The microenvironment provides cues that control the behavior of epithelial stem and progenitor cells. Here, we identify matrix metalloproteinase-3 (MMP3) as a regulator of Wnt signaling and mammary stem cell (MaSC) activity. We show that MMP3 overexpression promotes hyperplastic epithelial growth, surprisingly, in a nonproteolytic manner via its hemopexin (HPX) domain. We demonstrate that MMP3-HPX specifically binds and inactivates Wnt5b, a noncanonical Wnt ligand that inhibits canonical Wnt signaling and mammary epithelial outgrowth in vivo. Indeed, transplants overexpressing MMP3 display increased canonical Wnt signaling, demonstrating that MMP3 is an extracellular regulator of the Wnt signaling pathway. MMP3-deficient mice exhibit decreased MaSC populations and diminished mammary-reconstituting activity, whereas MMP3 overexpression elevates MaSC function, indicating that MMP3 is necessary for the maintenance of MaSCs. Our study reveals a mechanism by a microenvironmental protease that regulates Wnt signaling and impacts adult epithelial stem cell function.
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