Publication date: 25th July 2016
Tissues such as brain and fat normally have a characteristic softness while tissues such as striated muscle have a characteristic stiffness, but of course tissue and matrix physical properties emerge in development, with ill-characterized effects on the earliest lineages. We have begun to uncover systematic relationships between tissue physical properties in development and differentiation as well as disease, motivated by studies years ago that matrix elasticity can help specify tissue lineages [1]. Here we will focus primarily on embryonic heart, which is the first functional organ, and recovers elastically when measured with the appropriate meso-scale tools [2]. Broad analyses of protein levels in embryonic heart as well as mature, and fibrotic tissues [2, 3, 4] have revealed that fibrous collagen polymers increase with tissue elasticity E, as does nuclear lamin-A (related to keratins), following polymer physics-type scaling. Lamin-A assembly controls nuclear stiffness, and differentiation of various cell types is modulated by lamin-A levels downstream of matrix E and soluble factors such as retinoids [2,4], with pathways such as SRF also being co-regulated by lamin-A. Complementary insights are obtained in structure-property analyses of cell migration, from stem cells to cancer cells [5], with surprising new results emerging for genomic changes.
1. A. Engler ... D.E. Discher. Matrix elasticity directs stem cell lineage specification. Cell 126: 677-689 (2006).
2. Majkut ... D.E. Discher. Heart-specific stiffening in early embryos parallels matrix and myosin levels to optimize beating. Current Biology23: 2434-2439 (2013).
3. J. Swift ... D.E. Discher. Nuclear Lamin-A Scales with Tissue Stiffness and Enhances Matrix-directed Differentiation. Science341: 1240104-1 to 15 (2013).
4. P.C.D.P. Dingal ... 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).
5. T. Harada ... D.E. Discher. Nuclear lamin stiffness is a barrier to 3D-migration, but softness can limit survival. Journal of Cell Biology 204:669-682 (2014).
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