The TGFβ/Notch axis facilitates Müller cell-to-epithelial transition to ultimately form a chronic glial scar
Abstract Background Contrasting with zebrafish, retinal regeneration from Müller cells (MCs) is largely limited in mammals, where they undergo reactive gliosis that consist of a hypertrophic response and ultimately results in vision loss. Transforming growth factor β (TGFβ) is essential for wound he...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-09-01
|
| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13024-021-00482-z |
| _version_ | 1819020452970889216 |
|---|---|
| author | Federica Maria Conedera Ana Maria Quintela Pousa Nadia Mercader Markus Tschopp Volker Enzmann |
| author_facet | Federica Maria Conedera Ana Maria Quintela Pousa Nadia Mercader Markus Tschopp Volker Enzmann |
| author_sort | Federica Maria Conedera |
| collection | DOAJ |
| description | Abstract Background Contrasting with zebrafish, retinal regeneration from Müller cells (MCs) is largely limited in mammals, where they undergo reactive gliosis that consist of a hypertrophic response and ultimately results in vision loss. Transforming growth factor β (TGFβ) is essential for wound healing, including both scar formation and regeneration. However, targeting TGFβ may affect other physiological mechanisms, owing its pleiotropic nature. The regulation of various cellular activities by TGFβ relies on its interaction with other pathways including Notch. Here, we explore the interplay of TGFβ with Notch and how this regulates MC response to injury in zebrafish and mice. Furthermore, we aimed to characterize potential similarities between murine and human MCs during chronic reactive gliosis. Methods Focal damage to photoreceptors was induced with a 532 nm diode laser in TgBAC (gfap:gfap-GFP) zebrafish (ZF) and B6-Tg (Rlbp1-GFP) mice. Transcriptomics, immunofluorescence, and flow cytometry were employed for a comparative analysis of MC response to laser-induced injury between ZF and mouse. The laser-induced injury was paired with pharmacological treatments to inhibit either Notch (DAPT) or TGFβ (Pirfenidone) or TGFβ/Notch interplay (SIS3). To determine if the murine laser-induced injury model translates to the human system, we compared the ensuing MC response to human donors with early retinal degeneration. Results Investigations into injury-induced changes in murine MCs revealed TGFβ/Notch interplay during reactive gliosis. We found that TGFβ1/2 and Notch1/2 interact via Smad3 to reprogram murine MCs towards an epithelial lineage and ultimately to form a glial scar. Similar to what we observed in mice, we confirmed the epithelial phenotype of human Müller cells during gliotic response. Conclusion The study indicates a pivotal role for TGFβ/Notch interplay in tuning MC stemness during injury response and provides novel insights into the remodeling mechanism during retinal degenerative diseases. Graphical abstract |
| first_indexed | 2024-12-21T03:51:26Z |
| format | Article |
| id | doaj.art-43ff539d4e9d4da8a930484e568856aa |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-21T03:51:26Z |
| publishDate | 2021-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-43ff539d4e9d4da8a930484e568856aa2022-12-21T19:16:58ZengBMCMolecular Neurodegeneration1750-13262021-09-0116112110.1186/s13024-021-00482-zThe TGFβ/Notch axis facilitates Müller cell-to-epithelial transition to ultimately form a chronic glial scarFederica Maria Conedera0Ana Maria Quintela Pousa1Nadia Mercader2Markus Tschopp3Volker Enzmann4Department of Ophthalmology, University Hospital of Bern, University of BernDepartment of Ophthalmology, University Hospital of Bern, University of BernInstitute of Anatomy, University of BernDepartment of Ophthalmology, University Hospital of Bern, University of BernDepartment of Ophthalmology, University Hospital of Bern, University of BernAbstract Background Contrasting with zebrafish, retinal regeneration from Müller cells (MCs) is largely limited in mammals, where they undergo reactive gliosis that consist of a hypertrophic response and ultimately results in vision loss. Transforming growth factor β (TGFβ) is essential for wound healing, including both scar formation and