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- Title
Heparanome-Mediated Rescue of Oligodendrocyte Progenitor Quiescence following Inflammatory Demyelination.
- Authors
Saraswat, Darpan; Welliver, R. Ross; Ravichandar, Roopa; Tripathi, Ajai; Polanco, Jessie J.; Broome, Jacqueline; Hurley, Edward; Dutta, Ranjan; Feltri, M. Laura; Sim, Fraser J.
- Abstract
The proinflammatory cytokine IFN-c, which is chronically elevated in multiple sclerosis, induces pathologic quiescence in human oligodendrocyte progenitor cells (OPCs) via upregulation of the transcription factor PRRX1. In this study using animals of both sexes, we investigated the role of heparan sulfate proteoglycans in the modulation of IFN-c signaling following demyelination. We found that IFN-c profoundly impaired OPC proliferation and recruitment following adult spinal cord demyelination. IFN-c-induced quiescence was mediated by direct signaling in OPCs as conditional genetic ablation of IFNcR1 (Ifngr1) in adult NG21 OPCs completely abrogated these inhibitory effects. Intriguingly, OPC-specific IFN-c signaling contributed to failed oligodendrocyte differentiation, which was associated with hyperactive Wnt/Bmp target gene expression in OPCs. We found that PI-88, a heparan sulfate mimetic, directly antagonized IFN-c to rescue human OPC proliferation and differentiation in vitro and blocked the IFN-c-mediated inhibitory effects on OPC recruitment in vivo. Importantly, heparanase modulation by PI-88 or OGT2155 in demyelinated lesions rescued IFN-c-mediated axonal damage and demyelination. In addition to OPC-specific effects, IFN-c-augmented lesions were characterized by increased size, reactive astrogliosis, and proinflammatory microglial/macrophage activation along with exacerbated axonal injury and cell death. Heparanase inhibitor treatment rescued many of the negative IFN-c-induced sequelae suggesting a profound modulation of the lesion environment. Together, these results suggest that the modulation of the heparanome represents a rational approach to mitigate the negative effects of proinflammatory signaling and rescuing pathologic quiescence in the inflamed and demyelinated human brain.
- Subjects
HEPARAN sulfate proteoglycans; DEMYELINATION; MACROPHAGE activation syndrome; HEPARAN sulfate; MACROPHAGE activation
- Publication
Journal of Neuroscience, 2021, Vol 41, Issue 10, p2245
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.0580-20.2021