|
1
|
宋 添, 王 一, 孙 童, 刘 绪, 黄 胜, 冉 云. [ Zheng Gan Decoction inhibits diethylnitrosamine-induced hepatocellular carcinoma in rats by activating the Hippo/YAP signaling pathway]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2025; 45:799-809. [PMID: 40294930 PMCID: PMC12037285 DOI: 10.12122/j.issn.1673-4254.2025.04.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Indexed: 04/30/2025]
Abstract
OBJECTIVES To investigate the inhibitory effect of Zheng GanDecoction (ZGF) on tumor progression in a rat model of diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) and explore the possible mechanism. METHODS Seventy SD rats were subjected to regular intraperitoneal injections of DEN (50 mg/kg) for 12 weeks to induce HCC tumorigenesis, with another 10 rats receiving saline injections as the normal control. After successful modeling, the rats were randomized into 5 groups (n=10) for daily treatment with distilled water ( model group), Huaier Granules (4 g/kg; positive control group), or ZGF at low, medium, and high doses (2, 4, and 8 g/kg, respectively) via gavage for 17 weeks. Body weight changes of the rats were monitored, and after completion of the treatments, the rats were euthanized for measurement of liver, spleen and thymus indices and morphological and histopathological examinations of the liver tissues using HE staining. The expressions of YAP, p-YAP, MST1, LATS1 and p-LATS1 in the liver tissues were detected using immunohistochemistry and Western blotting. RESULTS Compared with the normal control rats, the rat models with DEN-induced HCC exhibited much poorer general condition with a significantly reduced survival rate, increased body weight and liver and spleen indices, and a lowered thymus index. ZGF treatment obviously reduced liver and spleen indices, increased the thymus index, and improved pathologies of the liver tissues of the rat models. Immunohistochemistry and Western blotting showed a dose-dependent reduction of YAP expression and an increment of p-YAP expression in ZGF-treated rats, which also exhibited significantly upregulated hepatic expressions of MST1, LATS1 and p-LATS1. CONCLUSIONS ZGF inhibits DEN-induced HCC in rats by activating the Hippo/YAP pathway via upregulating MST1 and LATS1 expression, which promotes YAP phosphorylation and degradation to suppress proliferation and induce apoptosis of the tumor cells.
Collapse
|
|
2
|
Sorrentino G. Microenvironmental control of the ductular reaction: balancing repair and disease progression. Cell Death Dis 2025; 16:246. [PMID: 40180915 PMCID: PMC11968979 DOI: 10.1038/s41419-025-07590-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 03/11/2025] [Accepted: 03/24/2025] [Indexed: 04/05/2025]
Abstract
The ductular reaction (DR) is a dynamic adaptive cellular response within the liver, triggered by various hepatic insults and characterized by an expansion of dysmorphic biliary epithelial cells and liver progenitors. This complex response presents a dual role, playing a pivotal function in liver regeneration but, paradoxically, contributing to the progression of liver diseases, depending upon specific contextual factors and signaling pathways involved. This comprehensive review aims to offer a holistic perspective on the DR, focusing into its intricate cellular and molecular mechanisms, highlighting its pathological significance, and exploring its potential therapeutic implications. An up-to-date understanding of the DR in the context of different liver injuries is provided, analyzing its contributions to liver regeneration, inflammation, fibrosis, and ultimately carcinogenesis. Moreover, the review highlights the role of multiple microenvironmental factors, including the influence of extracellular matrix, tissue mechanics and the interplay with the intricate hepatic cell ecosystem in shaping the DR's regulation. Finally, in vitro and in vivo experimental models of the DR will be discussed, providing insights into how researchers can study and manipulate this critical cellular response. By comprehensively addressing the multifaceted nature of the DR, this review contributes to a more profound understanding of its pathophysiological role in liver diseases, thus offering potential therapeutic avenues for hepatic disorders and improving patient outcomes.
