Tepavcevic, V. | Search bioRxiv

bioRxiv2022

GABABR agonist baclofen promotes central nervous system remyelination

Promoting remyelination - the endogenous response by which lost myelin sheaths are regenerated - is considered as a potential neuroprotective strategy to prevent/limit the development of permanent neurological disability in patients with multiple sclerosis (MS). To this end, a number of clinical trials are investigating the potential of existing drugs to enhance oligodendrocyte progenitor cell (OPC) differentiation, the process that fails in chronic MS lesions. As we previously reported that oligodendroglia lineage cells express GABAB receptors (GABABRs) both in vitro and in vivo, and that GABABR-mediated signaling enhances OPC differentiation and myelination in vitro, here we focused on the remyelinating potential of the best-known GABABR agonist baclofen (Bac), already approved to treat spasticity in MS. We demonstrated that Bac increases myelin protein production following lysolecithin (LPC)-induced demyelination in cerebellar ex vivo slices. In addition, Bac administration enhanced OPC differentiation and remyelination in LPC-induced spinal cord lesions in adult mice. Thus, our results suggest that Bac should be considered as a potential therapeutic agent, not only to treat spasticity, but also to improve remyelination in patients with MS.

neuroscience↗

bioRxiv2020

Genetically-Modified Macrophages Accelerate Myelin Repair

Preventing neurodegeneration-associated disability progression in patients with multiple sclerosis (MS) remains an unmet therapeutic need. As remyelination prevents degeneration of demyelinated axons, promoting this process in patients might halt the development of permanent disability. In demyelinating mouse lesions, local overexpression of Semaphorin 3F (Sema3F), an oligodendrocyte progenitor cell (OPC) attractant, increases OPC recruitment and remyelination. However, molecular targeting to MS lesions is a challenge because these are disseminated in the central nervous system. We hypothesized that a clinically-relevant paradigm to deliver Sema3F to demyelinating lesions and increase OPC recruitment may be to use blood-derived macrophages as vehicles. Thus, we chose transplantation of genetically-modified hematopoietic stem cells (HSCs) as means of obtaining circulating monocytes that overexpress Sema3F. We first demonstrated that the supernatant from Sema3F-lentiviral vector transduced HSCs stimulates OPC migration in Neuropilin 2 (Nrp2, Sema3F receptor)-dependent fashion. We then investigated whether OPCs remain responsive to Sema3F with age. While Sema3F expression in the lesions of middle-aged and old mice (characterized by decreased efficiency of OPC recruitment and remyelination) was decreased, middle-aged OPCs retained Nrp2 expression and migrated in response to both recombinant Sema3F and Sema3F-transduced cell supernatant in vitro. We then investigated whether blood cells engineered to overexpress Sema3F can target demyelinating CNS lesions and improve remyelination. Thus, we transplanted Sema3F-transduced HSCs and obtained chimeric mice (with Sema3F overexpression in blood cells), in which we induced demyelinating spinal cord lesions. Transgene-carrying cells, predominantly macrophages, quickly infiltrated lesions in both control and Sema3F chimeras. While infiltration of Sema3F-expressing cells did not alter the inflammatory status of the lesions nor OPC survival, it increased OPC recruitment, which accelerated the onset of remyelination. Our results provide a proof-of-concept that blood cells, particularly monocyte-derived macrophages, can be used to deliver pro-remyelinating agents "at the right time and place", suggesting novel means for remyelination-promoting strategies.

neuroscience↗