Hepatology (Baltimore, Md.), 2022-03, Vol.75 (3), p.584-599
2022
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- Autor(en) / Beteiligte
- Titel
- Shear stress–induced cellular senescence blunts liver regeneration through Notch–sirtuin 1–P21/P16 axis
- Ist Teil von
- Hepatology (Baltimore, Md.), 2022-03, Vol.75 (3), p.584-599
- Ort / Verlag
- United States: Wiley Subscription Services, Inc
- Erscheinungsjahr
- 2022
- Quelle
- Wiley Online Library Journals Frontfile Complete
- Beschreibungen/Notizen
- Background and Aims The mechanisms involved in liver regeneration after partial hepatectomy (pHx) are complicated. Cellular senescence, once linked to aging, plays a pivotal role in wound repair. However, the regulatory effects of cellular senescence on liver regeneration have not been fully elucidated. Approach and Results Mice subjected to pHx were analyzed 14 days after surgery. The incomplete remodeling of liver sinusoids affected shear stress–induced endothelial nitric oxide synthase (eNOS) signaling on day 14, resulting in the accumulation of senescent LSECs. Removing macrophages to augment LSEC senescence led to a malfunction of the regenerating liver. A dynamic fluctuation in Notch activity accompanied senescent LSEC accumulation during liver regeneration. Endothelial Notch activation by using Cdh5‐CreERT NICeCA mice triggered LSEC senescence and senescence‐associated secretory phenotype, which disrupted liver regeneration. Blocking the Notch by γ‐secretase inhibitor (GSI) diminished senescence and promoted LSEC expansion. Mechanically, Notch–hairy and enhancer of split 1 signaling inhibited sirtuin 1 (Sirt1) transcription by binding to its promoter region. Activation of Sirt1 by SRT1720 neutralized the up‐regulation of P53, P21, and P16 caused by Notch activation and eliminated Notch‐driven LSEC senescence. Finally, Sirt1 activator promoted liver regeneration by abrogating LSEC senescence and improving sinusoid remodeling. Conclusions Shear stress–induced LSEC senescence driven by Notch interferes with liver regeneration after pHx. Sirt1 inhibition accelerates liver regeneration by abrogating Notch‐driven senescence, providing a potential opportunity to target senescent cells and facilitate liver repair after injury.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0270-9139eISSN: 1527-3350DOI: 10.1002/hep.32209Titel-ID: cdi_proquest_miscellaneous_2584780357
- Format
- –
- Schlagworte
- Aging, Animals, Cellular Senescence - drug effects, Cellular Senescence - physiology, Cyclin-dependent kinase inhibitor p21, Enhancer-of-split protein, Gamma Secretase Inhibitors and Modulators - pharmacology, Hepatectomy, Hepatectomy - methods, Hepatocytes, Hepatology, Heterocyclic Compounds, 4 or More Rings - pharmacology, Liver, Liver Regeneration - drug effects, Liver Regeneration - physiology, Macrophages, Mice, Nitric oxide, Nitric Oxide Synthase Type III - metabolism, Nitric-oxide synthase, Phenotypes, Receptors, Notch - antagonists & inhibitors, Receptors, Notch - metabolism, Secretase, Senescence, Senescence-Associated Secretory Phenotype - genetics, Shear stress, Signal Transduction - drug effects, SIRT1 protein, Sirtuin 1 - metabolism, Transcription, Wound healing