Inhibition of MAPK/ERK pathway promotes oligodendrocytes generation and recovery of demyelinating diseases

Abstract

Oligodendrocytes (OLs) are the myelinating glia of the central nervous system. Injury to OLs causes myelin loss. In demyelinating diseases, such as multiple sclerosis, the remyelination is hindered principally due to a failure of the oligodendrocyte precursor cells (OPCs) to differentiate into mature OLs. To identify inducers of OPC to OL differentiation, a high‐throughput screening based on myelin basic protein expression using neural progenitor cells‐derived OPCs has been performed and, PD0325901—an MEK (MAPK kinase) inhibitor—is found to significantly enhance OPC to OL differentiation in a dose‐ and time‐dependent manner. Other MEK inhibitors also display similar effect, indicating blockade of MAPK–ERK signaling is sufficient to induce OPC differentiation into OLs. PD0325901 facilitates the formation of myelin sheaths in OPC–neuron co‐culture in vitro. And in experimental autoimmune encephalomyelitis model and cuprizone‐induced demyelination model, PD0325901 displays significant therapeutic effect by promoting myelin regeneration. Our results suggest that targeting the MAPK–ERK pathway might be an intriguing way to develop new therapies for demyelinating diseases.

The impact of RASopathy-associated mutations on CNS development in mice and humans

“…However, there are conflicting results about the role of ERK signaling in the differentiation of oligodendrocyte progenitors into mature oligodendrocytes. Recently, Suo and colleagues demonstrated that MEK inhibitors significantly enhance the differentiation of oligodendrocyte precursor cells into oligodendrocytes in vitro and in vivo [127]. Consistently, many studies have suggested that increased ERK activity negatively regulates oligodendrocyte differentiation.…”

Human Wharton’s Jelly Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles Drive Oligodendroglial Maturation by Restraining MAPK/ERK and Notch Signaling Pathways

“…Several characterized cancer drug candidates have been shown to successfully block the MAPK/ERK pathway (Burotto et al, 2014). The restraining of MAPK/ERK signaling activation could also be a promising therapy approach in premature WMI, as the activation of MAPK/ERK signaling arrests OPC maturation and thereby leads to defective myelination in other demyelinating diseases, as stated before (Titus et al, 2017;Suo et al, 2019). Our high-throughput sequencing results of WJ-MSC-derived sEV miR further strongly indicates that the negative effect of sEV on MAPK/ERK activation in MO3.13 cells may rely on their miR cargo.…”

“…a main negative regulator of myelination in the demyelinating diseases multiple sclerosis (Suo et al, 2019), the Costello syndrome, and neurofibromatosis type 1, which are Rasopathies caused by germline mutations in genes encoding for members of the MAPK pathway including HRAS (HRas proto-oncogene, GTPase) (Lopez-Juarez et al, 2017;Titus et al, 2017). The multiple sclerosis model has demonstrated that the inhibition of MAPK/ERK cascade was enough to drive OPC differentiation (Suo et al, 2019).…”

“…sEV Reduce the MAPK/ERK Signaling Pathway in MO3.13 Cells A more recently identified negative regulator of oligodendrocyte differentiation is the MAPK/ERK pathway (Suo et al, 2019;Allan et al, 2021). The MAPK/ERK signaling comprises the activation of RAS, including NRAS, and a subsequent kinase cascade leading, among others, to the phosphorylation of ERK1/2.…”

Oligodendrocyte Intrinsic miR-27a Controls Myelination and Remyelination

“…Failure of remyelination has been associated with the inability of oligodendrocyte progenitor cells (OPCs) to differentiate into mature oligodendrocytes (OLs), specifically in progressive stage of MS (Goldschmidt et al, 2009). At present, several genes (CD44, GPR37, LINGO1, PTEN), transcription factors (ID2, ID4, HES5, SOX5, SOX6), and pathways (WNTs, BMPs, Notch, MAPK/ERK) have been associated with developmental myelination, OL regeneration, and remyelination in animal models of MS (Emery and Lu, 2015; Guo et al, 2015; Suo et al, 2019). In addition, many genes/transcription factors (SOX2, SOX10, PRTM5) are reported to be critical for OPC proliferation and OL differentiation/maturation/myelination (Pozniak et al, 2010; Scaglione et al, 2018; Zhang et al, 2018).…”