Circulating GDF11 promotes oligodendrocyte differentiation, accelerating CNS remyelination in mouse demyelination models.

Remyelination failure is a critical factor contributing to progressive neurological disability in Multiple Sclerosis (MS) and other demyelinating diseases. Despite the presence of oligodendrocyte progenitor cells (OPCs) in demyelinated lesions, they often fail to differentiate into mature myelinating oligodendrocytes. Identifying circulating factors that can overcome this differentiation block and promote myelin repair is a major therapeutic goal. Growth Differentiation Factor 11 (GDF11), a member of the TGF-β superfamily, has emerged as a potential systemic regulator of tissue repair and regeneration, prompting investigation into its role in CNS myelination.

Researchers investigated GDF11's effects 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 in vitro via immunocytochemistry and morphological analysis. In vivo myelination and remyelination were evaluated using histological, ultrastructural, and behavioral approaches following systemic GDF11 administration. The study compared GDF11-treated groups against control arms, focusing on myelin gene expression, myelinated axon density, myelin thickness, and functional recovery.

GDF11 directly promoted OPC differentiation and maturation in vitro without affecting proliferation. Systemic GDF11 administration enhanced developmental myelination in neonatal mice, leading to increased myelin gene expression, myelinated axon density, and myelin thickness. While GDF11 did not prevent active demyelination, it significantly accelerated remyelination and functional recovery following cuprizone withdrawal. This beneficial effect was also observed in the EAE model, where GDF11 treatment led to enhanced oligodendrocyte differentiation and reduced neuroinflammation. > GDF11 significantly accelerated remyelination and functional recovery in both cuprizone-induced demyelination and EAE models, accompanied by enhanced oligodendrocyte differentiation and reduced neuroinflammation.