Shear stress-induced cellular senescence blunts liver regeneration through Notch-sirtuin 1-P21/P16 axis
| Autor: | Zhen-Sheng Yue, Guo-Rui Dou, Hua Han, Juan-Li Duan, Ping Song, Zhi-Qiang Fang, Jing-Jing Liu, Bai Ruan, Lin Wang |
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| Rok vydání: | 2021 |
| Předmět: |
Senescence
Hepatology biology Nitric Oxide Synthase Type III Receptors Notch Chemistry Activator (genetics) Gamma Secretase Inhibitors and Modulators biology.organism_classification Phenotype Heterocyclic Compounds 4 or More Rings Liver regeneration Cell biology Liver Regeneration Mice SRT1720 Sinusoid Sirtuin 1 Transcription (biology) Enos Animals Hepatectomy Senescence-Associated Secretory Phenotype Cellular Senescence Signal Transduction |
| Zdroj: | Hepatology (Baltimore, Md.)REFERENCES. 75(3) |
| ISSN: | 1527-3350 |
| Popis: | Background & 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 & results Mice subjected to PHx were analyzed 14 days after surgery. The incomplete remodeling of liver sinusoids affected shear stress-induced eNOS signaling on day 14, resulting in the accumulation of senescent liver sinusoidal endothelial cells (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 (SASP), which disrupted liver regeneration. Blocking the Notch by γ-secretase inhibitor (GSI) diminished senescence and promoted LSEC expansion. Mechanically, Notch-Hes1 signaling inhibited 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. |
| Databáze: | OpenAIRE |
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