Collapse
Affiliation(s)
- Giovanni Sorrentino
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
| |
Collapse
|
|
3
|
Lu Y, Yan Z, Sun J, Wang C, Xu L, Lyu X, Wang X, Lou J, Huang H, Meng L, Zhao Y. Selective Degradation of TEADs by a PROTAC Molecule Exhibited Robust Anticancer Efficacy In Vitro and In Vivo. J Med Chem 2025; 68:5616-5640. [PMID: 39804031 DOI: 10.1021/acs.jmedchem.4c02884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2025]
Abstract
Genetic mutations in components of the Hippo pathway frequently lead to the aberrant activation of TEADs, which is often associated with cancer. Consequently, TEADs have been actively pursued as therapeutic targets for diseases driven by TEAD overactivation. In this study, we report two series of TEAD PROTACs based on CRBN binders and VHL binders. Both series yielded potent TEAD degraders, including 19 and 40 (H122), which induced TEAD1 degradation with DC50 < 10 nM. Mechanistic studies demonstrated that the degradation of TEAD1 induced by 40 relied on CRBN binding, TEAD1 binding, E3 ligase activity, and a functional proteasome. RNA-seq analyses indicated that 40 significantly downregulated the expression of Myc target genes, as highlighted by GSEA analysis. More importantly, 40 exhibited robust antitumor efficacy in the MSTO-211H mouse xenograft model. Collectively, our results suggest that TEAD PROTACs have therapeutic potential for the treatment of cancers associated with TEAD overactivation.
Collapse
Affiliation(s)
- Yuhang Lu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Ziqin Yan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
| | - Jiaqi Sun
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Chenxu Wang
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Lan Xu
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Xilin Lyu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
| | - Xiancheng Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Jianfeng Lou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - He Huang
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
| | - Linghua Meng
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Yujun Zhao
- Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, Ningxia Province 750004, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
| |
Collapse
|
|
4
|
Guo P, Wan S, Guan KL. The Hippo pathway: Organ size control and beyond. Pharmacol Rev 2025; 77:100031. [PMID: 40148032 DOI: 10.1016/j.pharmr.2024.100031] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 12/17/2024] [Indexed: 03/29/2025] Open
Abstract
The Hippo signaling pathway is a highly conserved signaling network for controlling organ size, tissue homeostasis, and regeneration. It integrates a wide range of intracellular and extracellular signals, such as cellular energy status, cell density, hormonal signals, and mechanical cues, to modulate the activity of YAP/TAZ transcriptional coactivators. A key aspect of Hippo pathway regulation involves its spatial organization at the plasma membrane, where upstream regulators localize to specific membrane subdomains to regulate the assembly and activation of the pathway components. This spatial organization is critical for the precise control of Hippo signaling, as it dictates the dynamic interactions between pathway components and their regulators. Recent studies have also uncovered the role of biomolecular condensation in regulating Hippo signaling, adding complexity to its control mechanisms. Dysregulation of the Hippo pathway is implicated in various pathological conditions, particularly cancer, where alterations in YAP/TAZ activity contribute to tumorigenesis and drug resistance. Therapeutic strategies targeting the Hippo pathway have shown promise in both cancer treatment, by inhibiting YAP/TAZ signaling, and regenerative medicine, by enhancing YAP/TAZ activity to promote tissue repair. The development of small molecule inhibitors targeting the YAP-TEAD interaction and other upstream regulators offers new avenues for therapeutic intervention. SIGNIFICANCE STATEMENT: The Hippo signaling pathway is a key regulator of organ size, tissue homeostasis, and regeneration, with its dysregulation linked to diseases such as cancer. Understanding this pathway opens new possibilities for therapeutic approaches in regenerative medicine and oncology, with the potential to translate basic research into improved clinical outcomes.
