Constricted migration modulates stem cell differentiation
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Lucas R. Smith, Jerome Irianto, Yuntao Xia, Charlotte R. Pfeifer, Dennis E. Discher
2019 Volume 30, Issue 16, mbc.E19-02-0090
Abstract
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 stressed by migration. Here, constricted migration of myoblastic cell types and mesenchymal stem cells (MSCs) increases nuclear rupture, increases DNA damage, and modulates differentiation. Fewer myoblasts fuse into regenerating muscle in vivo after constricted migration in vitro, and myo-differentiation in vitro is likewise suppressed. Myosin-II inhibition rescues rupture and DNA damage, implicating nuclear forces, while mitosis and cell cycle are suppressed by constricted migration, consistent with a checkpoint. Although perturbed proliferation fails to explain defective differentiation, nuclear rupture mis-localizes differentiation-relevant MyoD and KU80 (a DNA repair factor), with nuclear entry of DNA-binding factor cGAS. Human MSCs exhibit similar damage, but osteogenesis increases – relevant to bone and calcified fibrotic tissues, including diseased muscle. Tissue repair can thus be modulated up or down by the curvature of pores through which stem cells squeeze.
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