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

P. C.Dave P. Dingal, Andrew M. Bradshaw, Sangkyun Cho, Matthew Raab, Amnon Buxboim, Joe Swift, Dennis E. Discher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

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 â scar markerâ €™ 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 â mechanical memoryâ €™ of rigidity by progressively suppressing NKX2.5, thereby elevating SMA in a scar-like state.

Original languageAmerican English
Pages (from-to)951-960
Number of pages10
JournalNature Materials
Volume14
Issue number9
DOIs
StatePublished - 21 Sep 2015
Externally publishedYes

Bibliographical note

Funding Information:
We thank H. Kasahara (University of Florida), H. L. Sweeney, C. Van Dang, J. D. Gearhart, A. Raj, and D. Lee (University of Pennsylvania), respectively, for NLS mutant NKX2.5 plasmids, normal and mdx mouse muscle, mouse liver tumour tissue, inducible NKX2.5 in virus, fluorescent probes against lamin-A mRNA, and help with peeling measurements. We thank the University of Pennsylvania’s Stem Cell Xenograft Core, Microscopy Core, and Microarray Core. We thank the Wistar Institute Proteomics Core for assistance with MS and standard data analyses. This work was supported by the National Institutes of Health, National Cancer Institute (grant U54-CA193417, D.E.D.), National Institute of Biomedical Imaging and Bioengineering (grant R01-EB007049, D.E.D.), National Heart, Lung, and Blood Institute (grant R01-HL124106, D.E.D.), National Institute of Diabetes and Digestive and Kidney Diseases (grants P01-DK032094 and P30-DK090969), National Center for Advancing Translational Sciences (grant 8UL1TR000003), the American Heart Association (14GRNT20490285, D.E.D.), the US/Israel Binational Science Foundation, and the National Science Foundation (1200834, Materials Research Science and Engineering Center, and Nano Science and Engineering Center-Nano Bio Interface Center).

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