Dataset Information

Proliferation of hepatic stellate cells, mediated by YAP and TAZ, contributes to liver repair and regeneration after liver ischemia-reperfusion injury.

ABSTRACT: 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.

SUBMITTER: Konishi T

PROVIDER: S-EPMC5966748 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Proliferation of hepatic stellate cells, mediated by YAP and TAZ, contributes to liver repair and regeneration after liver ischemia-reperfusion injury.

Konishi Takanori T Schuster Rebecca M RM Lentsch Alex B AB

American journal of physiology. Gastrointestinal and liver physiology 20180111 4

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, the ...[more]

PMID: 29351389

Similar Datasets

Project description:Background & aimsHepatic ischemia-reperfusion injury (IRI) is a major complication of hemorrhagic shock, liver resection and transplantation. YAP, a key downstream effector of the Hippo pathway, is essential for determining cell fate and maintaining homeostasis in the liver. We aimed to elucidate its role in IRI.MethodsThe role of YAP/Hippo signaling was systematically studied in biopsy specimens from 60 patients after orthotopic liver transplantation (OLT), and in a mouse model of liver warm IRI. Human biopsy specimens were collected after 2-10 h of cold storage and 3 h post-reperfusion, before being screened by western blot. In the mouse model, the role of YAP was probed by activating or inhibiting YAP prior to ischemia-reperfusion.ResultsIn human biopsies, high post-OLT YAP expression was correlated with well-preserved histology and improved hepatocellular function at postoperative day 1-7. In mice, the ischemia insult (90 min) triggered intrinsic hepatic YAP expression, which peaked at 1-6 h of reperfusion. Activation of YAP protected the liver against IR-stress, by promoting regenerative and anti-oxidative gene induction, while diminishing oxidative stress, necrosis/apoptosis and the innate inflammatory response. Inhibition of YAP aggravated hepatic IRI and suppressed repair/anti-oxidative genes. In mouse hepatocyte cultures, activating YAP prevented hypoxia-reoxygenation induced stress. Interestingly, YAP activation suppressed extracellular matrix synthesis and diminished hepatic stellate cell (HSC) activation, whereas YAP inhibition significantly delayed hepatic repair, potentiated HSC activation, and enhanced liver fibrosis at 7 days post-IRI. Notably, YAP activation failed to protect Nrf2-deficient livers against IR-mediated damage, leading to extensive fibrosis.ConclusionOur novel findings document the crucial role of YAP in IR-mediated hepatocellular damage and liver fibrogenesis, providing evidence of a potential therapeutic target for the management of sterile liver inflammation in transplant recipients.Lay summaryIn the clinical arm, graft YAP expression negatively correlated with liver function and tissue damage after human liver transplantation. YAP activation attenuated hepatocellular oxidative stress and diminished the innate immune response in mouse livers following ischemia-reperfusion injury. In the mouse model, YAP inhibited hepatic stellate cell activation, and abolished injury-mediated fibrogenesis up to 7 days after the ischemic insult.

