Myelinating glia differentiation is regulated by extracellular matrix elasticity

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.

Modulation of Oligodendrocyte Differentiation by Mechanotransduction

“…In line with our observations, a similar approach was recently published (Urbanski et al, 2016), showing a significant increase in branching complexity of OPCs undergoing differentiation on soft brain-like matrices (1.5 kPa) compared to those kept on rigid substrates (30 kPa; both coated with matrigel), in a NMM-II dependent manner. Differentiation of OPCs on soft conditions led to increased percentage of mature RIP+ and MBP+ OLs and lower nuclear Olig1 content (which translocates to the cytosol during differentiation) when compared to those on stiff substrates.…”

Mechanosensitivity of Embryonic Neurites Promotes Their Directional Extension and Schwann Cells Progenitors Migration

“…We assume that mechanosensitivity of SCs is important for their interaction with outgrowing neurites. Recent evidence demonstrate that SCs feel and respond to the stiffness of their substrate, and that mechanosensitivity plays key roles in SCs shape, adhesion, migration, differentiation, gene expression profiles and myelination [4, 6, 8, 11, 23, 24]. This strong impact of mechanosensitivity on SCs plays important roles in the PNS from biomedical and clinical aspects.…”

“…Mechanosensitive active pulling forces at the leading growth cones generate axonal tension and promote axonal growth [9]. Recent evidence demonstrates that PNS myelination is highly sensitive to substrate stiffness [6]; Yap and Taz, effectors of the Hippo pathway, which are known to integrate chemical and mechanical signals in cells [10], control the mechanosensitive PNS myelination [6, 11]. …”

The extracellular matrix: Focus on oligodendrocyte biology and targeting CSPGs for remyelination therapies

“…While Schwann cells are equally capable of thriving in both conditions, oligodendrocytes fail to extend processes in matrix that is stiffer (Urbanski et al, 2016). The notion that mechanical forces play a role in regulating cell biology is not new; however, few studies have examined this phenomenon in the context of myelin and oligodendrocyte biology.…”