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Reduced production of laminin by hepatic stellate cells contributes to impairment in oval cell response to liver injury in aged mice.

ABSTRACT: Aged liver is usually impaired in response to hepatic injury. Tissue-specific stem cells participate in the repair of tissue injury. However, how oval cells (OCs) respond to injury and how the process is regulated by tissue microenvironment in aged mice have not been fully understood. In this study, taking advantage of well-established murine OC activation model, we demonstrated that OCs were less activated upon injury in aged mice and the impairment was mainly attributed to dysfunction in their niche. Through analyzing global gene expression, we found that the genes differentially expressed in damaged young and aged mouse liver tissues were predominantly those required for the formation and remodeling of extracellular matrix. As one of the most important extracellular matrix components in the OC niche, laminin was shown to promote the proliferation of OCs. Not surprisingly, laminin was downregulated with aging. Consistent with the downregulation of genes encoding DNA-dependent protein kinase (DNA-PK) proteins in aged hepatic stellate cells (HSCs), inhibition of DNA-PK also led to reduced expression of laminin in HSCs. Moreover, impairment in OC activation caused by less supporting from DNA-damaged HSCs could be rescued by laminin. This study reveals a new cellular mechanism underlying impaired OCs functionality during aging.

SUBMITTER: Qian L

PROVIDER: S-EPMC6326669 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Reduced production of laminin by hepatic stellate cells contributes to impairment in oval cell response to liver injury in aged mice.

Qian Liu L Zhang Hui H Gu Yuting Y Li Dechun D He Songbing S Wang Hui H Cheng Yiji Y Yang Wanlin W Yu Hongshuang H Zhao Xiaonan X Cai Wei W Meng Lijun L Jin Min M Wang Yanan Y Zhang Yanyun Y

Aging 20181201 12

Aged liver is usually impaired in response to hepatic injury. Tissue-specific stem cells participate in the repair of tissue injury. However, how oval cells (OCs) respond to injury and how the process is regulated by tissue microenvironment in aged mice have not been fully understood. In this study, taking advantage of well-established murine OC activation model, we demonstrated that OCs were less activated upon injury in aged mice and the impairment was mainly attributed to dysfunction in their ...[more]

PMID: 30513510

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Project description:Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are key regulators of cell proliferation and organ size; however, their physiological contribution after liver injury has not been fully understood. In this study, we sought to determine the role of YAP and TAZ during liver recovery after ischemia-reperfusion (I/R). A murine model of partial (70%) I/R was used to induce liver injury and study the reparative and regenerative response. After liver injury, there was marked activation and proliferation of hepatic stellate cells. The Hippo pathway components, large tumor suppressor 1 (LATS1) and its adapter protein, Mps one binder 1 (MOB1), were inactivated during liver repair, and YAP and TAZ were activated selectively in hepatic stellate cells. Concurrently, the expression of connective tissue growth factor and survivin, both of which are YAP and TAZ target genes, were upregulated. Hepatic stellate cell expansion and concomitant activation of YAP and TAZ occurred only in the injured liver and were not observed in the nonischemic liver. Treatment of mice with verteporfin, an inhibitor of YAP and TAZ, decreased hepatic stellate cell proliferation, survivin, and cardiac ankyrin repeat protein expression. These changes were associated with a significant decrease in hepatocyte proliferation. The data suggest that liver repair and regeneration after I/R injury are dependent on hepatic stellate cell proliferation, which is mediated by YAP and TAZ. NEW & NOTEWORTHY This study is the first to assess the proliferation of hepatic stellate cells (HSCs) after ischemia-reperfusion (I/R) injury and their role in the reparative and regenerative process. Here we show that the Hippo pathway is inactivated after I/R and that Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) activation is detected in HSC. HSC proliferation and expansion are prominent during liver recovery after I/R injury. Inhibition of YAP/TAZ activation with verteporfin reduces HSC proliferation and target gene expression and attenuates hepatocyte proliferation.

Project description:BACKGROUND & AIMS:Hepatic stellate cells (HSCs) have a role in liver fibrosis. Guanine nucleotide-binding ?-subunit 12 (G?12) converges signals from G-protein-coupled receptors whose ligand levels are elevated in the environment during liver fibrosis; however, information is lacking on the effect of G?12 on HSC trans-differentiation. This study investigated the expression of G?12 in HSCs and the molecular basis of the effects of its expression on liver fibrosis. METHODS:G?12 expression was assessed by immunostaining, and immunoblot analyses of mouse fibrotic liver tissues and primary HSCs. The role of G?12 in liver fibrosis was estimated using a toxicant injury mouse model with G?12 gene knockout and/or HSC-specific G?12 delivery using lentiviral vectors, in addition to primary HSCs and LX-2 cells using microRNA (miR) inhibitors, overexpression vectors, or adenoviruses. miR-16, G?12, and LC3 were also examined in samples from patients with fibrosis. RESULTS:G?12 was overexpressed in activated HSCs and fibrotic liver, and was colocalised with desmin. In a carbon tetrachloride-induced fibrosis mouse model, G?12 ablation prevented increases in fibrosis and liver injury. This effect was attenuated by HSC-specific lentiviral delivery of G?12. Moreover, G?12 activation promoted autophagy accompanying c-Jun N-terminal kinase-dependent ATG12-5 conjugation. In addition, miR-16 was found to be a direct inhibitor of the de novo synthesis of G?12. Modulations of miR-16 altered autophagy in HSCs. In a fibrosis animal model or patients with severe fibrosis, miR-16 levels were lower than in their corresponding controls. Consistently, cirrhotic patient liver tissues showed G?12 and LC3 upregulation in desmin-positive areas. CONCLUSIONS:miR-16 dysregulation in HSCs results in G?12 overexpression, which activates HSCs by facilitating autophagy through ATG12-5 formation. This suggests that G?12 and its regulatory molecules could serve as targets for the amelioration of liver fibrosis. LAY SUMMARY:Guanine nucleotide-binding ?-subunit 12 (G?12) is upregulated in activated hepatic stellate cells (HSCs) as a consequence of the dysregulation of a specific microRNA that is abundant in HSCs, facilitating the progression of liver fibrosis. This event is mediated by c-Jun N-terminal kinase-dependent ATG12-5 formation and the promotion of autophagy. We suggest that G?12 and its associated regulators could serve as new targets in HSCs for the treatment of liver fibrosis.

Dataset Information

Reduced production of laminin by hepatic stellate cells contributes to impairment in oval cell response to liver injury in aged mice.

Publications

Reduced production of laminin by hepatic stellate cells contributes to impairment in oval cell response to liver injury in aged mice.

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