Tissues can be soft like fat, which bears little stress, or stiff like bone, which sustains high stress, but whether there is a systematic relationship between tissue mechanics and differentiation is unknown. Here, proteomics analyses revealed that levels of the nucleoskeletal protein lamin-A scaled with tissue elasticity, E, as did levels of collagens in the extracellular matrix that determine E. Stem cell differentiation into fat on soft matrix was enhanced by low lamin-A levels, whereas differentiation into bone on stiff matrix was enhanced by high lamin-A levels. Matrix stiffness directly influenced lamin-A protein levels, and, although lamin-A transcription was regulated by the vitamin A/retinoic acid (RA) pathway with broad roles in development, nuclear entry of RA receptors was modulated by lamin-A protein. Tissue stiffness and stress thus increase lamin-A levels, which stabilize the nucleus while also contributing to lineage determination.

Lamins impede 3D migration but also promote survival against migration-induced stresses.

Summary Tissue microenvironments are characterized not only in terms of chemical composition but also by collective properties such as stiffness, which influences the contractility of a cell, its adherent morphology, and even differentiation [1–8]. The nucleoskeletal protein lamin-A,C increases with matrix stiffness, confers nuclear mechanical properties, and influences differentiation of mesenchymal stem cells (MSCs) [9]. Here we show in single cell analyses that matrix stiffness couples to myosin-II activity to promote lamin-A,C dephosphorylation at Ser22, which regulates turnover, lamina physical properties, and actomyosin expression. Lamin-A,C phosphorylation is low in interphase versus dividing cells and its levels rise with states of nuclear rounding in which myosin-II generates little to no tension. Phosphorylated lamin-A,C localizes to nucleoplasm, and phosphorylation is enriched on lamin-A,C fragments and is suppressed by a cyclin-dependent kinase (CDK) inhibitor. Lamin-A,C knockdown in primary MSCs suppresses transcripts predominantly among actomyosin genes, especially in the Serum Response Factor (SRF) pathway. Levels of myosin-IIA thus parallel levels of lamin-A,C, with phosphosite mutants revealing a key role for phospho-regulation. In modeling the system as a parsimonious gene circuit, tension-dependent stabilization of lamin-A,C and myosin-IIA is shown to suitably couple nuclear and cell morphology downstream of matrix mechanics.

Cytoskeletal polarization occurs in response to mechanosensing of a transition from soft to stiff matrix during migration and promotes dephosphorylation of myosin-IIA, rearward localization of myosin-IIB, and durotaxis.

Graphene is a single-atomic-layer material with excellent mechanical properties and has the potential to enhance the strength of composites. Its two-dimensional geometry, high intrinsic strength and modulus can effectively constrain dislocation motion, resulting in the significant strengthening of metals. Here we demonstrate a new material design in the form of a nanolayered composite consisting of alternating layers of metal (copper or nickel) and monolayer graphene that has ultra-high strengths of 1.5 and 4.0 GPa for copper-graphene with 70-nm repeat layer spacing and nickel-graphene with 100-nm repeat layer spacing, respectively. The ultra-high strengths of these metal-graphene nanolayered structures indicate the effectiveness of graphene in blocking dislocation propagation across the metal-graphene interface. Ex situ and in situ transmission electron microscopy compression tests and molecular dynamics simulations confirm a build-up of dislocations at the graphene interface.