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Front Cell Neurosci. 2017 Apr 20;11:93. doi: 10.3389/fncel.2017.00093. eCollection 2017.

Mechanical Strain Promotes Oligodendrocyte Differentiation by Global Changes of Gene Expression.

Author information

1
Department of Materials Science and Engineering, Massachusetts Institute of TechnologyCambridge, MA, USA.
2
Department of Neuroscience, Wellesley CollegeWellesley, MA, USA.
3
Mechanobiology Institute, National University of SingaporeSingapore, Singapore.
4
Department of Biological Engineering, Massachusetts Institute of TechnologyCambridge, MA, USA.
5
Biotechnology Center, Technische Universität DresdenDresden, Germany.
6
Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute and Department of Clinical Neurosciences, University of CambridgeCambridge, UK.
7
BioSystems and Micromechanics Inter-Disciplinary Research Group, Singapore-MIT Alliance for Research and TechnologySingapore, Singapore.

Abstract

Differentiation of oligodendrocyte progenitor cells (OPC) to oligodendrocytes and subsequent axon myelination are critical steps in vertebrate central nervous system (CNS) development and regeneration. Growing evidence supports the significance of mechanical factors in oligodendrocyte biology. Here, we explore the effect of mechanical strains within physiological range on OPC proliferation and differentiation, and strain-associated changes in chromatin structure, epigenetics, and gene expression. Sustained tensile strain of 10-15% inhibited OPC proliferation and promoted differentiation into oligodendrocytes. This response to strain required specific interactions of OPCs with extracellular matrix ligands. Applied strain induced changes in nuclear shape, chromatin organization, and resulted in enhanced histone deacetylation, consistent with increased oligodendrocyte differentiation. This response was concurrent with increased mRNA levels of the epigenetic modifier histone deacetylase Hdac11. Inhibition of HDAC proteins eliminated the strain-mediated increase of OPC differentiation, demonstrating a role of HDACs in mechanotransduction of strain to chromatin. RNA sequencing revealed global changes in gene expression associated with strain. Specifically, expression of multiple genes associated with oligodendrocyte differentiation and axon-oligodendrocyte interactions was increased, including cell surface ligands (Ncam, ephrins), cyto- and nucleo-skeleton genes (Fyn, actinins, myosin, nesprin, Sun1), transcription factors (Sox10, Zfp191, Nkx2.2), and myelin genes (Cnp, Plp, Mag). These findings show how mechanical strain can be transmitted to the nucleus to promote oligodendrocyte differentiation, and identify the global landscape of signaling pathways involved in mechanotransduction. These data provide a source of potential new therapeutic avenues to enhance OPC differentiation in vivo.

KEYWORDS:

cell nucleus shape; chromatin remodeling; mechanical strain; mechanotransduction; multiple sclerosis (MS); oligodendrocyte differentiation; oligodendrocyte precursor cell (OPC); oligodendrocytes

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