title: Differentiation alters stem cell nuclear architecture, mechanics, and mechano-sensitivity.
abstract: Mesenchymal stem cell (MSC) differentiation is mediated by soluble and physical cues. In this study, we investigated differentiation-induced transformations in MSC cellular and nuclear biophysical properties and queried their role in mechanosensation. Our data show that nuclei in differentiated bovine and human MSCs stiffen and become resistant to deformation. This attenuated nuclear deformation was governed by restructuring of Lamin A/C and increased heterochromatin content. This change in nuclear stiffness sensitized MSCs to mechanical-loading-induced calcium signaling and differentiated marker expression. This sensitization was reversed when the 'stiff' differentiated nucleus was softened and was enhanced when the 'soft' undifferentiated nucleus was stiffened through pharmacologic treatment. Interestingly, dynamic loading of undifferentiated MSCs, in the absence of soluble differentiation factors, stiffened and condensed the nucleus, and increased mechanosensitivity more rapidly than soluble factors. These data suggest that the nucleus acts as a mechanostat to modulate cellular mechanosensation during differentiation.
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.|Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Pennsylvania, United States.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Heo
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.|Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Pennsylvania, United States.
authors.forename: Tristan P
authors.initials: TP
authors.lastname: Driscoll
authors.affiliation: Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, United Kingdom.
authors.forename: Stephen D
authors.identifier: 0000-0002-4707-7756
authors.initials: SD
authors.lastname: Thorpe
authors.affiliation: Department of Genetics, Harvard Medical School, Harvard University, Boston, United States.
authors.forename: Nandan L
authors.initials: NL
authors.lastname: Nerurkar
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Boston University, Boston, United States.|Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, United States.
authors.forename: Brendon M
authors.initials: BM
authors.lastname: Baker
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Boston University, Boston, United States.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Yang
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Boston University, Boston, United States.|Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, United States.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, United Kingdom.
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, United States.|Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Pennsylvania, United States.
authors.forename: Robert L
authors.identifier: 0000-0002-9537-603X
authors.initials: RL
authors.lastname: Mauck
mesh_terms: D000818:Animals; D055592:Biophysical Phenomena; D002417:Cattle; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D006570:Heterochromatin / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*
chemical_list: D006570:Heterochromatin; D034904:Lamin Type A
keywords: cell biology; developmental biology; mechanotransduction; nuclear mechanics; stem cells