Collapse
Affiliation(s)
- Pengfei Guo
- School of Life Sciences, Westlake University, Hangzhou, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
| | - Sicheng Wan
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Kun-Liang Guan
- School of Life Sciences, Westlake University, Hangzhou, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
| |
Collapse
|
|
5
|
Sharip A, Kunz J. Mechanosignaling via Integrins: Pivotal Players in Liver Fibrosis Progression and Therapy. Cells 2025; 14:266. [PMID: 39996739 PMCID: PMC11854242 DOI: 10.3390/cells14040266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 02/05/2025] [Accepted: 02/05/2025] [Indexed: 02/26/2025] Open
Abstract
Liver fibrosis, a consequence of chronic liver injury, represents a major global health burden and is the leading cause of liver failure, morbidity, and mortality. The pathological hallmark of this condition is excessive extracellular matrix deposition, driven primarily by integrin-mediated mechanotransduction. Integrins, transmembrane heterodimeric proteins that serve as primary ECM receptors, orchestrate complex mechanosignaling networks that regulate the activation, differentiation, and proliferation of hepatic stellate cells and other ECM-secreting myofibroblasts. These mechanical signals create self-reinforcing feedback loops that perpetuate the fibrotic response. Recent advances have provided insight into the roles of specific integrin subtypes in liver fibrosis and revealed their regulation of key downstream effectors-including transforming growth factor beta, focal adhesion kinase, RhoA/Rho-associated, coiled-coil containing protein kinase, and the mechanosensitive Hippo pathway. Understanding these mechanotransduction networks has opened new therapeutic possibilities through pharmacological manipulation of integrin-dependent signaling.
Collapse
Affiliation(s)
- Aigul Sharip
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana 020000, Kazakhstan;
- Laboratory of Bioinformatics and Systems Biology, National Laboratory Astana, Astana 020000, Kazakhstan
| | - Jeannette Kunz
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana 020000, Kazakhstan;
| |
Collapse
|
|
6
|
Tong W, Zhu L, Han P, Bai Y, Wang T, Chen D, Li Z, Chi H, Deng X, Zhang Y, Shen Z. TWEAK is an activator of Hippo-YAP signaling protecting against hepatic Ischemia/ reperfusion injury. Int Immunopharmacol 2024; 143:113567. [PMID: 39500083 DOI: 10.1016/j.intimp.2024.113567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/11/2024] [Accepted: 10/31/2024] [Indexed: 12/08/2024]
Abstract
Hepatic ischemia-reperfusion injury (IRI) represents a formidable complication commonly linked with hemorrhagic shock, liver resection, and transplantation. This study aims to elucidate the role of Tumor Necrosis Factor-like Weak Inducer of Apoptosis (TWEAK) in the pathogenesis of hepatic I/R injury and to delineate the underlying mechanisms involved. Utilizing a hypoxia-reoxygenation model in human liver organoids (HLOs) alongside a murine model of warm ischemia-reperfusion injury, we systematically investigated the interplay between TWEAK, its receptor Fn14, and the HIPPO signaling pathway. Our findings indicate that TWEAK pretreatment significantly mitigates IRI in murine livers as well as hypoxia/reoxygenation injury in HLOs. Notably, administration of adeno-associated virus (AAV) to knock down Fn14 abrogated the protective effects of TWEAK in the murine model. Transcriptome sequencing analysis revealed that the interaction between TWEAK and Fn14 enhances cellular resistance to IRI by activating the HIPPO signaling pathway. Overall, TWEAK emerges as a promising therapeutic target for mitigating hepatic I/R injury, potentially improving outcomes in liver transplantation.
Collapse
Affiliation(s)
- Wen Tong
- The First Central Clinical School, Tianjin Medical University, Tianjin 300070, China
| | - Liuyang Zhu
- The First Central Clinical School, Tianjin Medical University, Tianjin 300070, China
| | - Pinsheng Han
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Yi Bai
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin 300192, China
| | - Tianze Wang
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Dapeng Chen
- The First Central Clinical School, Tianjin Medical University, Tianjin 300070, China
| | - Zhongmin Li
- Department of Hepatobiliary Surgery, Tianjin Nankai Hospital, Tianjin 300100, China
| | - Hao Chi
- The First Central Clinical School, Tianjin Medical University, Tianjin 300070, China
| | - Xiyue Deng
- The First Central Clinical School, Tianjin Medical University, Tianjin 300070, China
| | - Yamin Zhang
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin 300192, China.
