title: Biophysical Regulation of Chromatin Architecture Instills a Mechanical Memory in Mesenchymal Stem Cells.
abstract: Mechanical cues direct the lineage commitment of mesenchymal stem cells (MSCs). In this study, we identified the operative molecular mechanisms through which dynamic tensile loading (DL) regulates changes in chromatin organization and nuclear mechanics in MSCs. Our data show that, in the absence of exogenous differentiation factors, short term DL elicits a rapid increase in chromatin condensation, mediated by acto-myosin based cellular contractility and the activity of the histone-lysine N-methyltransferase EZH2. The resulting change in chromatin condensation stiffened the MSC nucleus, making it less deformable when stretch was applied to the cell. We also identified stretch induced ATP release and purinergic calcium signaling as a central mediator of this chromatin condensation process. Further, we showed that DL, through differential stabilization of the condensed chromatin state, established a 'mechanical memory' in these cells. That is, increasing strain levels and number of loading events led to a greater degree of chromatin condensation that persisted for longer periods of time after the cessation of loading. These data indicate that, with mechanical perturbation, MSCs develop a mechanical memory encoded in structural changes in the nucleus which may sensitize them to future mechanical loading events and define the trajectory and persistence of their lineage specification.
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Heo
authors.affiliation: Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, UK.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Thorpe
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA.|Translational Musculoskeletal Research Center, Philadelphia VA Medical Center, Philadelphia, PA, USA.
authors.forename: Tristan P
authors.initials: TP
authors.lastname: Driscoll
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, DE, USA.
authors.forename: Randall L
authors.initials: RL
authors.lastname: Duncan
authors.affiliation: Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Lee
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA.|Translational Musculoskeletal Research Center, Philadelphia VA Medical Center, Philadelphia, PA, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Mauck
mesh_terms: D000205:Actomyosin / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002417:Cattle; D019070:Cell Lineage / Q000235:genetics; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism* / Q000648:ultrastructure; D003599:Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000648:ultrastructure; D013264:Stifle / Q000166:cytology / Q000378:metabolism; D013314:Stress, Mechanical
chemical_list: D002843:Chromatin; D000255:Adenosine Triphosphate; D000205:Actomyosin; D011495:Histone-Lysine N-Methyltransferase; D002118:Calcium