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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| Format: | Article |
| Language: | English |
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Springer Nature
2022-07-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202114759 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Marie‐Stéphane Aigrot |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c1839741b7e847299f847e6b2eb4852c |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-c1839741b7e847299f847e6b2eb4852c2025-08-20T04:03:02ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-07-0114811710.15252/emmm.202114759Genetically modified macrophages accelerate myelin repairMarie‐Stéphane Aigrot0Clara Barthelemy1Sarah Moyon2Gaelle Dufayet‐Chaffaud3Leire Izagirre‐Urizar4Beatrix Gillet‐Legrand5Satoru Tada6Laura Bayón‐Cordero7Juan‐Carlos Chara8Carlos Matute9Nathalie Cartier10Catherine Lubetzki11Vanja Tepavčević12INSERM UMR1127 Sorbonne Université, Paris Brain Institute (ICM)INSERM UMR1127 Sorbonne Université, Paris Brain Institute (ICM)NYU Langone Health, Neuroscience InstituteINSERM UMR1127 Sorbonne Université, Paris Brain Institute (ICM)Achucarro Basque Center for Neuroscience/Department of Neuroscience, School of Medicine University of the Basque CountryINSERM UMR1127 Sorbonne Université, Paris Brain Institute (ICM)INSERM UMR1127 Sorbonne Université, Paris Brain Institute (ICM)Achucarro Basque Center for Neuroscience/Department of Neuroscience, School of Medicine University of the Basque CountryAchucarro Basque Center for Neuroscience/Department of Neuroscience, School of Medicine University of the Basque CountryAchucarro Basque Center for Neuroscience/Department of Neuroscience, School of Medicine University of the Basque CountryAsklepios Biopharmaceutical, Inc., Institut du Cerveau (ICM)INSERM UMR1127 Sorbonne Université, Paris Brain Institute (ICM)Achucarro Basque Center for Neuroscience/Department of Neuroscience, School of Medicine University of the Basque CountryAbstract 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.https://doi.org/10.15252/emmm.202114759gene therapymultiple sclerosisoligodendrocyte progenitor cellsremyelinationsemaphorin 3F |
| spellingShingle | 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 Genetically modified macrophages accelerate myelin repair EMBO Molecular Medicine gene therapy multiple sclerosis oligodendrocyte progenitor cells remyelination semaphorin 3F |
| title | Genetically modified macrophages accelerate myelin repair |
| title_full | Genetically modified macrophages accelerate myelin repair |
| title_fullStr | Genetically modified macrophages accelerate myelin repair |
| title_full_unstemmed | Genetically modified macrophages accelerate myelin repair |
| title_short | Genetically modified macrophages accelerate myelin repair |
| title_sort | genetically modified macrophages accelerate myelin repair |
| topic | gene therapy multiple sclerosis oligodendrocyte progenitor cells remyelination semaphorin 3F |
| url | https://doi.org/10.15252/emmm.202114759 |
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