Modulation of Oligodendrocyte Differentiation by Mechanotransduction

Abstract

Oligodendrocytes (OLs) are responsible for the myelination of axons in the central nervous system (CNS). The differentiation of OLs encompasses several stages, through which cells undergo dramatic biochemical and morphological changes. OL differentiation is modulated by soluble factors (SFs)-such as growth factors and hormones-, known to be essential for each maturation stage. Besides SFs, insoluble factors such as extracellular matrix (ECM) proteins and other microenvironmental elements also play a pivotal role during OL differentiation. Recently, a growing number of studies were published concerning the effect of biophysical properties of the extracellular milieu on OL differentiation and myelination, showing the importance of ECM stiffness and topography, strain forces and spatial constraints. For instance, it was shown in vitro that OL differentiation and maturation is enhanced by substrates within the reported range of stiffness of the brain and that this effect is potentiated by the presence of merosin, whereas the myelination process is influenced by the diameter of axonal-like fibers. In this mini review article, we will discuss the effect of mechanical cues during OL differentiation and the possible molecular mechanisms involved in such regulation.

Keywords: differentiation; extracellular matrix; integrins; mechanobiology; mechanotransduction; myelination; neural stem cells; oligodendrocyte.

Figure 1

Factors affecting cell fate of neural stem/progenitor cells (NSCs) and the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs). The fate of NSCs is influenced by several soluble factors (SFs; top left), as widely described in the literature (Rivera et al., 2010), but is also modulated by several biophysical cues (top right) such as stiffness (Keung et al., 2011, 2012) and the combination of strain and insoluble factors like extracellular matrix (ECM) proteins (Arulmoli et al., 2015). Maturation of OLs is also influenced by SFs (Baumann and Pham-Dinh, ; top left), ECM composition (Buttery and ffrench-Constant, ; Colognato et al., ; bottom left) and biophysical elements, like stiffness (Kippert et al., ; Jagielska et al., ; Lourenço et al., ; top right), spatial constraints and cell density (Rosenberg et al., ; Hernandez et al., 2016) and topography (Lee et al., ; Bechler et al., ; bottom right).

Figure 2

Signaling pathways generically involved in mechanotransduction and proposed model for the influence of biophysical elements during OL differentiation. (A) Integrins (heterodimeric transmembrane receptors composed by α and β subunits) engage ECM proteins (Wang et al., 1993) on the extracellular region, in turn recruiting intracellular adaptor proteins that subsequently bind to actin cytoskeleton. Upon integrin activation, several focal adhesion proteins (SFKs, Focal Adhesion Kinase (FAK), Talin) are recruited and activated, promoting cytoskeleton and cellular dynamics (Huveneers and Danen, 2009). On stiffer platforms, focal adhesions (FAs) are reinforced, inducing further activation of RhoA, ROCK and myosin-II, and consequently, cytoskeleton tension increases (left panel). On softer substrates, cytoskeleton tension is lower, due to reduced maturation of FAs and lower activation of RhoA, ROCK and myosin-II (right panel). (B) The model presented proposes that inactivation of RhoA caused by activation of Fyn in response to engagement of α6β1 integrin by laminin-2 (Colognato et al., ; Bechler et al., 2015) combined with soft substrates contributes to low actomyosin contractility, favoring OL differentiation (left panel). Engagement of αvβ3 integrin by fibronectin leads to activation of Lyn (Colognato et al., 2004), promoting maintenance of OPCs, which also seems to be favored by soft substrates (right panel). Please refer to the main text for further details.