Use of hematopoietic stem cells to target remyelination signals in multiple sclerosis – STEMIMUS

Multiple sclerosis (MS), the first cause of acquired non traumatic disability in the young adult, is a two-steps disease, with a relapsing-remitting phase, related to CNS inflammatory bouts, and a chronic phase, during which irreversible disability progressively increases. This later phase, partially independent of inflammation, is mostly due to the loss of chronically demyelinated axons. Available therapies in MS limit central nervous system (CNS) inflammation, but have no demonstrated effect on disability progression during the progressive phase of the disease. Spontaneous remyelination occurs in MS, and is achieved by oligodendrocyte precursor cells (OPCs). Albeit insufficient in most cases, remyelination prevents axonal degeneration. Promoting myelin repair is therefore a major therapeutic goal in MS. Why remyelination fails depends on different and non exclusive factors. Among these, inhibitors of OPCs differentiation might play a role in some cases. In other lesions, however, remyelination failure is associated with an oligodendroglial depopulation within the demyelinated plaque, suggesting a defect of recruitment of OPCs towards the demyelinated lesion.

This project is based on our recent identification of guidance cues involved in OPCs recruitment in the adult CNS, and the proof of concept that favoring adult OPCs recruitment increases remyelination rate. Our objective is now to target these pro-remyelinating cues, at the right time and space after demyelination. For that purpose, we will take advantage of the recent demonstration, in different models of MS, of an early invasion of the lesion by hematopoietic stem cells (HSC)-derived cells from the monocytic lineage. We therefore plan to graft HSC, over-expressing, after lentiviral gene transfer, guidance cues influencing OPCs recruitment. After induction of demyelination, HSC-derived monocytes/macrophages should reach the lesion, resulting in a very early and targeted release of pro-remyelinating cues. This strategy will be, in a first series of experiments, tested in a chemical mouse model of demyelination, which has a well-known chronology of demyelination and remyelination. It will be then evaluated on other MS models, both inflammatory and non inflammatory. In addition, new guidance cues identified from a recently performed OPC transcriptomic screen, will be evaluated. The goal of this project, which is, to our knowledge, the first attempt to target pro-remyelinating cues to demyelinated lesions, is to establish a pre-clinical strategy of remyelination, before translation into the clinic in MS patients.