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.
Highlights
Myelination of axons by oligodendrocytes in the central nervous system (CNS) is a key distinguishing process in vertebrate development
Most myelination studies focus on the biochemical regulation, including the biochemical aspects of axon-oligodendrocyte contact (Barres and Raff, 1999; Nave and Werner, 2014), whereas much less is known about the role of mechanical cues in oligodendrocyte differentiation and myelination
We find that static tensile strains within the range observed in vivo (10–15%) significantly decrease proliferation and increase differentiation of oligodendrocyte progenitor cells (OPC), and that this response is mediated by specific ligand-receptor interactions between the cell and substrata
Summary
Myelination of axons by oligodendrocytes in the central nervous system (CNS) is a key distinguishing process in vertebrate development. Sources of mechanical strain in vivo include developmental growth (Bray, 1979, 1984; Van Essen, 1997; Smith, 2009), physiological processes such as spinal cord bending, blood and cerebrospinal fluid pulsation, and pathological conditions such as trauma, axon swelling, glial scaring, or tumor growth (Cullen et al, 2007; Fisher et al, 2007; Nikic et al, 2011; Payne et al, 2012) Related to this question is a long-standing hypothesis that axon growth (increase in length and diameter) could contribute to the control of myelin sheath length and thickness (Franklin and Hinks, 1999). Such findings prompt further consideration of the physical environments in vivo that may stimulate myelination, and show opportunities to engineer environments and therapies based on mechanotransduction pathways that promote remyelination
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