Project description:BackgroundAs a critical cellular component in the hepatic stem cell niche, hepatic stellate cells (HSCs) play critical roles in regulating the expansion of hepatic stem cells, liver regeneration, and fibrogenesis. However, the signaling of HSCs, particularly that involved in promoting hepatic stem cell expansion, remains unclear. While the overexpression of galectins has been identified in regenerating liver tissues, their involvement in cell-cell interactions between HSCs and hepatic stem cells remains to be elucidated.MethodsTo generate a liver regeneration rat model and establish a hepatic oval cell microenvironment as a stem cell niche, 2-acetylaminofluorene treatment plus partial hepatectomy was performed. Immunofluorescence staining was conducted to detect the emergence of hepatic stem cells and their niche. Liver parenchymal cells, non-parenchymal cells, and HSCs were isolated for gene and protein expression analysis by qPCR or western blotting. To evaluate the effect of galectins on the colony-forming efficiency of hepatic stem cells, c-Kit-CD29+CD49f+/lowCD45-Ter-119- cells were cultured with recombinant galectin protein, galectin antibody, galectin-producing HSCs, and galectin-knockdown HSCs.ResultsFollowing liver injury, the cytokeratin 19+ ductal cells were robustly induced together with the emergence of OV6+CD44+CD133+EpCAM+ hepatic stem cells. The activated desmin+ HSCs were recruited around the periportal area and markedly enriched in the galectin-positive domain compared to the other non-parenchymal cells. Notably, the HSC fraction isolated from regenerating liver was accompanied by dramatically elevated gene and protein expression of galectins. Hepatic stem cells co-cultured with HSCs significantly enhanced colony-forming efficiency. Conversely, single or double knockdown of galectin-1 and galectin-3 led into a significant function loss, impaired the co-cultured hepatic stem cells to attenuated colony size, inhibited colony frequency, and reduced total cell numbers in colonies. On the other hand, the promotive function of galectins was further confirmed by recombinant galectin protein supplementation and galectins blocking antibodies.ConclusionsOur findings, for the first time, demonstrated that galectins from activated HSCs contribute to hepatic stem cell expansion during liver regeneration, suggesting that galectins serve as important stem cell niche components.

Project description:Background and aims: Biological mechanisms that control liver regeneration remain poorly defined. However, these mechanisms are remarkable issues in the clinic that affect management of hepatic loss caused by liver surgery, traumatic injury, chronic infection, or liver poisoning. Increasing evidence has shown that various growth factors, cytokines, and metabolic signaling pathways affect the liver regenerative process. Our aim is to study the effect of bromodomain and extraterminal (BET) protein inhibition on liver regeneration and its mechanism. Methods: We studied the role of BET protein inhibitor, JQ1, in liver regeneration in a mouse model after 70% partial hepatectomy (PH). We evaluated yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) and Notch signaling pathways, which were affected by BET protein inhibitor in mouse hepatic tissues and primary hepatocytes in vivo and AML12 cell lines in vitro. We evaluated the relationship of YAP/TAZ and Notch signaling pathway using YAP/TAZ pathway inhibitor in liver regeneration in vivo. Moreover, we analyzed the relationship of YAP/TAZ and Notch signaling pathways via overexpression or RNA silencing of Yap in AML12 cells. Furthermore, we used Yap overexpression mouse model to examine whether it can rescue liver regeneration damage caused by inhibition of BET proteins. Results: In this study, we report that BET protein inhibitor JQ1 molecule impairs the early phase of liver regeneration in a mouse model after 70% PH. Mechanistically, YAP/TAZ and Notch1-NICD pathways were suppressed by BET protein inhibitor in mouse hepatic tissues and primary hepatocytes in vivo and mouse AML12 cell lines in vitro. By using YAP/TAZ pathway inhibitor, we confirmed that the liver regeneration and the activation of Notch pathway were impaired by the inhibition of YAP/TAZ pathway in vivo. Furthermore, the study showed that Yap knockdown by shRNA in normal mouse hepatic cell line downregulated Notch1 signal transduction, whereas Yap overexpression promoted Notch1-NICD signals. Specific overexpression of Yap in mouse liver could rescue the effect of BET protein inhibition on liver regeneration injury. Conclusion: These results revealed the crucial role of the YAP/TAZ-Notch1-NICD axis in liver regeneration. Therefore, BET protein inhibitors must be used in caution in the treatment of hepatic diseases by reason of its suppressive roles in liver regeneration.

Dataset Information

Proliferation of hepatic stellate cells, mediated by YAP and TAZ, contributes to liver repair and regeneration after liver ischemia-reperfusion injury.

Publications

Proliferation of hepatic stellate cells, mediated by YAP and TAZ, contributes to liver repair and regeneration after liver ischemia-reperfusion injury.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets