The hippo pathway: A master regulator of liver metabolism, regeneration, and disease

Nguyen-Lefebvre, Anh Thu; Selzner, Nazia; Wrana, Jeffrey L.; Bhat, Mamatha

doi:10.1096/fj.202002284rr

Cited by 40 publications

(30 citation statements)

References 283 publications

(732 reference statements)

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“…MST1/2-dependent phosphorylation leads to activation of LATS1/2, which culminates in phosphorylation YAP and TAZ preventing their import into the nucleus and terminating expression of YAP/TAZ-dependent target genes. Numerous proteins involved in regulation of cell growth, polarity, and homeostasis regulate activity of Hippo signalling pathways (for recent reviews see [ 4 , 5 ]).…”

Section: Introductionmentioning

confidence: 99%

Lack of WWC2 Protein Leads to Aberrant Angiogenesis in Postnatal Mice

Brücher

Egbring

Plagemann

et al. 2021

IJMS

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The WWC protein family is an upstream regulator of the Hippo signalling pathway that is involved in many cellular processes. We examined the effect of an endothelium-specific WWC1 and/or WWC2 knock-out on ocular angiogenesis. Knock-outs were induced in C57BL/6 mice at the age of one day (P1) and evaluated at P6 (postnatal mice) or induced at the age of five weeks and evaluated at three months of age (adult mice). We analysed morphology of retinal vasculature in retinal flat mounts. In addition, in vivo imaging and functional testing by electroretinography were performed in adult mice. Adult WWC1/2 double knock-out mice differed neither functionally nor morphologically from the control group. In contrast, the retinas of the postnatal WWC knock-out mice showed a hyperproliferative phenotype with significantly enlarged areas of sprouting angiogenesis and a higher number of tip cells. The branching and end points in the peripheral plexus were significantly increased compared to the control group. The deletion of the WWC2 gene was decisive for these effects; while knocking out WWC1 showed no significant differences. The results hint strongly that WWC2 is an essential regulator of ocular angiogenesis in mice. As an activator of the Hippo signalling pathway, it prevents excessive proliferation during physiological angiogenesis. In adult animals, WWC proteins do not seem to be important for the maintenance of the mature vascular plexus.

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Section: Introductionmentioning

confidence: 99%

Lack of WWC2 Protein Leads to Aberrant Angiogenesis in Postnatal Mice

Brücher

Egbring

Plagemann

et al. 2021

IJMS

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“…The Hippo pathway plays an important role in regulating stem cell proliferation and apoptosis [45,46]. Previous studies have shown that the activated Hippo pathway can inhibit cell proliferation and promote cell apoptosis of the intervertebral disc cells [47][48][49][50].…”

Section: Discussionmentioning

confidence: 99%

Pretreatment of NPMSCs with Appropriate Concentration of H2O2 Enhances its Ability to Treat IVDD

Zhang

et al. 2022

Preprint

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Background: Nucleus pulposus mesenchymal stem cells (NPMSCs) transplantation is a promising treatment for intervertebral disc degeneration (IVDD). However, the transplanted NPMSCs exhibited weak cell proliferation, high cell apoptosis, and low ability to resist the harsh microenvironment of the degenerated intervertebral disc. There is an urgent need in exploring feasible methods to enhance the therapeutic efficacy of NPMSCs transplantation.Objective: To identify the optimal concentration for NPMSCs pretreatment with hydrogen peroxide (H2O2) and explore the therapeutic efficacy of NPMSCs transplantation using H2O2 pretreatment in IVDD.Methods: Rat NPMSCs were pretreated with different concentrations of H2O2. The proliferation, ROS level, and apoptosis of NPMSCs were detected by CCK-8 test, EdU staining, and flow cytometry in vitro. The underlying signaling pathways were explored utilizing western blot. A rat needle-puncture stimulated IVDD model was established. X-ray, histological staining, and multi-mode small animal live imaging system were performed to evaluate the therapeutic effect of H2O2-pretreated NPMSCs in vivo.Results: 75 μM H2O2 pretreated NPMSCs demonstrated the strongest elevated cell proliferation by inhibiting the Hippo pathway. Meanwhile, 75 μM H2O2 pretreated NPMSCs exhibited significantly enhanced anti-oxidative stress ability, which is related to downregulated Brd4, Keap1, and upregulated Nrf2. 75 μM H2O2 pretreated NPMSCs also exhibited distinctly declined apoptosis. In vivo experiments results verified that 75 μM H2O2 pretreated NPMSCs-transplanted rats exhibited enhanced disc height index (DHI%) and better histological morphology, which means 75 μM H2O2 pretreated NPMSCs can better adapt to the environment of degenerative intervertebral discs and promote the repair of IVDD.Conclusions: Pretreatment with 75 μM H2O2 was the optimal concentration to improve the ability of proliferation, anti-oxidative stress, and anti-apoptosis of transplanted NPMSCs, which is expected to provide a new feasible method to improve the stem cell therapy efficacy of IVDD.

