Sox2 Sustains Recruitment of Oligodendrocyte Progenitor Cells following CNS Demyelination and Primes Them for Differentiation during Remyelination

Abstract

The Sox family of transcription factors have been widely studied in the context of oligodendrocyte development. However, comparatively little is known about the role of Sox2, especially during CNS remyelination. Here we show that the expression of Sox2 occurs in oligodendrocyte progenitor cells (OPCs) in rodent models during myelination and in activated adult OPCs responding to demyelination, and is also detected in multiple sclerosis lesions. In normal adult white matter of both mice and rats, it is neither expressed by adult OPCs nor by oligodendrocytes (although it is expressed by a subpopulation of adult astrocytes). Overexpression of Sox2 in rat OPCs in vitro maintains the cells in a proliferative state and inhibits differentiation, while Sox2 knockout results in decreased OPC proliferation and survival, suggesting that Sox2 contributes to the expansion of OPCs during the recruitment phase of remyelination. Loss of function in cultured mouse OPCs also results in an impaired ability to undergo normal differentiation in response to differentiation signals, suggesting that Sox2 expression in activated OPCs also primes these cells to eventually undergo differentiation. In vivo studies on remyelination following experimental toxin-induced demyelination in mice with inducible loss of Sox2 revealed impaired remyelination, which was largely due to a profound attenuation of OPC recruitment and likely also due to impaired differentiation. Our results reveal a key role of Sox2 expression in OPCs responding to demyelination, enabling them to effectively contribute to remyelination.

Paired Related Homeobox Protein 1 Regulates Quiescence in Human Oligodendrocyte Progenitors

“…Activation of adult OPC proliferation by upregulation of the transcription factor SOX2 is required for efficient remyelination (Zhao et al, 2015). Because failure to remyelinate has been attributed to impaired activation of OPC proliferation (Wolswijk, 1998; Morris et al, 1994; Dowling et al, 1997), this process may also occur in chronic MS lesions.…”

A single‐cell analysis reveals multiple roles of oligodendroglial lineage cells during post‐ischemic regeneration

“…Dcx was expressed in a significantly higher number of OL-NG2 cells than A-NG2 cells, and remained expressed in many IM-and PM-OLs, which suggests that Dcx expression is associated with NG2 cell differentiation to OLs, but not to astrocytes. Since Sox genes are crucial players in remyelination (Duncan et al, 2017;Zhao et al, 2015), and Sox2 expression was significantly increased in IM-and PM-OLs compared with M-OLs, a similar Trpv4-dependent mechanism could take part in the process of OLs maturation. A possible explanation could rise from the observation of Masuyama et al (2008) and Muramatsu et al (2007), who found that Trpv4 mediates Ca 21 -dependent terminal differentiation of osteoclasts and chondrocytes, respectively.…”

“…Moreover, Muramatsu et al (2007) showed that activation of Trpv4 triggers the expression of Sox genes, which consequently induces chondrogenesis. Since Sox genes are crucial players in remyelination (Duncan et al, 2017;Zhao et al, 2015), and Sox2 expression was significantly increased in IM-and PM-OLs compared with M-OLs, a similar Trpv4-dependent mechanism could take part in the process of OLs maturation. The significant difference between M-OLs 1 and 2 is the expression of Gria2, of which the protein product GluA2 renders AMPA receptors impermeable for Ca 21 (Spitzer et al, 2016;Wright & Vissel, 2012).…”

“…IM-OLs also displayed the lowest expression level of OL-specific genes Mbp, Cldn11, and Cnp, as well as Glul among OL subpopulations (Figure 7b), which further confirms their immature nature. The phenotype of PM-OLs was verified by an exceptionally high expression of Tcf7l2 (Guo et al, 2015;Marques et al, 2016) as well as Axin2 and Sox2 (Figure 7b), which was shown to be critically involved in the final differentiation of OL precursors (Zhao et al, 2015). The most intriguing finding was a dramatic difference between M-OLs 1 and 2 in the incidence of cells expressing Gria2, encoding AMPA receptor subunit GluA2.…”

NG2-Glia, a New Player in Energy Balance

“…Within populations of NG2-glia located in the same region there also appears to be considerable heterogeneity, with some studies suggesting that NG2-glia can be divided into distinct functional subtypes, such as those with differences in electrophysiological responses [28] or mitotic behaviour [14]. Underlying this are likely differences in protein expression, such as the neural stem cell-associated transcription factor Sox2, which may be associated with a proliferative state [11, 29], and the G-protein-coupled receptor GPR17, which may delineate a population with reduced proliferation and propensity to differentiate [30]. …”