title: Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation.
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.
authors.affiliation: Molecular and Cell Biophysics Laboratory, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Swift
authors.forename: Irena L
authors.initials: IL
authors.lastname: Ivanovska
authors.forename: Amnon
authors.initials: A
authors.lastname: Buxboim
authors.forename: Takamasa
authors.initials: T
authors.lastname: Harada
authors.forename: P C Dave P
authors.initials: PC
authors.lastname: Dingal
authors.forename: Joel
authors.initials: J
authors.lastname: Pinter
authors.forename: J David
authors.initials: JD
authors.lastname: Pajerowski
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Spinler
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Shin
authors.forename: Manorama
authors.initials: M
authors.lastname: Tewari
authors.forename: Florian
authors.initials: F
authors.lastname: Rehfeldt
authors.forename: David W
authors.initials: DW
authors.lastname: Speicher
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Discher
mesh_terms: D050156:Adipogenesis; D000818:Animals; D002454:Cell Differentiation; D003094:Collagen / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D004548:Elasticity; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D034904:Lamin Type A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008954:Models, Biological; D034881:Nuclear Lamina / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D011487:Protein Conformation; D020543:Proteome; D013314:Stress, Mechanical; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism
chemical_list: D034904:Lamin Type A; D020543:Proteome; D014801:Vitamin A; D014212:Tretinoin; D003094:Collagen