Mechanosensing of matrix by stem cells: From matrix heterogeneity, contractility, and the nucleus in pore-migration to cardiogenesis and muscle stem cells in vivo

Abstract

Stem cells are particularly ‘plastic’ cell types that are induced by various cues to become specialized, tissuefunctional lineages by switching on the expression of specific gene programs. Matrix stiffness is among the cues that multiple stem cell types can sense and respond to. This seminar-style review focuses on mechanosensing of matrix elasticity in the differentiation or early maturation of a few illustrative stem cell types, with an intended audience of biologists and physical scientists. Contractile forces applied by a cell’s acto-myosin cytoskeleton are often resisted by the extracellular matrix and transduced through adhesions and the cytoskeleton ultimately into the nucleus to modulate gene expression. Complexity is added by matrix heterogeneity, and careful scrutiny of the evident stiffness heterogeneity in some model systems resolves some controversies concerning matrix mechanosensing. Importantly, local stiffness tends to dominate, and ‘durotaxis’ of stem cells toward stiff matrix reveals a dependence of persistent migration on myosin-II force generation and also rigid microtubules that confer directionality. Stem and progenitor cell migration in 3D can be further affected by matrix porosity as well as stiffness, with nuclear size and rigidity influencing niche retention and fate choices. Cell squeezing through rigid pores can even cause DNA damage and genomic changes that contribute to de-differentiation toward stem cell-like states. Contraction of acto-myosin is the essential function of striated muscle, which also exhibit mechanosensitive differentiation and maturation as illustrated in vivo by beating heart cells and by the regenerative mobilization of skeletal muscle stem cells.

Cellular Mechanotransduction: From Tension to Function

“…The nanostructure and the composition of the ECM is strictly controlled in a tissue-specific fashion during development and in adulthood in order to favor cell and organ function ( Smith et al, 2017 ). Changes in ECM composition and mechanics are encountered during the progression of all degenerative diseases as the result of aging or as a compensatory attempt of the tissue to preserve its function ( Kim et al, 2000 ; Parker et al, 2014 ; Klaas et al, 2016 ).…”

Mechanical Cues Affect Migration and Invasion of Cells From Three Different Directions

“…The nanostructure of the extracellular matrix and specific collection of the extracellular matrix molecules is precisely guided in a tissue-specific manner during tissue development to provide proper functions of cells and entire organs (Smith et al, 2017). Alterations of the composition in extracellular matrix scaffold and the mechanical phenotype are observed in the course of the progression of most degenerative diseases and show the outcome of aging or, as a compensatory effort of the tissue, maintain its proper function (Kim et al, 2000;Parker et al, 2014;Klaas et al, 2016).…”

How the mechanobiome drives cell behavior, viewed through the lens of control theory

“…Studies have found that physiologically relevant mechanical cues, such as substrate stiffness, help dictate the differentiation of progenitor stem cells, and that myosin II plays a central role (Engler et al, 2006). Moreover, YAP translocation in and out of the nucleus in response to substrate stiffness is required for stem cells to differentiate accurately (Guilak et al, 2009;Lian et al, 2010;Smith et al, 2017;Totaro et al, 2017). This mechanically transduced transcriptional pathway also engages in positive feedback with the cytoskeletal network.…”