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“…Pathways were characterized by the number of hits (the number of genes targeted by differentially expressed miRNAs) and the significance of enrichment ( p < 0.05). The Hippo signaling pathway plays a crucial role in the processes of apoptosis, proliferation, and cell regeneration ( Nguyen-Lefebvre et al, 2021 ). The Hippo signaling pathway is an essential modulator of liver metabolism ( Koo and Guan, 2018 ), acting through the hormone receptor GPCR.…”

Section: Discussionmentioning

confidence: 99%

Analysis of miRNAs Profiles in Serum of Patients With Steatosis and Steatohepatitis

Vulf

Skuratovskaia

Komar

et al. 2021

Front. Cell Dev. Biol.

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Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the most common chronic liver diseases worldwide, affecting 25% of the world population. In recent years, there has been increasing evidence for the involvement of microRNAs in the epigenetic regulation of genes taking part in the development of steatosis and steatohepatitis—two main stages of NAFLD pathogenesis. In the present study, miRNA profiles were studied in groups of patients with steatosis and steatohepatitis to compare the characteristics of RNA-dependent epigenetic regulation of the stages of NAFLD development. According to the results of miRNA screening, 23 miRNAs were differentially expressed serum in a group of patients with steatohepatitis and 2 in a group of patients with steatosis. MiR-195-5p and miR-16-5p are common differentially expressed miRNAs for both steatosis and steatohepatitis. We analyzed the obtained results: the search for target genes for the differentially expressed miRNAs in our study and the subsequent gene set enrichment analysis performed on KEGG and REACTOME databases revealed which metabolic pathways undergo changes in RNA-dependent epigenetic regulation in steatosis and steatohepatitis. New findings within the framework of this study are the dysregulation of neurohumoral pathways in the pathogenesis of NAFLD as an object of changes in RNA-dependent epigenetic regulation. The miRNAs differentially expressed in our study were found to target 7% of genes in the classic pathogenesis of NAFLD in the group of patients with steatosis and 50% in the group of patients with steatohepatitis. The effects of these microRNAs on genes for the pathogenesis of NAFLD were analyzed in detail. MiR-374a-5p, miR-1-3p and miR-23a-3p do not target genes directly involved in the pathogenesis of NAFLD. The differentially expressed miRNAs found in this study target genes largely responsible for mitochondrial function. The role of miR-423-5p, miR-143-5p and miR-200c-3 in regulating apoptotic processes in the liver and hepatocarcinogenesis is of interest for future experimental studies. These miR-374a, miR-143, miR-1, miR-23a, and miR-423 have potential for steatohepatitis diagnosis and are poorly studied in the context of NAFLD. Thus, this work opens up prospects for further studies of microRNAs as diagnostic and therapeutic biomarkers for NAFLD.

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The hippo pathway: A master regulator of liver metabolism, regeneration, and disease

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 40 publications

References 283 publications

Lack of WWC2 Protein Leads to Aberrant Angiogenesis in Postnatal Mice

Lack of WWC2 Protein Leads to Aberrant Angiogenesis in Postnatal Mice

Pretreatment of NPMSCs with Appropriate Concentration of H2O2 Enhances its Ability to Treat IVDD

Analysis of miRNAs Profiles in Serum of Patients With Steatosis and Steatohepatitis

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