Activin receptors and their ligands are key drivers of remyelination

Alessandra Dillenburg, Claire Davies, Daniel Soong, Anna Williams, Veronique E. Miron

Centre for Reproductive Health and Centre for Regenerative Medicine, University of Edinburgh

Myelin damage in central nervous system white matter disorders such as multiple sclerosis leads to axonal dysfunction/ degeneration and clinical disability. Regeneration of myelin (termed remyelination) can occur and requires oligodendrocyte progenitor cells (OPCs) to differentiate into mature oligodendrocytes which then re-ensheath axons with myelin. However, these processes fail in progressive multiple sclerosis. The lack of approved therapies aimed at promoting remyelination highlight the need to identify mechanisms driving this regenerative process to develop novel therapeutic strategies. Our previous work identified the TGF-β superfamily member activin-A as being increased during remyelination in vivo and sufficient in stimulating activin receptor-driven OPC differentiation into oligodendrocytes in vitro.  Here, we followed up on these studies by undertaking a comprehensive assessment of the role of activin receptors and their ligands during remyelination. Using an ex vivo brain explant model of demyelination, we found that stimulation of activin receptors using activin-A was sufficient to enhance remyelination. Blocking activin receptors using the inhibitor inhibin-α prevented remyelination, demonstrating the requirement of activin receptor signaling for this process. Surprisingly, blocking the binding of endogenous activin-A to activin receptors using follistatin did not impact remyelination, suggesting that other activin receptor ligands are involved in driving remyelination. As activin receptors can also bind other ligands of the TGF-β superfamily, we investigated the expression and function of alternative activin receptor ligands. These studies demonstrate previously undefined roles of a subset of TGFβ superfamily members in regulating remyelination and have implications for development of novel approaches to enhancing remyelination in disease.

Funded by: Commonwealth Scholarship Commission, MS Society, MRC

* entered into the PhD student poster competition