Overcoming the inhibitory microenvironment surrounding oligodendrocyte progenitor cells following demyelination

Darpan Saraswat, Jessie J. Polanco, Hani J. Shayya, Ajai Tripathi, R. Ross Welliver, Suyog U. Pol, Jacqueline E. Broome, Melanie A. O’Bara, Toin H. van Kuppervelt, Joanna J. Phillips, Ranjan Dutta, Fraser J. Sim

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Received Date: 18th February 20

Following demyelination in the adult CNS, an inhibitory microenvironment impairs recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) leading to failed remyelination and axonal atrophy. By network-based transcriptomics, we identified sulfatase 2 (Sulf2) mRNA in activated human primary OPCs. Sulf2, an extracellular endosulfatase, modulates the signaling microenvironment by editing the pattern of sulfation on heparan sulfate proteoglycans. Sulf2 was actively secreted by human OPCs and Sulf2 expression increased following experimental demyelination and in multiple sclerosis. In this study, we found that Sulf1/2 conditional deletion in adult OPCs increased OPC recruitment and oligodendrocyte generation in demyelinated lesions leading to accelerated remyelination. Sulf1/2 deletion created a favorable microenvironment by impairing Bmp and Wnt signaling in OPCs. Importantly, pharmacological sulfatase inhibition using PI-88 accelerated oligodendrocyte generation and remyelination by blocking OPC-expressed sulfatases. Our findings define an important inhibitory role of Sulf1/2 and highlight the therapeutic potential for sulfatase inhibition in chronic demyelinating disease.

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Nature Communications

Nature Research, Springer Nature