Nuclear Lamin-A Scales with Tissue Stiffness and Enhances Matrix-Directed Differentiation

Lamins and Tissue Stiffness

Microenvironment can influence cell fate and behavior; for example, extracellular matrix (ECM) stiffness increases cell proliferation, and ECM rigidity induces disorders in tissue morphogenesis by increasing cell tension. Swift et al. ( 1240104 ; see the Perspective by [Related article:] Bainer and Weaver ) used proteomics to identify molecules that are mechanical sensors for tissue elasticity in the nucleus and discovered that expression of lamin-A levels apparently functions as a “mechanostat.”

Abstract

Tissues that need to remain stiff under stress rely on lamin-A to keep the cell nucleus whole. [Also see Perspective by [Related article:]Bainer and Weaver ]

Abstract

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.