Single-cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablation
We sought to define the mechanism underlying lung microvascular regeneration in a model of severe acute lung injury (ALI) induced by selective lung endothelial cell ablation. Intratracheal instillation of DT in transgenic mice expressing human diphtheria toxin (DT) receptor targeted to ECs resulted...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/80900 |
| _version_ | 1797828600101076992 |
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| author | Rafael Soares Godoy Nicholas D Cober David P Cook Emma McCourt Yupu Deng Liyuan Wang Kenny Schlosser Katelynn Rowe Duncan J Stewart |
| author_facet | Rafael Soares Godoy Nicholas D Cober David P Cook Emma McCourt Yupu Deng Liyuan Wang Kenny Schlosser Katelynn Rowe Duncan J Stewart |
| author_sort | Rafael Soares Godoy |
| collection | DOAJ |
| description | We sought to define the mechanism underlying lung microvascular regeneration in a model of severe acute lung injury (ALI) induced by selective lung endothelial cell ablation. Intratracheal instillation of DT in transgenic mice expressing human diphtheria toxin (DT) receptor targeted to ECs resulted in ablation of >70% of lung ECs, producing severe ALI with near complete resolution by 7 days. Using single-cell RNA sequencing, eight distinct endothelial clusters were resolved, including alveolar aerocytes (aCap) ECs expressing apelin at baseline and general capillary (gCap) ECs expressing the apelin receptor. At 3 days post-injury, a novel gCap EC population emerged characterized by de novo expression of apelin, together with the stem cell marker, protein C receptor. These stem-like cells transitioned at 5 days to proliferative endothelial progenitor-like cells, expressing apelin receptor together with the pro-proliferative transcription factor, Foxm1, and were responsible for the rapid replenishment of all depleted EC populations by 7 days post-injury. Treatment with an apelin receptor antagonist prevented ALI resolution and resulted in excessive mortality, consistent with a central role for apelin signaling in EC regeneration and microvascular repair. The lung has a remarkable capacity for microvasculature EC regeneration which is orchestrated by newly emergent apelin-expressing gCap endothelial stem-like cells that give rise to highly proliferative, apelin receptor-positive endothelial progenitors responsible for the regeneration of the lung microvasculature. |
| first_indexed | 2024-04-09T13:08:00Z |
| format | Article |
| id | doaj.art-6be9dda738014335b2a97fbb476221b2 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-09T13:08:00Z |
| publishDate | 2023-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-6be9dda738014335b2a97fbb476221b22023-05-12T13:22:25ZengeLife Sciences Publications LtdeLife2050-084X2023-04-011210.7554/eLife.80900Single-cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablationRafael Soares Godoy0Nicholas D Cober1https://orcid.org/0000-0001-8061-806XDavid P Cook2https://orcid.org/0000-0001-7639-6724Emma McCourt3https://orcid.org/0000-0003-2796-9279Yupu Deng4Liyuan Wang5Kenny Schlosser6Katelynn Rowe7Duncan J Stewart8https://orcid.org/0000-0002-9113-8691Ottawa Hospital Research Institute, Ottawa, Canada; Sinclair Centre for Regenerative Medicine, Ottawa, CanadaOttawa Hospital Research Institute, Ottawa, Canada; Sinclair Centre for Regenerative Medicine, Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, CanadaOttawa Hospital Research Institute, Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, CanadaOttawa Hospital Research Institute, Ottawa, CanadaOttawa Hospital Research Institute, Ottawa, Canada; Sinclair Centre for Regenerative Medicine, Ottawa, CanadaOttawa Hospital Research Institute, Ottawa, Canada; Sinclair Centre for Regenerative Medicine, Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, CanadaOttawa Hospital Research Institute, Ottawa, Canada; Sinclair Centre for Regenerative Medicine, Ottawa, CanadaOttawa Hospital Research Institute, Ottawa, Canada; Sinclair Centre for Regenerative Medicine, Ottawa, CanadaOttawa Hospital Research Institute, Ottawa, Canada; Sinclair Centre for Regenerative Medicine, Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, CanadaWe sought to define the mechanism underlying lung microvascular regeneration in a model of severe acute lung injury (ALI) induced by selective lung endothelial cell ablation. Intratracheal instillation of DT in transgenic mice expressing human diphtheria toxin (DT) receptor targeted to ECs resulted in ablation of >70% of lung ECs, producing severe ALI with near complete resolution by 7 days. Using single-cell RNA sequencing, eight distinct endothelial clusters were resolved, including alveolar aerocytes (aCap) ECs expressing apelin at baseline and general capillary (gCap) ECs expressing the apelin receptor. At 3 days post-injury, a novel gCap EC population emerged characterized by de novo expression of apelin, together with the stem cell marker, protein C receptor. These stem-like cells transitioned at 5 days to proliferative endothelial progenitor-like cells, expressing apelin receptor together with the pro-proliferative transcription factor, Foxm1, and were responsible for the rapid replenishment of all depleted EC populations by 7 days post-injury. Treatment with an apelin receptor antagonist prevented ALI resolution and resulted in excessive mortality, consistent with a central role for apelin signaling in EC regeneration and microvascular repair. The lung has a remarkable capacity for microvasculature EC regeneration which is orchestrated by newly emergent apelin-expressing gCap endothelial stem-like cells that give rise to highly proliferative, apelin receptor-positive endothelial progenitors responsible for the regeneration of the lung microvasculature.https://elifesciences.org/articles/80900angiogenesisendothelial cellspulmonary biologystem cellsapelin |
| spellingShingle | Rafael Soares Godoy Nicholas D Cober David P Cook Emma McCourt Yupu Deng Liyuan Wang Kenny Schlosser Katelynn Rowe Duncan J Stewart Single-cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablation eLife angiogenesis endothelial cells pulmonary biology stem cells apelin |
| title | Single-cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablation |
| title_full | Single-cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablation |
| title_fullStr | Single-cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablation |
| title_full_unstemmed | Single-cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablation |
| title_short | Single-cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablation |
| title_sort | single cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablation |
| topic | angiogenesis endothelial cells pulmonary biology stem cells apelin |
| url | https://elifesciences.org/articles/80900 |
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