| | - Zhongyang Shen
- Organ Transplantation Centre, Tianjin First Central Hospital, Tianjin 300192, China.
| |
Collapse
|
|
7
|
Zheng Y, Zhang X, Wang Z, Zhang R, Wei H, Yan X, Jiang X, Yang L. MCC950 as a promising candidate for blocking NLRP3 inflammasome activation: A review of preclinical research and future directions. Arch Pharm (Weinheim) 2024; 357:e2400459. [PMID: 39180246 DOI: 10.1002/ardp.202400459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 07/19/2024] [Accepted: 07/30/2024] [Indexed: 08/26/2024]
Abstract
The NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome is a key component of the innate immune system that triggers inflammation and pyroptosis and contributes to the development of several diseases. Therefore, blocking the activation of the NLRP3 inflammasome has therapeutic potential for the treatment of these diseases. MCC950, a selective small molecule inhibitor, has emerged as a promising candidate for blocking NLRP3 inflammasome activation. Ongoing research is focused on elucidating the specific targets of MCC950 as well as assessfing its metabolism and safety profile. This review discusses the diseases that have been studied in relation to MCC950, with a focus on stroke, Alzheimer's disease, liver injury, atherosclerosis, diabetes mellitus, and sepsis, using bibliometric analysis. It then summarizes the potential pharmacological targets of MCC950 and discusses its toxicity. Furthermore, it traces the progression from preclinical to clinical research for the treatment of these diseases. Overall, this review provides a solid foundation for the clinical therapeutic potential of MCC950 and offers insights for future research and therapeutic approaches.
Collapse
Affiliation(s)
- Yujia Zheng
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Jinghai, Tianjin, China
| | - Xiaolu Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Jinghai, Tianjin, China
| | - Ziyu Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Jinghai, Tianjin, China
| | - Ruifeng Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Jinghai, Tianjin, China
| | - Huayuan Wei
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Jinghai, Tianjin, China
| | - Xu Yan
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Jinghai, Tianjin, China
| | - Xijuan Jiang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Jinghai, Tianjin, China
| | - Lin Yang
- School of Medicial Technology, Tianjin University of Traditional Chinese Medicine, Tianjin, Jinghai, China
| |
Collapse
|
|
8
|
Wang N, Huang Z, Guan F, Wang J, Chen Y, Wang H, Jin L, Wang Y. HIF-1α induced FGF18 alleviates renal ischemia/reperfusion injury via YAP. FASEB J 2024; 38:e70092. [PMID: 39373977 DOI: 10.1096/fj.202401238r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 09/03/2024] [Accepted: 09/23/2024] [Indexed: 10/08/2024]
Abstract
Acute kidney injury (AKI) is a devastating clinical condition characterized by an abrupt loss of renal function. The pathophysiology of AKI involves diverse processes and elements, of which survival and regeneration have been established to be significant hallmarks. And early studies have confirmed the fundamental role of FGFs in the regulation of AKI pathology, although the association between FGF18 and AKI still remains elusive. Our study demonstrates a substantial up-regulation of FGF18 in the renal tubules of mice subjected to ischemia. Notably, targeted overexpression of FGF18 effectively mitigates the impairment of kidney function induced by AKI. Mechanistically, FGF18 facilitates cell proliferation and anti-apoptosis in RTECs by enhancing the expression of YAP and facilitating its translocation to the nucleus. Aside from that, we also discovered that the substantial expression of FGF18 under ischemic conditions is HIF-1α dependent. This study aims to uncover the inherent mechanism behind the beneficial effects of FGF18 in attenuating AKI. By doing so, it aims to offer novel insights into the development of therapeutic strategies for AKI.
