Simultaneous cyclin D1 overexpression and p27kip1 knockdown enable robust Müller glia cell cycle reactivation in uninjured mouse retina
Harnessing the regenerative potential of endogenous stem cells to restore lost neurons is a promising strategy for treating neurodegenerative disorders. Müller glia (MG), the primary glial cell type in the retina, exhibit extraordinary regenerative abilities in zebrafish, proliferating and different...
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eLife Sciences Publications Ltd
2025-04-01
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| Online Access: | https://elifesciences.org/articles/100904 |
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| author | Zhifei Wu Baoshan Liao Julia Ying Jan Keung Zongli Zheng Virpi Ahola Wenjun Xiong |
| author_facet | Zhifei Wu Baoshan Liao Julia Ying Jan Keung Zongli Zheng Virpi Ahola Wenjun Xiong |
| author_sort | Zhifei Wu |
| collection | DOAJ |
| description | Harnessing the regenerative potential of endogenous stem cells to restore lost neurons is a promising strategy for treating neurodegenerative disorders. Müller glia (MG), the primary glial cell type in the retina, exhibit extraordinary regenerative abilities in zebrafish, proliferating and differentiating into neurons post-injury. However, the regenerative potential of mouse MG is limited by their inherent inability to re-enter the cell cycle, constrained by high levels of the cell cycle inhibitor p27Kip1 and low levels of cyclin D1. Here, we report a method to drive robust MG proliferation by adeno-associated virus (AAV)-mediated cyclin D1 overexpression and p27Kip1 knockdown. MG proliferation induced by this dual targeting vector was self-limiting, as MG re-entered cell cycle only once. As shown by single-cell RNA-sequencing, cell cycle reactivation led to suppression of interferon signaling, activation of reactive gliosis, and downregulation of glial genes in MG. Over time, the majority of the MG daughter cells retained the glial fate, resulting in an expanded MG pool. Interestingly, about 1% MG daughter cells expressed markers for retinal interneurons, suggesting latent neurogenic potential in a small MG subset. By establishing a safe, controlled method to promote MG proliferation in vivo while preserving retinal integrity, this work provides a valuable tool for combinatorial therapies integrating neurogenic stimuli to promote neuron regeneration. |
| format | Article |
| id | doaj-art-e2d218b81901480d9dfa6a84add2c61b |
| institution | OA Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-e2d218b81901480d9dfa6a84add2c61b2025-08-20T01:55:57ZengeLife Sciences Publications LtdeLife2050-084X2025-04-011310.7554/eLife.100904Simultaneous cyclin D1 overexpression and p27kip1 knockdown enable robust Müller glia cell cycle reactivation in uninjured mouse retinaZhifei Wu0Baoshan Liao1https://orcid.org/0009-0007-6599-624XJulia Ying2https://orcid.org/0009-0006-4574-1058Jan Keung3Zongli Zheng4https://orcid.org/0000-0003-4849-4903Virpi Ahola5Wenjun Xiong6https://orcid.org/0000-0001-6836-2807Department of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong, ChinaDepartment of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong, ChinaDepartment of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong, ChinaDepartment of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong, China; Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Hong Kong, ChinaDepartment of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong, China; Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Hong Kong, ChinaMing Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Hong Kong, China; Institute of Biomedicine, University of Eastern Finland, Kuopio, FinlandDepartment of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong, ChinaHarnessing the regenerative potential of endogenous stem cells to restore lost neurons is a promising strategy for treating neurodegenerative disorders. Müller glia (MG), the primary glial cell type in the retina, exhibit extraordinary regenerative abilities in zebrafish, proliferating and differentiating into neurons post-injury. However, the regenerative potential of mouse MG is limited by their inherent inability to re-enter the cell cycle, constrained by high levels of the cell cycle inhibitor p27Kip1 and low levels of cyclin D1. Here, we report a method to drive robust MG proliferation by adeno-associated virus (AAV)-mediated cyclin D1 overexpression and p27Kip1 knockdown. MG proliferation induced by this dual targeting vector was self-limiting, as MG re-entered cell cycle only once. As shown by single-cell RNA-sequencing, cell cycle reactivation led to suppression of interferon signaling, activation of reactive gliosis, and downregulation of glial genes in MG. Over time, the majority of the MG daughter cells retained the glial fate, resulting in an expanded MG pool. Interestingly, about 1% MG daughter cells expressed markers for retinal interneurons, suggesting latent neurogenic potential in a small MG subset. By establishing a safe, controlled method to promote MG proliferation in vivo while preserving retinal integrity, this work provides a valuable tool for combinatorial therapies integrating neurogenic stimuli to promote neuron regeneration.https://elifesciences.org/articles/100904retinaregenerationMüller gliacell cycle regulatorcyclin D1p27kip1 |
| spellingShingle | Zhifei Wu Baoshan Liao Julia Ying Jan Keung Zongli Zheng Virpi Ahola Wenjun Xiong Simultaneous cyclin D1 overexpression and p27kip1 knockdown enable robust Müller glia cell cycle reactivation in uninjured mouse retina eLife retina regeneration Müller glia cell cycle regulator cyclin D1 p27kip1 |
| title | Simultaneous cyclin D1 overexpression and p27kip1 knockdown enable robust Müller glia cell cycle reactivation in uninjured mouse retina |
| title_full | Simultaneous cyclin D1 overexpression and p27kip1 knockdown enable robust Müller glia cell cycle reactivation in uninjured mouse retina |
| title_fullStr | Simultaneous cyclin D1 overexpression and p27kip1 knockdown enable robust Müller glia cell cycle reactivation in uninjured mouse retina |
| title_full_unstemmed | Simultaneous cyclin D1 overexpression and p27kip1 knockdown enable robust Müller glia cell cycle reactivation in uninjured mouse retina |
| title_short | Simultaneous cyclin D1 overexpression and p27kip1 knockdown enable robust Müller glia cell cycle reactivation in uninjured mouse retina |
| title_sort | simultaneous cyclin d1 overexpression and p27kip1 knockdown enable robust muller glia cell cycle reactivation in uninjured mouse retina |
| topic | retina regeneration Müller glia cell cycle regulator cyclin D1 p27kip1 |
| url | https://elifesciences.org/articles/100904 |
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