Vimentin protects cells against nuclear rupture and DNA damage during migration

Abstract

Mammalian cells frequently migrate through tight spaces during normal embryogenesis, wound healing, diapedesis, or in pathological situations such as metastasis. Nuclear size and shape are important factors in regulating the mechanical properties of cells during their migration through such tight spaces. At the onset of migratory behavior, cells often initiate the expression of vimentin, an intermediate filament protein that polymerizes into networks extending from a juxtanuclear cage to the cell periphery. However, the role of vimentin intermediate filaments (VIFs) in regulating nuclear shape and mechanics remains unknown. Here, we use wild-type and vimentin-null mouse embryonic fibroblasts to show that VIFs regulate nuclear shape and perinuclear stiffness, cell motility in 3D, and the ability of cells to resist large deformations. These changes increase nuclear rupture and activation of DNA damage repair mechanisms, which are rescued by exogenous reexpression of vimentin. Our findings show that VIFs provide mechanical support to protect the nucleus and genome during migration.

Correlating nuclear morphology and external force with combined atomic force microscopy and light sheet imaging separates roles of chromatin and lamin A/C in nuclear mechanics

“…Nuclear mechanics are primarily dictated by the nuclear lamina and chromatin, as well as indirectly influenced by the cytoskeleton (Stephens, Banigan, and Marko 2019). The cytoskeleton protects the nucleus both through an actin cap (Khatau et al 2009;Haase et al 2016;Kim et al 2018) and a peri-nuclear cage of the intermediate filament vimentin (Neelam et al 2015;Patteson et al 2019;Rosso, Liashkovich, and Shahin 2019). The nuclear lamina, primarily lamin A/C, has consistently been shown to be a major mechanical constituent of the nucleus through constricted migration, micropipette aspiration, atomic force microscopy, micromanipulation, and other techniques (Dahl et al 2004;Lammerding et al 2004;Dahl et al 2005;Lammerding et al 2006;Lee et al 2007;Pajerowski et al 2007;Schape et al 2009;Swift et al 2013;Hanson et al 2015;Neelam et al 2015;Stephens et al 2017).…”

Keratins couple with the nuclear lamina and regulate proliferation in colonic epithelial cells

“…This is supported by the findings that epidermal K1/K10 loss in mice is associated with decreased levels of lamin A/C, emerin and SUN1 and a likely decoupling of the cytoskeleton and the nuclear lamina, leading to weakened nuclear integrity and premature loss of nuclei (Wallace et al, 2012). Similarly, mesenchymal vimentin IFs were recently shown to mechanically support nuclei, as the loss of vimentin caused increased nuclear rupture and DNA damage during cell migration (Patteson et al, 2019).…”

Nuclear Plasticity Increases Susceptibility to Damage During Confined Migration

“…Compact chromatin network acts as an elastic spring to resist small deformations [49]. While small strains lead to strain stiening of nuclei due to chromatin compaction [48], large deformation of nuclei is facilitated by the actin and vimentin cytoskeleton [40] and Lamin A/C [48]. A full rupture in the membrane allows the intranuclear pressure to become more than the intracellular pressure, thus facilitating the leakage of genetic material into the cytosol.…”