment and differentiation. While the mechanisms by which the MSC‐ECM interface is regulated and the outcome of such interactions on stem cell fate in vivo remains largely unexplored, we recently demonstrated that the membrane‐anchored metalloproteinase, MT1‐MMP (Mmp14), directs MSC fate decisions, including osteogenesis as well as adipo‐ and chondro‐genesis. 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, that serve to control MSC lineage commitment. Furthermore, we find that MT1‐MMP‐mediated proteolysis of the ECM additionally, but unexpectedly, controls nuclear architecture, chromatin remodeling and RNA transcription via a process dependent on the linker of nucleoskeleton and cytoskeleton (LINC) complex. These data identify a critical MT1‐MMP/nuclear axis operative in the 3D stem cell niche that oversees MSC fate determination.