(F1162) OLIGODENDROCYTE DERIVED R-SPONDIN3(RSPO3): KEY ROLE IN WHITE MATTER DEVELOPMENT AND INJURY REPAIR THROUGH OLIGODENDROCYTE PROGENITOR CELL DIFFERENTIATION

Abstract: White matter injury (WMI) and repair frequently happens during central nervous system degeneration and regeneration processes. Current therapeutic interventions for WMI are very limited. Demyelination is a pathological process characterized by myelin loss and oligodendrocyte damage. While remyelination involves the proliferation, migration, and differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes, this process is often insufficient to restore axonal function or improve neurological deficits in humans following WMI. Thus, novel, effective and targeted therapies aiming to promote endogenous oligodendrogenesis and remyelination are urgently needed. The R-Spondin (Rspo) cytokine family plays important roles in development and acts as powerful stem cell regulators; however, their roles in brain development and neurological diseases remain largely unknown. We observed that Rspo3 expression in brain white matter tracts increased during postnatal development and correlated spatially and temporally with OL lineage markers. Loss of Rspo3 in Cspg4 positive cells both in-vivo and in-vitro, resulted in hypomyelination and remyelination failure due to OL production. In-vitro, Rspo3 promoted oligodendrogenesis via enhancing differentiation. Both focal and systemic administration of recombinant RSPO3 significantly increased OL maturation and remyelination, and improved motor function in injured animals following lysolecithin (LPC) and hypoxia-ischemic brain damage. Together, these data indicate that Rspo3 acts as a positive regulator of OL development and remyelination, highlighting its potential as a therapeutic strategy for promoting remyelination to combat WMI.

Funding Source: GRF/UGC, 14116622, Hong Kong
Basic research funding of Guangdong Province, 2024A1515012929, China

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