Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis
Progressive fibrosis and maladaptive organ repair result in significant morbidity and millions of premature deaths annually. Senescent cells accumulate with aging and after injury and are implicated in organ fibrosis, but the mechanisms by which senescence influences repair are poorly understood. Us...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-12-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.154124 |
| _version_ | 1797634355970965504 |
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| author | Eoin D. O’Sullivan Katie J. Mylonas Rachel Bell Cyril Carvalho David P. Baird Carolynn Cairns Kevin M. Gallagher Ross Campbell Marie Docherty Alexander Laird Neil C. Henderson Tamir Chandra Kristina Kirschner Bryan Conway Gry H. Dihazi Michael Zeisberg Jeremy Hughes Laura Denby Hassan Dihazi David A. Ferenbach |
| author_facet | Eoin D. O’Sullivan Katie J. Mylonas Rachel Bell Cyril Carvalho David P. Baird Carolynn Cairns Kevin M. Gallagher Ross Campbell Marie Docherty Alexander Laird Neil C. Henderson Tamir Chandra Kristina Kirschner Bryan Conway Gry H. Dihazi Michael Zeisberg Jeremy Hughes Laura Denby Hassan Dihazi David A. Ferenbach |
| author_sort | Eoin D. O’Sullivan |
| collection | DOAJ |
| description | Progressive fibrosis and maladaptive organ repair result in significant morbidity and millions of premature deaths annually. Senescent cells accumulate with aging and after injury and are implicated in organ fibrosis, but the mechanisms by which senescence influences repair are poorly understood. Using 2 murine models of injury and repair, we show that obstructive injury generated senescent epithelia, which persisted after resolution of the original injury, promoted ongoing fibrosis, and impeded adaptive repair. Depletion of senescent cells with ABT-263 reduced fibrosis in reversed ureteric obstruction and after renal ischemia/reperfusion injury. We validated these findings in humans, showing that senescence and fibrosis persisted after relieved renal obstruction. We next characterized senescent epithelia in murine renal injury using single-cell RNA-Seq. We extended our classification to human kidney and liver disease and identified conserved profibrotic proteins, which we validated in vitro and in human disease. We demonstrated that increased levels of protein disulfide isomerase family A member 3 (PDIA3) augmented TGF-β–mediated fibroblast activation. Inhibition of PDIA3 in vivo significantly reduced kidney fibrosis during ongoing renal injury and as such represented a new potential therapeutic pathway. Analysis of the signaling pathways of senescent epithelia connected senescence to organ fibrosis, permitting rational design of antifibrotic therapies. |
| first_indexed | 2024-03-11T12:06:31Z |
| format | Article |
| id | doaj.art-4b3de86c4fb74e508d5ddb5a3c0e0003 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:31Z |
| publishDate | 2022-12-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-4b3de86c4fb74e508d5ddb5a3c0e00032023-11-07T16:24:52ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-12-01722Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosisEoin D. O’SullivanKatie J. MylonasRachel BellCyril CarvalhoDavid P. BairdCarolynn CairnsKevin M. GallagherRoss CampbellMarie DochertyAlexander LairdNeil C. HendersonTamir ChandraKristina KirschnerBryan ConwayGry H. DihaziMichael ZeisbergJeremy HughesLaura DenbyHassan DihaziDavid A. FerenbachProgressive fibrosis and maladaptive organ repair result in significant morbidity and millions of premature deaths annually. Senescent cells accumulate with aging and after injury and are implicated in organ fibrosis, but the mechanisms by which senescence influences repair are poorly understood. Using 2 murine models of injury and repair, we show that obstructive injury generated senescent epithelia, which persisted after resolution of the original injury, promoted ongoing fibrosis, and impeded adaptive repair. Depletion of senescent cells with ABT-263 reduced fibrosis in reversed ureteric obstruction and after renal ischemia/reperfusion injury. We validated these findings in humans, showing that senescence and fibrosis persisted after relieved renal obstruction. We next characterized senescent epithelia in murine renal injury using single-cell RNA-Seq. We extended our classification to human kidney and liver disease and identified conserved profibrotic proteins, which we validated in vitro and in human disease. We demonstrated that increased levels of protein disulfide isomerase family A member 3 (PDIA3) augmented TGF-β–mediated fibroblast activation. Inhibition of PDIA3 in vivo significantly reduced kidney fibrosis during ongoing renal injury and as such represented a new potential therapeutic pathway. Analysis of the signaling pathways of senescent epithelia connected senescence to organ fibrosis, permitting rational design of antifibrotic therapies.https://doi.org/10.1172/jci.insight.154124Cell biologyNephrology |
| spellingShingle | Eoin D. O’Sullivan Katie J. Mylonas Rachel Bell Cyril Carvalho David P. Baird Carolynn Cairns Kevin M. Gallagher Ross Campbell Marie Docherty Alexander Laird Neil C. Henderson Tamir Chandra Kristina Kirschner Bryan Conway Gry H. Dihazi Michael Zeisberg Jeremy Hughes Laura Denby Hassan Dihazi David A. Ferenbach Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis JCI Insight Cell biology Nephrology |
| title | Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis |
| title_full | Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis |
| title_fullStr | Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis |
| title_full_unstemmed | Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis |
| title_short | Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis |
| title_sort | single cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis |
| topic | Cell biology Nephrology |
| url | https://doi.org/10.1172/jci.insight.154124 |
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