Opposing BMP and Wnt signaling drive astrocyte-like phenotypic transition of oligodendrocyte precursor cells at the expense of remyelination in a mouse model of demyelination

Abstract

Oligodendrocyte precursor cells (OPCs) are a widely distributed glial population in the adult central nervous system that retain the ability to differentiate into mature oligodendrocytes (OLs), or under pathological conditions, adopt alternative phenotypic transition. The post-injury phenotype of OPCs critically determines remyelination efficiency, yet the molecular cues controlling OPC transformation and their impact on myelin repair remain poorly understood. Here, using PDGFRα-CreER; Rosa-YFP transgenic mice for lineage tracing and a Lysophosphatidylcholine-induced focal demyelination model, we show that OPCs acquire astrocytic characteristics within lesions, accompanied by opposing activation of bone morphogenic protein (BMP) and Wnt signaling. Specifically, transforming OPCs exhibit marked downregulation of β-catenin, phosphorylated glycogen synthase kinase-3 beta at serine 9 (p-Ser9-GSK-3β) and Smad7, together with upregulation of phosphorylated Smad1/5 (p-Smad1/5), reflecting concurrent BMP activation and Wnt inhibition. Although pharmacological activation of BMP or inhibition of Wnt alone had no effect, suggesting an antagonistic interplay, counteracting endogenous BMP upregulation or Wnt downregulation effectively governed the balance between OPC differentiation and transformation. Notably, combined inhibition of BMP and Wnt significantly reduced astrocyte accumulation in lesions and expanded the MBP + remyelinated area, indicating that blocking both signals diverts OPCs from astrocyte-like phenotypic transition and promotes robust remyelination. Together, these findings reveal that opposing activation of BMP and Wnt drives the astrocyte-like phenotypic transition of OPCs and impairs myelin repair, positioning this signaling axis as a promising therapeutic target to enhance remyelination in multiple sclerosis.

The authors' abstract, as published at the source. Frontiers in Cellular Neuroscience, 2026 · DOI ↗