Minimal matrix models of scars with fractal heterogeneity modulate stiff-niche stem-cell responses via nuclear exit of a mechanorepressor

摘要

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 a synthetic polymer hydorgel produces minimal matrix models of scars (MMMS), in which fractal-fibre bundles segregate heterogeneously to the hydrogel subsurface and stain strongly with Sirius Red (a histology dye). Matrix stiffens locally - as measured for scars-while allowing separate control over adhesive-ligand density. Comparing to public transcriptomes for fibrotic tissues, the MMMS elicits scar-like phenotypes from mesenchymal stem cells (MSCs) that are found in many tissues, often as pericytes around vessels. MSCs spread and polarize quickly on the MMMS but express the 'scar marker' smooth muscle actin (SMA) more slowly. Surprisingly, expression responses to scarlike matrix exhibit less cell-to-cell noise than homogeneously stiff gels. Such differences from bulk-average responses arise because a strong repressor of SMA transcription, 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. P.C.D.P. Dingal, A.M. Bradshaw, S. Cho, M. Raab, A. Buxboim, J. Swift, and D.E. Discher. Fractal heterogeneity in minimal matrix models of scars modulates stiff-niche stem-cell responses via nuclear exit of a mechanorepressor. Nature Materials 14:951-960 (2015).