Genetically modified macrophages accelerate myelin repair

Genetically modified macrophages accelerate myelin repair

Abstract Preventing neurodegeneration‐associated disability progression in patients with multiple sclerosis (MS) remains an unmet therapeutic need. As remyelination prevents axonal degeneration, promoting this process in patients might enhance neuroprotection. In demyelinating mouse lesions, local o...

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Main Authors: Marie‐Stéphane Aigrot, Clara Barthelemy, Sarah Moyon, Gaelle Dufayet‐Chaffaud, Leire Izagirre‐Urizar, Beatrix Gillet‐Legrand, Satoru Tada, Laura Bayón‐Cordero, Juan‐Carlos Chara, Carlos Matute, Nathalie Cartier, Catherine Lubetzki, Vanja Tepavčević
Format: Article
Language:English
Published: Springer Nature 2022-07-01
Series:EMBO Molecular Medicine
Subjects:
gene therapy
multiple sclerosis
oligodendrocyte progenitor cells
remyelination
semaphorin 3F
Online Access:https://doi.org/10.15252/emmm.202114759
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Summary:Abstract Preventing neurodegeneration‐associated disability progression in patients with multiple sclerosis (MS) remains an unmet therapeutic need. As remyelination prevents axonal degeneration, promoting this process in patients might enhance neuroprotection. In demyelinating mouse lesions, local overexpression of semaphorin 3F (Sema3F), an oligodendrocyte progenitor cell (OPC) attractant, increases remyelination. However, molecular targeting to MS lesions is a challenge. A clinically relevant paradigm for delivering Sema3F to demyelinating lesions could be to use blood‐derived macrophages as vehicles. Thus, we chose transplantation of genetically modified hematopoietic stem cells (HSCs) as means of obtaining chimeric mice with circulating Sema3F‐overexpressing monocytes. We demonstrated that Sema3F‐transduced HSCs stimulate OPC migration in a neuropilin 2 (Nrp2, Sema3F receptor)‐dependent fashion, which was conserved in middle‐aged OPCs. While demyelinating lesions induced in mice with Sema3F‐expressing blood cells showed no changes in inflammation and OPC survival, OPC recruitment was enhanced which accelerated the onset of remyelination. Our results provide a proof of concept that blood cells, particularly monocytes/macrophages, can be used to deliver pro‐remyelinating agents “at the right time and place,” suggesting novel means for remyelination‐promoting strategies in MS.
ISSN:1757-4676
1757-4684

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