Role of Chitinase-3-like 3 protein in endogenous oligodendrogenesis and remyelination during experimental multiple sclerosis

• Applicant: Dr. Sarah C Staroßom
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 405224879

In demyelinating diseases, such as multiple sclerosis (MS) and its mouse model experimental autoimmune encephalomyelitis (EAE), failure of oligodendrogenesis and remyelination result in chronic demyelination and axon degeneration, causing devastating disabilities. Thus, understanding the molecular and cellular mechanisms that drive oligodendrogenesis is crucial for developing therapeutic strategies for remyelination.Although remyelination has long been considered to be driven by parenchymal oligodendrocyte precursor cells (pOPSc), we and others have shown that adult neural stem cells (NSCs) from the subventricular zone get activated in response to demyelination and significantly contribute to myelin repair, if local microenvironments allow. We have demonstrated that Chitinase-3-like-3 (Chi3l3), also known as Ym1, forms part of this permissive local microenvironment and induces the generation of myelinating oligodendrocytes by activating both neural stem cells and OPCs. Additionally, we have shown that silencing endogenous Chi3l3 expression aggravates disease severity and reduced oligodendrogenesis and remyelination in EAE. Our results show that Chi3l3 constitutes an hitherto unknown intrinsic inductor for oligodendrogenic fate choice and remyelination. This raises the question as to whether therapeutic application of Chi3l3 can be used to modulate oligodendrogenesis, remyelination and clinical symptoms in different disease phases and to which extent neural stem cell-driven repair – in contrast to pOPC driven repair- contributes to clinical changes.To investigate these questions, I aim here to apply Chi3l3-treatment in different phases of the relapsing-remitting EAE, and subsequently analyze endogenous repair by a combination of immunohistochemical/ confocal analysis and flow cytometry. The use of wild type SJL mice will allow the detailed characterization of NSC- and OPC- driven oligodendrogenesis/remyelination and its correlation to clinical disease modulation. The additional use of Nestin-HSVTK SJL mice, a tool for conditional depletion of NSCs in vivo, will allow the causal link between NSC-driven functional remyelination and changes in clinical symptoms, both under non-manipulated and therapeutic conditions. This way I will delineate the therapeutic potential of Chi3l3 and the underlying cellular mechanism of repair with the ultimate goal to develop effective remyelinating therapies for MS and other demyelinating disorders.

• DFG Programme: Research Grants