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A role for matrix metalloproteinases in regulating mammary stem cell function via the Wnt signaling pathway

Kai Kessenbrock1, Gerrit J P Dijkgraaf, Devon A Lawson

  • 1Department of Anatomy and Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94143, USA.

Cell Stem Cell
|July 23, 2013
PubMed

Insights

Matrix metalloproteinase-3 (MMP3) regulates mammary stem cell (MaSC) activity by inactivating Wnt5b. This microenvironmental protease is crucial for maintaining MaSC function and epithelial growth.

Area of Science:

  • Stem cell biology
  • Molecular and cell biology
  • Cancer research

Background:

  • The tissue microenvironment significantly influences epithelial stem and progenitor cell behavior.
  • Wnt signaling pathways are critical regulators of stem cell function and tissue homeostasis.

Purpose of the Study:

  • To identify microenvironmental factors regulating mammary stem cell (MaSC) activity and Wnt signaling.
  • To elucidate the role of matrix metalloproteinase-3 (MMP3) in mammary gland development and MaSC maintenance.

Main Methods:

  • Investigated MMP3 function in mammary stem cells using mouse models.
  • Analyzed MMP3's interaction with Wnt ligands, specifically Wnt5b.
  • Assessed canonical Wnt signaling and MaSC activity in MMP3-deficient and overexpressing mice.

Main Results:

  • MMP3 overexpression promotes hyperplastic epithelial growth via its hemopexin (HPX) domain in a nonproteolytic manner.
  • MMP3-HPX directly binds and inactivates Wnt5b, a Wnt ligand that normally inhibits canonical Wnt signaling.
  • MMP3 is essential for maintaining MaSC populations and mammary-reconstituting activity; its absence diminishes these functions.

Conclusions:

  • MMP3 acts as an extracellular regulator of Wnt signaling, impacting adult epithelial stem cell function.
  • The nonproteolytic activity of MMP3's HPX domain is key to its regulation of Wnt5b and subsequent effects on MaSCs.
  • MMP3 is indispensable for the maintenance and function of mammary stem cells within their microenvironment.

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