Growth Differentiation Factor 11 Is a Circulating Regulator of Oligodendrocyte Differentiation and CNS Myelin Formation and Repair.

AIMS: Remyelination failure is a major contributor to progressive neurological disability in multiple sclerosis (MS). Although oligodendrocyte progenitor cells (OPCs) persist in demyelinated lesions, they often fail to differentiate into myelinating oligodendrocytes. This study aimed to determine whether growth differentiation factor 11 (GDF11), a circulating member of the TGF-β superfamily, regulates oligodendrocyte differentiation, CNS myelination, and remyelination.

METHODS: The effects of GDF11 were examined using purified mouse OPC cultures, a neonatal developmental myelination model, and two demyelination models: cuprizone-induced demyelination and experimental autoimmune encephalomyelitis (EAE). OPC differentiation was assessed by immunocytochemistry and morphological analysis. In vivo myelination and remyelination were evaluated using histological, ultrastructural, and behavioral approaches following systemic GDF11 administration.

RESULTS: GDF11 directly promoted OPC differentiation and maturation in vitro without affecting proliferation. Systemic GDF11 enhanced developmental myelination in neonatal mice, increasing myelin gene expression, myelinated axon density, and myelin thickness. Although GDF11 did not prevent active demyelination, it significantly accelerated remyelination and functional recovery following cuprizone withdrawal and in the EAE model, and this was accompanied by enhanced oligodendrocyte differentiation and reduced neuroinflammation.

CONCLUSION: These findings identify GDF11 as a circulating regulator of oligodendrocyte maturation and CNS myelin formation and repair, highlighting its therapeutic potential for demyelinating diseases.