Characterizing oligodendrocyte lineage cell dynamics during remyelination

Authors

• H Gaitsch
• P Assinck
• P Dimas
• L Morcom
• C Zhao
• DH Rowitch
• DS Reich
• RJM Franklin

Abstract

Remyelination is a regenerative process resulting from successful differentiation of oligodendrocyte progenitor cells (OPC) into myelinating oligodendrocytes that can repair demyelinated lesions. Remyelination failure leaves denuded axons vulnerable to damage and contributes to clinical progression of demyelinating diseases such as multiple sclerosis. While several potential remyelinating agents have proceeded to clinical trials, methods for accurately and non-invasively assessing changes in remyelination status remain limited. A better understanding of remyelination-associated glial cell turnover dynamics may aid in the discovery of relevant biomarkers to meet this clinical need. In this study, a toxin-induced model of demyelination was used to profile oligodendrocyte cell death and OPC proliferation dynamics over the course of remyelination, from initial demyelinating injury to near-complete myelin regeneration. Eight-week-old Sprague Dawley rats (n = 24) were injected bilaterally with ethidium bromide targeting the caudal cerebellar peduncles. Perfusion and brain dissection were performed at 2-, 5-, 10-, 14-, and 21-days post-lesion (4-5 animals/timepoint). Unlesioned age-/sex-matched controls were used (n = 5). Fixed, frozen tissue was cryosectioned and co-labeled with antibody markers for cell identity (PDGFRα – OPC; Olig2 – oligodendrocyte lineage; GFAP – astrocytes; Iba1 – microglia/macrophages), proliferation (Ki67), and apoptosis/DNA damage (TUNEL assay). Remyelinating lesions were characterized by widespread DNA fragmentation and proliferation as compared to control tissue, indicating a high degree of cell turnover during regeneration. These results provide the foundation for future investigation of the role of cell death in brain regeneration as well as biomarkers that may be used to track that process, such as cell-free DNA.

Scientific Focus Area: Neuroscience

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