Abstract
The mechanical properties of living tissues have a significant impact on cell differentiation, but remain unexplored in the context of myelin formation and repair. In the PNS, the extracellular matrix (ECM) incorporates a basal lamina significantly denser than the loosely organized CNS matrix. Inhibition of non-muscle myosin II (NMII) enhances central but impairs peripheral myelination and NMII has been implicated in cellular responses to changes in the elasticity of the ECM. To directly evaluate whether mechanotransduction plays a role in glial cell differentiation, we cultured Schwann cells (SC) and oligodendrocytes (OL) on matrices of variable elastic modulus, mimicking either their native environment or conditions found in injured tissue. We found that a rigid, lesion-like matrix inhibited branching and differentiation of OL in NMII-dependent manner. By contrast, SC developed normally in both soft and stiffer matrices. Although SC differentiation was not significantly affected by changes in matrix stiffness alone, we found that expression of Krox-20 was potentiated on rigid matrices at high laminin concentration. These findings are relevant to the design of biomaterials to promote healing and regeneration in both CNS and PNS, via transplantation of glial progenitors or the implantation of tissue scaffolds.
Highlights
The cell behavior that drives glial cells to ensheath and myelinate axons depends upon cell-cell interactions, and involves active remodeling of the cytoskeleton
We found that OL grown on rigid substrates displayed a less complex branching morphology in both proliferating (Fig. 1A,B) and differentiating conditions (Fig. 1C) and expressed lower levels of maturation markers upon stimulation with T3 (Fig. 1D), suggesting that increased extracellular matrix (ECM) rigidity impairs OL differentiation
non-muscle myosin II (NMII) activity has been shown to regulate the extent of cell branching in response to changes in the elastic properties of the ECM16,17
Summary
The cell behavior that drives glial cells to ensheath and myelinate axons depends upon cell-cell interactions, and involves active remodeling of the cytoskeleton. We identified non-muscle myosin II (NMII) as a key regulator of glial cell differentiation and myelin formation in both the PNS and the CNS6. Mind, we have tested whether myelinating glial cells might detect and respond to the unique elastic properties of ECM where they develop via NMII-mediated mechanotransduction. SC develop normally in both soft and stiffer matrices, but expression of Krox-20 after cAMP treatment was enhanced in rigid matrices at a high concentration of laminin 2, 1, 1. This supports a biphasic SC differentiation model that integrates both the mechanical and biochemical properties of the ECM and the signals received by the axon
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