regeneration. However, targeting TGFβ may affect other physiological mechanisms, owing its pleiotropic nature. The regulation of various cellular activities by TGFβ relies on its interaction with other pathways including Notch. Here, we explore the interplay of TGFβ with Notch and how this regulates MC response to injury in zebrafish and mice. Furthermore, we aimed to characterize potential similarities between murine and human MCs during chronic reactive gliosis. Methods Focal damage to photoreceptors was induced with a 532 nm diode laser in TgBAC (gfap:gfap-GFP) zebrafish (ZF) and B6-Tg (Rlbp1-GFP) mice. Transcriptomics, immunofluorescence, and flow cytometry were employed for a comparative analysis of MC response to laser-induced injury between ZF and mouse. The laser-induced injury was paired with pharmacological treatments to inhibit either Notch (DAPT) or TGFβ (Pirfenidone) or TGFβ/Notch interplay (SIS3). To determine if the murine laser-induced injury model translates to the human system, we compared the ensuing MC response to human donors with early retinal degeneration. Results Investigations into injury-induced changes in murine MCs revealed TGFβ/Notch interplay during reactive gliosis. We found that TGFβ1/2 and Notch1/2 interact via Smad3 to reprogram murine MCs towards an epithelial lineage and ultimately to form a glial scar. Similar to what we observed in mice, we confirmed the epithelial phenotype of human Müller cells during gliotic response. Conclusion The study indicates a pivotal role for TGFβ/Notch interplay in tuning MC stemness during injury response and provides novel insights into the remodeling mechanism during retinal degenerative diseases. Graphical abstracthttps://doi.org/10.1186/s13024-021-00482-zLaser injuryMüller cellsNotch pathwayRetinal degenerationRetinal regenerationSmad3 |
| spellingShingle | Federica Maria Conedera Ana Maria Quintela Pousa Nadia Mercader Markus Tschopp Volker Enzmann The TGFβ/Notch axis facilitates Müller cell-to-epithelial transition to ultimately form a chronic glial scar Molecular Neurodegeneration Laser injury Müller cells Notch pathway Retinal degeneration Retinal regeneration Smad3 |
| title | The TGFβ/Notch axis facilitates Müller cell-to-epithelial transition to ultimately form a chronic glial scar |
| title_full | The TGFβ/Notch axis facilitates Müller cell-to-epithelial transition to ultimately form a chronic glial scar |
| title_fullStr | The TGFβ/Notch axis facilitates Müller cell-to-epithelial transition to ultimately form a chronic glial scar |
| title_full_unstemmed | The TGFβ/Notch axis facilitates Müller cell-to-epithelial transition to ultimately form a chronic glial scar |
| title_short | The TGFβ/Notch axis facilitates Müller cell-to-epithelial transition to ultimately form a chronic glial scar |
| title_sort | tgfβ notch axis facilitates muller cell to epithelial transition to ultimately form a chronic glial scar |
| topic | Laser injury Müller cells Notch pathway Retinal degeneration Retinal regeneration Smad3 |
| url | https://doi.org/10.1186/s13024-021-00482-z |
| work_keys_str_mv | AT federicamariaconedera thetgfbnotchaxisfacilitatesmullercelltoepithelialtransitiontoultimatelyformachronicglialscar AT anamariaquintelapousa thetgfbnotchaxisfacilitatesmullercelltoepithelialtransitiontoultimatelyformachronicglialscar AT nadiamercader thetgfbnotchaxisfacilitatesmullercelltoepithelialtransitiontoultimatelyformachronicglialscar AT markustschopp thetgfbnotchaxisfacilitatesmullercelltoepithelialtransitiontoultimatelyformachronicglialscar AT volkerenzmann thetgfbnotchaxisfacilitatesmullercelltoepithelialtransitiontoultimatelyformachronicglialscar AT federicamariaconedera tgfbnotchaxisfacilitatesmullercelltoepithelialtransitiontoultimatelyformachronicglialscar AT anamariaquintelapousa tgfbnotchaxisfacilitatesmullercelltoepithelialtransitiontoultimatelyformachronicglialscar AT nadiamercader tgfbnotchaxisfacilitatesmullercelltoepithelialtransitiontoultimatelyformachronicglialscar AT markustschopp tgfbnotchaxisfacilitatesmullercelltoepithelialtransitiontoultimatelyformachronicglialscar AT volkerenzmann tgfbnotchaxisfacilitatesmullercelltoepithelialtransitiontoultimatelyformachronicglialscar |