Hierarchical control of remyelination by heparan sulfate sulfation
- 1SUNY University at Buffalo
Abstract
Efficient myelin regeneration requires coordinated signaling between oligodendrocyte progenitor cells (OPCs) and the extracellular matrix, yet how specific heparan sulfate sulfation patterns regulate this process remains poorly understood. The extracellular endosulfatases Sulf1 and Sulf2 selectively remove 6-O-sulfate groups from heparan sulfate proteoglycans (HSPGs). We previously demonstrated that these enzymes are highly expressed by OPCs following demyelination and inhibit OPC recruitment, differentiation, and remyelination through activation of BMP and WNT signaling. We investigated whether sulfotransferases that establish 2-O and 6-O sulfation during HSPG biosynthesis regulate remyelination. Using OPC-specific conditional knockout models, deletion of the 2-O sulfotransferase Hs2st1 enhanced OPC recruitment, oligodendrocyte differentiation, and remyelination through suppression of BMP and WNT signaling. Loss of 2-O sulfation induced compensatory remodeling of the heparan sulfate glycome, with a marked enrichment of 6-O-sulfated HS species. Conversely, deletion of 6-O sulfotransferases impaired OPC recruitment and differentiation and reversed the Hs2st1 phenotype, identifying 6-O sulfation as the dominant functional determinant of remyelination. Together, these findings establish hierarchical control of remyelination by heparan sulfate sulfation, demonstrating that compensatory remodeling of the heparan sulfate glycome governs regenerative signaling following demyelination.
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BibTeX
@misc{muthaiah2026hierarchical,
title = {{Hierarchical control of remyelination by heparan sulfate sulfation}},
author = {R. Muthaiah and R. Ravichandar and R. Poddeti and A. P. Shah and B. Kulkarni and T. Rudra and D. Xu and N. Rai and R. Dutta and F. J. Sim},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.754157},
url = {https://www.biorxiv.org/content/10.64898/2026.09.24.754157v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Hierarchical control of remyelination by heparan sulfate sulfation
AU - R. Muthaiah
AU - R. Ravichandar
AU - R. Poddeti
AU - A. P. Shah
AU - B. Kulkarni
AU - T. Rudra
AU - D. Xu
AU - N. Rai
AU - R. Dutta
AU - F. J. Sim
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.754157
UR - https://www.biorxiv.org/content/10.64898/2026.09.24.754157v1
AB - Efficient myelin regeneration requires coordinated signaling between oligodendrocyte progenitor cells (OPCs) and the extracellular matrix, yet how specific heparan sulfate sulfation patterns regulate this process remains poorly understood. The extracellular endosulfatases Sulf1 and Sulf2 selectively remove 6-O-sulfate groups from heparan sulfate proteoglycans (HSPGs). We previously demonstrated that these enzymes are highly expressed by OPCs following demyelination and inhibit OPC recruitment, differentiation, and remyelination through activation of BMP and WNT signaling. We investigated whether sulfotransferases that establish 2-O and 6-O sulfation during HSPG biosynthesis regulate remyelination. Using OPC-specific conditional knockout models, deletion of the 2-O sulfotransferase Hs2st1 enhanced OPC recruitment, oligodendrocyte differentiation, and remyelination through suppression of BMP and WNT signaling. Loss of 2-O sulfation induced compensatory remodeling of the heparan sulfate glycome, with a marked enrichment of 6-O-sulfated HS species. Conversely, deletion of 6-O sulfotransferases impaired OPC recruitment and differentiation and reversed the Hs2st1 phenotype, identifying 6-O sulfation as the dominant functional determinant of remyelination. Together, these findings establish hierarchical control of remyelination by heparan sulfate sulfation, demonstrating that compensatory remodeling of the heparan sulfate glycome governs regenerative signaling following demyelination.
ER -