Skeletal muscle is representative: a sparse population of muscle stem cells (MuSC), or myoblasts, are squeezed within an interstitial matrix between adjacent myofibers, and the MuSC are activated by nearby injury to proliferate, migrate, and fuse into damaged myofibers ( Figure 1A Yin et al., 2013). As a cell migrates through either a dense tissue or a diseased fibrotic matrix, cell contortions invariably distort the nucleus, but for a stem cell nucleus, the consequences of constricted migration are largely unknown. Tissue repair can thus be modulated up or down by the curvature of pores through which stem cells squeeze.įor many solid tissues, a stem or progenitor cell must physically travel to a site of injury for regeneration of the tissue. Human MSCs exhibit similar damage, but osteogenesis increases-which is relevant to bone and to calcified fibrotic tissues, including diseased muscle. Although perturbed proliferation fails to explain defective differentiation, nuclear rupture mislocalizes differentiation-relevant MyoD and KU80 (a DNA repair factor), with nuclear entry of the DNA-binding factor cGAS.
Myosin II inhibition rescues rupture and DNA damage, implicating nuclear forces, while mitosis and the cell cycle are suppressed by constricted migration, consistent with a checkpoint. Fewer myoblasts fuse into regenerating muscle in vivo after constricted migration in vitro, and myodifferentiation in vitro is likewise suppressed. In this study, constricted migration of myoblastic cell types and mesenchymal stem cells (MSCs) increases nuclear rupture, increases DNA damage, and modulates differentiation. Tissue regeneration at an injured site depends on proliferation, migration, and differentiation of resident stem or progenitor cells, but solid tissues are often sufficiently dense and constricting that nuclei are highly stressed by migration.
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