title: Cell guidance into quiescent state through chromatin remodeling induced by elastic modulus of substrate.
abstract: Substrate stiffness is known to strongly influence the fate of adhering cells. Yet, little is known about the influence of the substrate stiffness on chromatin. Chromatin integrates a multitude of biochemical signals interpreted by activation or gene silencing. Here we investigate for the first time the organization of chromatin of epithelial cells on substrate with various mechanical properties. On stiff substrates (100-200 kPa), where cells preferentially adhere, chromatin is mainly found in its euchromatin form. Decreasing the Young modulus to 50 kPa is correlated with a partial shift from euchromatin to heterochromatin. On very soft substrates (≪10 kPa) this is accompanied by cell lysis. On these very soft substrates, histone deacetylase inhibition by adding a drug preserves acetylated histone and thus maintains the euchromatin form, thereby keeping intact the nuclear envelope as well as a residual intermediate filament network around the nucleus. This allows cells to survive in a non-adherent state without undergoing proliferation. When transfer on a stiff substrate these cells retain their capacity to adhere, to spread and to enter a novel mitotic cycle. A similar effect is observed on soft substrates (50 kPa) without need of histone deacetylase inhibition. These new results suggest that on soft substrates cells might enter in a quiescence state. Cell quiescence may thus be triggered by the Young modulus of a substrate, a major result for strategies focusing on the design of scaffold in tissue engineering.
authors.affiliation: INSERM UMR 1121, 11 rue Humann, 67085 Strasbourg, France; Faculté de Chirurgie Dentaire, Université de Strasbourg, 8 rue Sainte-Elisabeth, 67000 Strasbourg, France; Fédération de Médecine Translationnelle, Strasbourg, France.
authors.forename: Morgane
authors.initials: M
authors.lastname: Rabineau
authors.affiliation: INSERM UMR 1121, 11 rue Humann, 67085 Strasbourg, France; Faculté de Chirurgie Dentaire, Université de Strasbourg, 8 rue Sainte-Elisabeth, 67000 Strasbourg, France; Fédération de Médecine Translationnelle, Strasbourg, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Flick
authors.affiliation: INSERM UMR 1121, 11 rue Humann, 67085 Strasbourg, France; Faculté de Chirurgie Dentaire, Université de Strasbourg, 8 rue Sainte-Elisabeth, 67000 Strasbourg, France; Fédération de Médecine Translationnelle, Strasbourg, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Mathieu
authors.affiliation: INSERM UMR 1121, 11 rue Humann, 67085 Strasbourg, France; Faculté de Chirurgie Dentaire, Université de Strasbourg, 8 rue Sainte-Elisabeth, 67000 Strasbourg, France; Fédération de Médecine Translationnelle, Strasbourg, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Tu
authors.affiliation: INSERM UMR 1121, 11 rue Humann, 67085 Strasbourg, France; Faculté de Chirurgie Dentaire, Université de Strasbourg, 8 rue Sainte-Elisabeth, 67000 Strasbourg, France; Fédération de Médecine Translationnelle, Strasbourg, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Senger
authors.affiliation: INSERM UMR 1121, 11 rue Humann, 67085 Strasbourg, France; Faculté de Chirurgie Dentaire, Université de Strasbourg, 8 rue Sainte-Elisabeth, 67000 Strasbourg, France; Fédération de Médecine Translationnelle, Strasbourg, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Voegel
authors.affiliation: INSERM UMR 1121, 11 rue Humann, 67085 Strasbourg, France; Faculté de Chirurgie Dentaire, Université de Strasbourg, 8 rue Sainte-Elisabeth, 67000 Strasbourg, France; Fédération de Médecine Translationnelle, Strasbourg, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lavalle
authors.affiliation: INSERM UMR 1121, 11 rue Humann, 67085 Strasbourg, France; Faculté de Chirurgie Dentaire, Université de Strasbourg, 8 rue Sainte-Elisabeth, 67000 Strasbourg, France; Fédération de Médecine Translationnelle, Strasbourg, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Schaaf
authors.affiliation: INSERM UMR S1113, Université de Strasbourg, 3 Avenue Molière, 67200 Strasbourg, France; Fédération de Médecine Translationnelle, Strasbourg, France.
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Freund
authors.affiliation: INSERM UMR 1121, 11 rue Humann, 67085 Strasbourg, France; Faculté de Chirurgie Dentaire, Université de Strasbourg, 8 rue Sainte-Elisabeth, 67000 Strasbourg, France; Fédération de Médecine Translationnelle, Strasbourg, France.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Haikel
authors.affiliation: INSERM UMR 1121, 11 rue Humann, 67085 Strasbourg, France; Faculté de Chirurgie Dentaire, Université de Strasbourg, 8 rue Sainte-Elisabeth, 67000 Strasbourg, France; Fédération de Médecine Translationnelle, Strasbourg, France. Electronic address: Vautier@unistra.fr.
authors.forename: Dominique
authors.initials: D
authors.lastname: Vautier
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D055119:Elastic Modulus / Q000187:drug effects; D004573:Electrolytes / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D022041:Euchromatin / Q000378:metabolism; D006570:Heterochromatin / Q000378:metabolism; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D013379:Substrate Specificity / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004573:Electrolytes; D022041:Euchromatin; D006570:Heterochromatin; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000090266:Chromobox Protein Homolog 5; C012589:trichostatin A; D006655:Histone Deacetylases
keywords: Biomaterials; Chromatin plasticity; Histone deacetylase inhibition; Nucleus; Polyelectrolyte multilayer films; Substrate stiffness