Fractal heterogeneity in minimal matrix models of scars modulates stiff-niche stem-cell responses via nuclear exit of a mechanorepressor

Nat Mater. 2015 Sep;14(9):951-60. doi: 10.1038/nmat4350. Epub 2015 Jul 13.


Scarring is a long-lasting problem in higher animals, and reductionist approaches could aid in developing treatments. Here, we show that copolymerization of collagen I with polyacrylamide produces minimal matrix models of scars (MMMS), in which fractal-fibre bundles segregate heterogeneously to the hydrogel subsurface. Matrix stiffens locally-as in scars-while allowing separate control over adhesive-ligand density. The MMMS elicits scar-like phenotypes from mesenchymal stem cells (MSCs): cells spread and polarize quickly, increasing nucleoskeletal lamin-A yet expressing the 'scar marker' smooth muscle actin (SMA) more slowly. Surprisingly, expression responses to MMMS exhibit less cell-to-cell noise than homogeneously stiff gels. Such differences from bulk-average responses arise because a strong SMA repressor, NKX2.5, slowly exits the nucleus on rigid matrices. NKX2.5 overexpression overrides rigid phenotypes, inhibiting SMA and cell spreading, whereas cytoplasm-localized NKX2.5 mutants degrade in well-spread cells. MSCs thus form a 'mechanical memory' of rigidity by progressively suppressing NKX2.5, thereby elevating SMA in a scar-like state.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylic Resins / chemistry
  • Actins / metabolism
  • Active Transport, Cell Nucleus
  • Animals
  • Cell Nucleus / metabolism*
  • Cell Nucleus / pathology
  • Cicatrix / metabolism*
  • Cicatrix / pathology
  • Collagen Type I / chemistry
  • Extracellular Matrix / chemistry*
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins / metabolism*
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Models, Biological
  • Stem Cell Niche*
  • Transcription Factors / metabolism*


  • Acrylic Resins
  • Actins
  • Collagen Type I
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins
  • Nkx2-5 protein, mouse
  • Transcription Factors
  • alpha-smooth muscle actin, mouse
  • polyacrylamide