Collapse
Affiliation(s)
- Nan Wang
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
- Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China
| | - Zhiyuan Huang
- Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China
| | - Fangqian Guan
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Jiaqi Wang
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Yinyun Chen
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Hong Wang
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Litai Jin
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Yang Wang
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| |
Collapse
|
|
9
|
Yu Z, Zhang H, Li L, Li Z, Chen D, Pang X, Ji Y, Wang Y. Microglia-mediated pericytes migration and fibroblast transition via S1P/S1P3/YAP signaling pathway after spinal cord injury. Exp Neurol 2024; 379:114864. [PMID: 38866101 DOI: 10.1016/j.expneurol.2024.114864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 06/04/2024] [Accepted: 06/09/2024] [Indexed: 06/14/2024]
Abstract
Platelet-derived growth factor receptor β positive (PDGFRβ+) pericytes detach from the microvascular wall and migrate into the injury center following spinal cord injury (SCI), which has been widely regarded as the main source of fibrotic scar, but the mechanism of migration and fibroblast transition remains elusive. Here we show the associated spatiotemporal distribution between microglia and pericytes at three and seven days post-injury (dpi). The increased expression of Sphingosine kinase-1 (SPHK1) in microglia significantly raised the concentration of Sphingosine-1-phosphate (S1P) in the spinal cord, which promotes migration and fibroblast transition of pericyte. In vitro experiments, we found the elevated Sphingosine 1-phosphate receptor 3 (S1P3), the S1P/S1PR3 axis inhibited the phosphorylation of YAP and promoted its nuclear translocation, which contributed to the formation of alpha-smooth muscle actin (α-SMA) and collagen type I (COL1) protein, This process can be blocked by an S1P3 specific inhibitor TY52156 in vitro. The S1P/S1P3/YAP pathway might be a potential target for treatment in SCI.
Collapse
Affiliation(s)
- Ziyuan Yu
- Guangzhou Med Univ, Inst Neurosci, Dept Neurosurg, Affiliated Hosp 2, Guangzhou 510260, PR China
| | - Huabin Zhang
- Guangzhou Med Univ, Inst Neurosci, Dept Neurosurg, Affiliated Hosp 2, Guangzhou 510260, PR China
| | - Linxi Li
- Guangzhou Med Univ, Inst Neurosci, Dept Neurosurg, Affiliated Hosp 2, Guangzhou 510260, PR China
| | - Zhi Li
- Guangzhou Med Univ, Inst Neurosci, Dept Neurosurg, Affiliated Hosp 2, Guangzhou 510260, PR China
| | - Danmin Chen
- Guangzhou Med Univ, Inst Neurosci, Dept Neurosurg, Affiliated Hosp 2, Guangzhou 510260, PR China
| | - Xiao Pang
- Guangzhou Med Univ, Inst Neurosci, Dept Neurosurg, Affiliated Hosp 2, Guangzhou 510260, PR China
| | - Yunxiang Ji
- Guangzhou Med Univ, Inst Neurosci, Dept Neurosurg, Affiliated Hosp 2, Guangzhou 510260, PR China
| | - Yezhong Wang
- Guangzhou Med Univ, Inst Neurosci, Dept Neurosurg, Affiliated Hosp 2, Guangzhou 510260, PR China.
| |
Collapse
|
|
10
|
van Luyk ME, Krotenberg Garcia A, Lamprou M, Suijkerbuijk SJE. Cell competition in primary and metastatic colorectal cancer. Oncogenesis 2024; 13:28. [PMID: 39060237 PMCID: PMC11282291 DOI: 10.1038/s41389-024-00530-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 07/05/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024] Open
Abstract
Adult tissues set the scene for a continuous battle between cells, where a comparison of cellular fitness results in the elimination of weaker "loser" cells. This phenomenon, named cell competition, is beneficial for tissue integrity and homeostasis. In fact, cell competition plays a crucial role in tumor suppression, through elimination of early malignant cells, as part of Epithelial Defense Against Cancer. However, it is increasingly apparent that cell competition doubles as a tumor-promoting mechanism. The comparative nature of cell competition means that mutational background, proliferation rate and polarity all factor in to determine the outcome of these processes. In this review, we explore the intricate and context-dependent involvement of cell competition in homeostasis and regeneration, as well as during initiation and progression of primary and metastasized colorectal cancer. We provide a comprehensive overview of molecular and cellular mechanisms governing cell competition and its parallels with regeneration.
