Ectopic Expression of Neurod1 Is Sufficient for Functional Recovery following a Sensory–Motor Cortical Stroke
Stroke is the leading cause of adult disability worldwide. The majority of stroke survivors are left with devastating functional impairments for which few treatment options exist. Recently, a number of studies have used ectopic expression of transcription factors that direct neuronal cell fate with...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-03-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/12/3/663 |
| _version_ | 1827306979221045248 |
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| author | Jessica M. Livingston Tina T. Lee Tom Enbar Emerson Daniele Clara M. Phillips Alexandra Krassikova K. W. Annie Bang Ines Kortebi Brennan W. Donville Omadyor S. Ibragimov Nadia Sachewsky Daniela Lozano Casasbuenas Arman Olfat Cindi M. Morshead |
| author_facet | Jessica M. Livingston Tina T. Lee Tom Enbar Emerson Daniele Clara M. Phillips Alexandra Krassikova K. W. Annie Bang Ines Kortebi Brennan W. Donville Omadyor S. Ibragimov Nadia Sachewsky Daniela Lozano Casasbuenas Arman Olfat Cindi M. Morshead |
| author_sort | Jessica M. Livingston |
| collection | DOAJ |
| description | Stroke is the leading cause of adult disability worldwide. The majority of stroke survivors are left with devastating functional impairments for which few treatment options exist. Recently, a number of studies have used ectopic expression of transcription factors that direct neuronal cell fate with the intention of converting astrocytes to neurons in various models of brain injury and disease. While there have been reports that question whether astrocyte-to-neuron conversion occurs in vivo, here, we have asked if ectopic expression of the transcription factor <i>Neurod1</i> is sufficient to promote improved functional outcomes when delivered in the subacute phase following endothelin-1-induced sensory–motor cortex stroke. We used an adeno-associated virus to deliver <i>Neurod1</i> from the short GFAP promoter and demonstrated improved functional outcomes as early as 28 days post-stroke and persisting to at least 63 days post-stroke. Using <i>Cre</i>-based cell fate tracking, we showed that functional recovery correlated with the expression of neuronal markers in transduced cells by 28 days post-stroke. By 63 days post-stroke, the reporter-expressing cells comprised ~20% of all the neurons in the perilesional cortex and expressed markers of cortical neuron subtypes. Overall, our findings indicate that ectopic expression of <i>Neurod1</i> in the stroke-injured brain is sufficient to enhance neural repair. |
| first_indexed | 2024-04-24T18:31:35Z |
| format | Article |
| id | doaj.art-bd79272862d64e0c9a0bb4df21383a27 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-04-24T18:31:35Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-bd79272862d64e0c9a0bb4df21383a272024-03-27T13:23:04ZengMDPI AGBiomedicines2227-90592024-03-0112366310.3390/biomedicines12030663Ectopic Expression of Neurod1 Is Sufficient for Functional Recovery following a Sensory–Motor Cortical StrokeJessica M. Livingston0Tina T. Lee1Tom Enbar2Emerson Daniele3Clara M. Phillips4Alexandra Krassikova5K. W. Annie Bang6Ines Kortebi7Brennan W. Donville8Omadyor S. Ibragimov9Nadia Sachewsky10Daniela Lozano Casasbuenas11Arman Olfat12Cindi M. Morshead13Department of Surgery, Division of Anatomy, 1 King’s College Circle, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Surgery, Division of Anatomy, 1 King’s College Circle, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Surgery, Division of Anatomy, 1 King’s College Circle, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Surgery, Division of Anatomy, 1 King’s College Circle, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Surgery, Division of Anatomy, 1 King’s College Circle, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Surgery, Division of Anatomy, 1 King’s College Circle, University of Toronto, Toronto, ON M5S 1A8, CanadaLunenfeld-Tanenbaum Research Institute, 600 University Ave., Toronto, ON M5G 1X7, CanadaDepartment of Surgery, Division of Anatomy, 1 King’s College Circle, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Surgery, Division of Anatomy, 1 King’s College Circle, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Surgery, Division of Anatomy, 1 King’s College Circle, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Surgery, Division of Anatomy, 1 King’s College Circle, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Surgery, Division of Anatomy, 1 King’s College Circle, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Surgery, Division of Anatomy, 1 King’s College Circle, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Surgery, Division of Anatomy, 1 King’s College Circle, University of Toronto, Toronto, ON M5S 1A8, CanadaStroke is the leading cause of adult disability worldwide. The majority of stroke survivors are left with devastating functional impairments for which few treatment options exist. Recently, a number of studies have used ectopic expression of transcription factors that direct neuronal cell fate with the intention of converting astrocytes to neurons in various models of brain injury and disease. While there have been reports that question whether astrocyte-to-neuron conversion occurs in vivo, here, we have asked if ectopic expression of the transcription factor <i>Neurod1</i> is sufficient to promote improved functional outcomes when delivered in the subacute phase following endothelin-1-induced sensory–motor cortex stroke. We used an adeno-associated virus to deliver <i>Neurod1</i> from the short GFAP promoter and demonstrated improved functional outcomes as early as 28 days post-stroke and persisting to at least 63 days post-stroke. Using <i>Cre</i>-based cell fate tracking, we showed that functional recovery correlated with the expression of neuronal markers in transduced cells by 28 days post-stroke. By 63 days post-stroke, the reporter-expressing cells comprised ~20% of all the neurons in the perilesional cortex and expressed markers of cortical neuron subtypes. Overall, our findings indicate that ectopic expression of <i>Neurod1</i> in the stroke-injured brain is sufficient to enhance neural repair.https://www.mdpi.com/2227-9059/12/3/663direct lineage conversion<i>Neurod1</i>brain repairstrokefunctional recoveryectopic transcription factor expression |
| spellingShingle | Jessica M. Livingston Tina T. Lee Tom Enbar Emerson Daniele Clara M. Phillips Alexandra Krassikova K. W. Annie Bang Ines Kortebi Brennan W. Donville Omadyor S. Ibragimov Nadia Sachewsky Daniela Lozano Casasbuenas Arman Olfat Cindi M. Morshead Ectopic Expression of Neurod1 Is Sufficient for Functional Recovery following a Sensory–Motor Cortical Stroke Biomedicines direct lineage conversion <i>Neurod1</i> brain repair stroke functional recovery ectopic transcription factor expression |
| title | Ectopic Expression of Neurod1 Is Sufficient for Functional Recovery following a Sensory–Motor Cortical Stroke |
| title_full | Ectopic Expression of Neurod1 Is Sufficient for Functional Recovery following a Sensory–Motor Cortical Stroke |
| title_fullStr | Ectopic Expression of Neurod1 Is Sufficient for Functional Recovery following a Sensory–Motor Cortical Stroke |
| title_full_unstemmed | Ectopic Expression of Neurod1 Is Sufficient for Functional Recovery following a Sensory–Motor Cortical Stroke |
| title_short | Ectopic Expression of Neurod1 Is Sufficient for Functional Recovery following a Sensory–Motor Cortical Stroke |
| title_sort | ectopic expression of neurod1 is sufficient for functional recovery following a sensory motor cortical stroke |
| topic | direct lineage conversion <i>Neurod1</i> brain repair stroke functional recovery ectopic transcription factor expression |
| url | https://www.mdpi.com/2227-9059/12/3/663 |
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