The laminin-keratin link shields the nucleus from mechanical deformation and signalling

Abstract

The mechanical properties of the extracellular matrix (ECM) dictate tissue behaviour. In epithelial tissues, laminin is both a very abundant ECM component, and a key supporting element. Here we show that laminin hinders the mechanoresponses of breast epithelial cells by shielding the nucleus from mechanical deformation. Coating substrates with laminin-111, unlike fibronectin or collagen I, impairs cell response to substrate rigidity, and YAP nuclear localization. Blocking the laminin-specific integrin β4 increases nuclear YAP ratios in a rigidity dependent manner, without affecting cell forces or focal adhesions. By combining mechanical perturbations and mathematical modelling, we show that β4 integrins establish a mechanical linkage between the substrate and the keratin cytoskeleton, which stiffens the network and shields the nucleus from actomyosin-mediated mechanical deformation. In turn, this affects nuclear YAP mechanoresponses and chromatin methylation. Our results demonstrate a mechanism by which tissues can regulate their sensitivity to mechanical signals.

Spatial cell fate manipulation of human pluripotent stem cells by controlling the microenvironment using photocurable hydrogel

“…The difference from our observations is likely due to our gel's high protein binding capacity(~2.2 times of glass surface), which results in a dense ECM ligand (Fig. 1G-H), thus promoting nuclear YAP, as observed previously (Kechagia et al, 2023;Lee et al, 2019;Stanton et al, 2019).…”

“…1G-H), thus promoting nuclear YAP, as observed previously. (Kechagia et al, 2023; Lee et al, 2019; Stanton et al, 2019).…”

“…Furthermore, even for a similar stiffness range, studies using different materials, such as electrospun nanofibers, have different results from those using hydrogels (Chen et al, 2020; Maldonado et al, 2017; Przybyla et al, 2016), indicating the culture substrate might not only affect cells by mechanotransduction but also other factors such as the substrate dimensionality and surface chemistry. The type and distribution of ECM proteins have been shown to influence stem cell mechanosensation and fate in conjunction with substrate stiffness (Kechagia et al, 2023; Lee et al, 2019; Shibata et al, 2018; Stanton et al, 2019; Wang et al, 2015; Zhang et al, 2017). In our research, to provide stable cell attachment, we used a high density of laminin 511, known for its strong cell attachment properties.…”

Matrix viscoelasticity controls epithelial cell mechanobiology through dimensionality

“…To delineate epithelial cell response to matrix energy dissipation, we employed MCF-10A cells, a wellestablished model for the breast epithelium (51). Focussing on single cells devoid of cell-cell contacts allowed us to isolate ECM mechanics-mediated mechanotransduction effects (52).…”

Emerging Co‐Assembled and Sustained Released Natural Medicinal Nanoparticles for Multitarget Therapy of Choroidal Neovascularization

“…[5] Therefore, the development of high compliance strategies based on noninvasive drug delivery techniques and long-term sustained-release and multifunctional formulations to effectively combat the complex pathogenesis of AMD is urgently needed. [6] Recently, various novel strategies or drugs have been developed for AMD treatment by inhibiting the complement pathway, [7,8] targeting the progression of fibrosis, [9,10] reducing the metabolism, [11] and deposition of lipofuscin precursors, neutralizing oxidative stress, [12] alleviating hypoxic levels, [13] improving vascular stability to inhibit pathological angiogenesis, [14][15][16][17] reducing intraocular chronic inflammation, [18][19][20][21] and so on. Nintedanib is a first-line drug used to treat pulmonary fibrosis by inhibiting nonreceptor tyrosine kinases and multiple receptor tyrosine kinases and also acts as an effective inhibitor for vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptors (FGFR), and platelet-derived growth factor receptors (PDGFR).…”