Collapse
Affiliation(s)
- Merel Elise van Luyk
- Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Ana Krotenberg Garcia
- Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Maria Lamprou
- Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Saskia Jacoba Elisabeth Suijkerbuijk
- Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
| |
Collapse
|
|
11
|
Hubel E, Neumann A, Fishman S, Schaffer O, Erez N, Shrkihe BA, Shteingard Y, Gross T, Shibolet O, Varol C, Zvibel I. Sortilin in Biliary Epithelial Cells Promotes Ductular Reaction and Fibrosis during Cholestatic Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:941-957. [PMID: 38493927 DOI: 10.1016/j.ajpath.2024.01.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 01/03/2024] [Accepted: 01/29/2024] [Indexed: 03/19/2024]
Abstract
Cholestatic injuries are accompanied by ductular reaction, initiated by proliferation and activation of biliary epithelial cells (BECs), leading to fibrosis. Sortilin (encoded by Sort1) facilitates IL-6 secretion and leukemia inhibitory factor (LIF) signaling. This study investigated the interplay between sortilin and IL-6 and LIF in cholestatic injury-induced ductular reaction, morphogenesis of new ducts, and fibrosis. Cholestatic injury was induced by bile duct ligation (BDL) in wild-type and Sort1-/- mice, with or without augmentation of IL-6 or LIF. Mice with BEC sortilin deficiency (hGFAPcre.Sort1fl/fl) and control mice were subjected to BDL and 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet (DDC) induced cholestatic injury. Sort1-/- mice displayed reduced BEC proliferation and expression of BEC-reactive markers. Administration of LIF or IL-6 restored BEC proliferation in Sort1-/- mice, without affecting BEC-reactive or inflammatory markers. Sort1-/- mice also displayed impaired morphogenesis, which was corrected by LIF treatment. Similarly, hGFAPcre.Sort1fl/fl mice exhibited reduced BEC proliferation, but similar reactive and inflammatory marker expression. Serum IL-6 and LIF were comparable, yet liver pSTAT3 was reduced, indicating that sortilin is essential for co-activation of LIF receptor/gp130 signaling in BECs, but not for IL-6 secretion. hGFAPcre.Sortfl/fl mice displayed impaired morphogenesis and diminished fibrosis after BDL and DDC. In conclusion, sortilin-mediated engagement of LIF signaling in BECs promoted ductular reaction and morphogenesis during cholestatic injury. This study indicates that BEC sortilin is pivotal for the development of fibrosis.
Collapse
Affiliation(s)
- Einav Hubel
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Anat Neumann
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Sigal Fishman
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Ortal Schaffer
- Department of Pediatric Surgery, Assaf Harofe Hospital, Tzrifin, Israel
| | - Noam Erez
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Bander Abu Shrkihe
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Yuval Shteingard
- Department of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Tamar Gross
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Oren Shibolet
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Chen Varol
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel; Department of Clinical Microbiology and Immunology, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel.
| | - Isabel Zvibel
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel.
| |
Collapse
|
|
12
|
Zhong Z, Jiao Z, Yu FX. The Hippo signaling pathway in development and regeneration. Cell Rep 2024; 43:113926. [PMID: 38457338 DOI: 10.1016/j.celrep.2024.113926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 02/05/2024] [Accepted: 02/20/2024] [Indexed: 03/10/2024] Open
Abstract
The Hippo signaling pathway is a central growth control mechanism in multicellular organisms. By integrating diverse mechanical, biochemical, and stress cues, the Hippo pathway orchestrates proliferation, survival, differentiation, and mechanics of cells, which in turn regulate organ development, homeostasis, and regeneration. A deep understanding of the regulation and function of the Hippo pathway therefore holds great promise for developing novel therapeutics in regenerative medicine. Here, we provide updates on the molecular organization of the mammalian Hippo signaling network, review the regulatory signals and functional outputs of the pathway, and discuss the roles of Hippo signaling in development and regeneration.
