期刊
NATURE MATERIALS
卷 14, 期 9, 页码 951-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NMAT4350
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资金
- National Institutes of Health, National Cancer Institute [U54-CA193417]
- National Institute of Biomedical Imaging and Bioengineering [R01 EB007049]
- National Heart Lung, and Blood Institute [R01-HL124106]
- National Institute of Diabetes and Digestive and Kidney Diseases [P01-DK032094, P30-DK090969]
- National Center for Advancing Translational Sciences [8UL1TR000003]
- American Heart Association [14GRNT20490285]
- US/Israel Binational Science Foundation
- National Science Foundation [1200834]
- Directorate For Engineering
- Div Of Civil, Mechanical, & Manufact Inn [1200834] Funding Source: National Science Foundation
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.
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