Type I collagen secreted in white matter lesions inhibits remyelination and functional recovery
Abstract White matter injury is caused by cerebral blood flow disturbances associated with stroke and demyelinating diseases such as multiple sclerosis. Remyelination is induced spontaneously after white matter injury, but progressive multiple sclerosis and white matter stroke are usually characteri...
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| Format: | Article |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07633-w |
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| author | Reiji Yamazaki Morio Azuma Yasuyuki Osanai Tom Kouki Takeshi Inagaki Akiyoshi Kakita Masaki Takao Nobuhiko Ohno |
| author_facet | Reiji Yamazaki Morio Azuma Yasuyuki Osanai Tom Kouki Takeshi Inagaki Akiyoshi Kakita Masaki Takao Nobuhiko Ohno |
| author_sort | Reiji Yamazaki |
| collection | DOAJ |
| description | Abstract White matter injury is caused by cerebral blood flow disturbances associated with stroke and demyelinating diseases such as multiple sclerosis. Remyelination is induced spontaneously after white matter injury, but progressive multiple sclerosis and white matter stroke are usually characterised by remyelination failure. However, the mechanisms underlying impaired remyelination in lesions caused by demyelination and stroke remain unclear. In the current study, we demonstrated that collagen fibres accumulated in the demyelinated lesions of multiple sclerosis patients (age range 23–80 years) and white matter lesions of stroke patients (age range 80–87 years), suggesting that the accumulation of collagen fibres correlates with remyelination failure in these lesions. To investigate the function of collagen fibres in the white matter lesions, we generated two types of white matter injury in mice. We induced focal demyelination by lysolecithin (LPC) injection and ischemic stroke by endothelin 1 (ET1) injection into the internal capsule. We found that type I collagen fibres were secreted in ET1-induced lesions with impaired white matter regeneration in the chronic phase of disease. We also showed that monocyte-derived macrophages that infiltrated into lesions from the peripheral blood produced type I collagen after white matter injury, and that type I collagen also exacerbated microglial activation, astrogliosis, and axonal injury. Finally, we demonstrated that oligodendrocyte differentiation and remyelination were inhibited in the presence of type I collagen after LPC-induced demyelination. These results suggest that type I collagen secreted by monocyte-derived macrophages inhibited white matter regeneration, and therefore, the modulation of type I collagen metabolism might be a novel therapeutic target for white matter injury. |
| format | Article |
| id | doaj-art-0d6c5f8aa8e84def8d2a7d7b0f6d74be |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-0d6c5f8aa8e84def8d2a7d7b0f6d74be2025-08-20T03:10:08ZengNature Publishing GroupCell Death and Disease2041-48892025-04-0116111610.1038/s41419-025-07633-wType I collagen secreted in white matter lesions inhibits remyelination and functional recoveryReiji Yamazaki0Morio Azuma1Yasuyuki Osanai2Tom Kouki3Takeshi Inagaki4Akiyoshi Kakita5Masaki Takao6Nobuhiko Ohno7Department of Anatomy, Division of Histology and Cell Biology, School of Medicine, Jichi Medical UniversityDepartment of Pharmacology, Division of Molecular Pharmacology, School of Medicine, Jichi Medical UniversityDepartment of Anatomy, Division of Histology and Cell Biology, School of Medicine, Jichi Medical UniversityDepartment of Anatomy, Division of Histology and Cell Biology, School of Medicine, Jichi Medical UniversityDepartment of Anatomy, Division of Forensic Medicine, School of Medicine, Jichi Medical UniversityDepartment of Pathology, Brain Research Institute, Niigata UniversityDepartment of Clinical Laboratory, National Center of Neurology and PsychiatryDepartment of Anatomy, Division of Histology and Cell Biology, School of Medicine, Jichi Medical UniversityAbstract White matter injury is caused by cerebral blood flow disturbances associated with stroke and demyelinating diseases such as multiple sclerosis. Remyelination is induced spontaneously after white matter injury, but progressive multiple sclerosis and white matter stroke are usually characterised by remyelination failure. However, the mechanisms underlying impaired remyelination in lesions caused by demyelination and stroke remain unclear. In the current study, we demonstrated that collagen fibres accumulated in the demyelinated lesions of multiple sclerosis patients (age range 23–80 years) and white matter lesions of stroke patients (age range 80–87 years), suggesting that the accumulation of collagen fibres correlates with remyelination failure in these lesions. To investigate the function of collagen fibres in the white matter lesions, we generated two types of white matter injury in mice. We induced focal demyelination by lysolecithin (LPC) injection and ischemic stroke by endothelin 1 (ET1) injection into the internal capsule. We found that type I collagen fibres were secreted in ET1-induced lesions with impaired white matter regeneration in the chronic phase of disease. We also showed that monocyte-derived macrophages that infiltrated into lesions from the peripheral blood produced type I collagen after white matter injury, and that type I collagen also exacerbated microglial activation, astrogliosis, and axonal injury. Finally, we demonstrated that oligodendrocyte differentiation and remyelination were inhibited in the presence of type I collagen after LPC-induced demyelination. These results suggest that type I collagen secreted by monocyte-derived macrophages inhibited white matter regeneration, and therefore, the modulation of type I collagen metabolism might be a novel therapeutic target for white matter injury.https://doi.org/10.1038/s41419-025-07633-w |
| spellingShingle | Reiji Yamazaki Morio Azuma Yasuyuki Osanai Tom Kouki Takeshi Inagaki Akiyoshi Kakita Masaki Takao Nobuhiko Ohno Type I collagen secreted in white matter lesions inhibits remyelination and functional recovery Cell Death and Disease |
| title | Type I collagen secreted in white matter lesions inhibits remyelination and functional recovery |
| title_full | Type I collagen secreted in white matter lesions inhibits remyelination and functional recovery |
| title_fullStr | Type I collagen secreted in white matter lesions inhibits remyelination and functional recovery |
| title_full_unstemmed | Type I collagen secreted in white matter lesions inhibits remyelination and functional recovery |
| title_short | Type I collagen secreted in white matter lesions inhibits remyelination and functional recovery |
| title_sort | type i collagen secreted in white matter lesions inhibits remyelination and functional recovery |
| url | https://doi.org/10.1038/s41419-025-07633-w |
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