Collapse
Affiliation(s)
- Zhenxing Zhong
- Institute of Pediatrics, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Zhihan Jiao
- Institute of Pediatrics, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Fa-Xing Yu
- Institute of Pediatrics, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| |
Collapse
|
|
13
|
Liu K, Wehling L, Wan S, Weiler SME, Tóth M, Ibberson D, Marhenke S, Ali A, Lam M, Guo T, Pinna F, Pedrini F, Damle-Vartak A, Dropmann A, Rose F, Colucci S, Cheng W, Bissinger M, Schmitt J, Birner P, Poth T, Angel P, Dooley S, Muckenthaler MU, Longerich T, Vogel A, Heikenwälder M, Schirmacher P, Breuhahn K. Dynamic YAP expression in the non-parenchymal liver cell compartment controls heterologous cell communication. Cell Mol Life Sci 2024; 81:115. [PMID: 38436764 PMCID: PMC10912141 DOI: 10.1007/s00018-024-05126-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 12/11/2023] [Accepted: 12/30/2023] [Indexed: 03/05/2024]
Abstract
INTRODUCTION The Hippo pathway and its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are targets for cancer therapy. It is important to determine if the activation of one factor compensates for the inhibition of the other. Moreover, it is unknown if YAP/TAZ-directed perturbation affects cell-cell communication of non-malignant liver cells. MATERIALS AND METHODS To investigate liver-specific phenotypes caused by YAP and TAZ inactivation, we generated mice with hepatocyte (HC) and biliary epithelial cell (BEC)-specific deletions for both factors (YAPKO, TAZKO and double knock-out (DKO)). Immunohistochemistry, single-cell sequencing, and proteomics were used to analyze liver tissues and serum. RESULTS The loss of BECs, liver fibrosis, and necrosis characterized livers from YAPKO and DKO mice. This phenotype was weakened in DKO tissues compared to specimens from YAPKO animals. After depletion of YAP in HCs and BECs, YAP expression was induced in non-parenchymal cells (NPCs) in a cholestasis-independent manner. YAP positivity was detected in subgroups of Kupffer cells (KCs) and endothelial cells (ECs). The secretion of pro-inflammatory chemokines and cytokines such as C-X-C motif chemokine ligand 11 (CXCL11), fms-related receptor tyrosine kinase 3 ligand (FLT3L), and soluble intercellular adhesion molecule-1 (ICAM1) was increased in the serum of YAPKO animals. YAP activation in NPCs could contribute to inflammation via TEA domain transcription factor (TEAD)-dependent transcriptional regulation of secreted factors. CONCLUSION YAP inactivation in HCs and BECs causes liver damage, and concomitant TAZ deletion does not enhance but reduces this phenotype. Additionally, we present a new mechanism by which YAP contributes to cell-cell communication originating from NPCs.
