Differentiation alters stem cell nuclear architecture, mechanics, and mechano-sensitivity
Su-Jin Heo,
Tristan P Driscoll,
Stephen D Thorpe,
Nandan L Nerurkar,
Brendon M Baker,
Michael T Yang,
Christopher S Chen,
David A Lee,
Robert L Mauck
Affiliations
Su-Jin Heo
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
Tristan P Driscoll
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
Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, United Kingdom
Nandan L Nerurkar
Department of Genetics, Harvard Medical School, Harvard University, Boston, United States
Brendon M Baker
Department of Biomedical Engineering, College of Engineering, Boston University, Boston, United States; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, United States
Michael T Yang
Department of Biomedical Engineering, College of Engineering, Boston University, Boston, United States
Christopher S Chen
Department of Biomedical Engineering, College of Engineering, Boston University, Boston, United States; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, United States
David A Lee
Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, United Kingdom
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
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.