Collapse
Affiliation(s)
- Kaijing Liu
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangdong, China
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Sun Yat-Sen University, Guangzhou, China
| | - Lilija Wehling
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
- Department of Modeling of Biological Processes, COS Heidelberg/BioQuant, Heidelberg University, Heidelberg, Germany
| | - Shan Wan
- Department of Pathology, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, China
| | - Sofia M E Weiler
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Marcell Tóth
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - David Ibberson
- Deep Sequencing Core Facility, CellNetworks Excellence Cluster, Heidelberg University, Heidelberg, Germany
| | - Silke Marhenke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
| | - Adnan Ali
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Macrina Lam
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Te Guo
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Federico Pinna
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Fabiola Pedrini
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Amruta Damle-Vartak
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Anne Dropmann
- Department of Medicine II, Molecular Hepatology Section, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Fabian Rose
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Silvia Colucci
- Department of Pediatric Oncology, Hematology & Immunology, University Hospital Heidelberg, Heidelberg, Germany
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Wenxiang Cheng
- Translational Medicine R&D Center, Institute of Biomedical & Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Michaela Bissinger
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Jennifer Schmitt
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Patrizia Birner
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Tanja Poth
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Peter Angel
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Steven Dooley
- Department of Medicine II, Molecular Hepatology Section, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Martina U Muckenthaler
- Department of Pediatric Oncology, Hematology & Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas Longerich
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Kai Breuhahn
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
| |
Collapse
|
|
14
|
Ye L, Ziesch A, Schneider JS, Ofner A, Nieß H, Denk G, Hohenester S, Mayr D, Mahajan UM, Munker S, Khaled NB, Wimmer R, Gerbes AL, Mayerle J, He Y, Geier A, Toni END, Zhang C, Reiter FP. The inhibition of YAP Signaling Prevents Chronic Biliary Fibrosis in the Abcb4 -/- Model by Modulation of Hepatic Stellate Cell and Bile Duct Epithelium Cell Pathophysiology. Aging Dis 2024; 15:338-356. [PMID: 37307826 PMCID: PMC10796084 DOI: 10.14336/ad.2023.0602] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 06/02/2023] [Indexed: 06/14/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) represents a chronic liver disease characterized by poor prognosis and lacking causal treatment options. Yes-associated protein (YAP) functions as a critical mediator of fibrogenesis; however, its therapeutic potential in chronic biliary diseases such as PSC remains unestablished. The objective of this study is to elucidate the possible significance of YAP inhibition in biliary fibrosis by examining the pathophysiology of hepatic stellate cells (HSC) and biliary epithelial cells (BEC). Human liver tissue samples from PSC patients were analyzed to assess the expression of YAP/connective tissue growth factor (CTGF) relative to non-fibrotic control samples. The pathophysiological relevance of YAP/CTGF in HSC and BEC was investigated in primary human HSC (phHSC), LX-2, H69, and TFK-1 cell lines through siRNA or pharmacological inhibition utilizing verteporfin (VP) and metformin (MF). The Abcb4-/- mouse model was employed to evaluate the protective effects of pharmacological YAP inhibition. Hanging droplet and 3D matrigel culture techniques were utilized to investigate YAP expression and activation status of phHSC under various physical conditions. YAP/CTGF upregulation was observed in PSC patients. Silencing YAP/CTGF led to inhibition of phHSC activation and reduced contractility of LX-2 cells, as well as suppression of epithelial-mesenchymal transition (EMT) in H69 cells and proliferation of TFK-1 cells. Pharmacological inhibition of YAP mitigated chronic liver fibrosis in vivo and diminished ductular reaction and EMT. YAP expression in phHSC was effectively modulated by altering extracellular stiffness, highlighting YAP's role as a mechanotransducer. In conclusion, YAP regulates the activation of HSC and EMT in BEC, thereby functioning as a checkpoint of fibrogenesis in chronic cholestasis. Both VP and MF demonstrate effectiveness as YAP inhibitors, capable of inhibiting biliary fibrosis. These findings suggest that VP and MF warrant further investigation as potential therapeutic options for the treatment of PSC.
Collapse
Affiliation(s)
- Liangtao Ye
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Andreas Ziesch
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | | | - Andrea Ofner
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Hanno Nieß
- Biobank of the Department of General, Visceral and Transplantion Surgery, University Hospital, LMU Munich, Germany.
| | - Gerald Denk
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Simon Hohenester
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Doris Mayr
- Institute of Pathology, Faculty of Medicine, LMU Munich, Germany.
| | - Ujjwal M. Mahajan
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Stefan Munker
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Ralf Wimmer
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | | | - Julia Mayerle
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Yulong He
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
| | - Andreas Geier
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany.
| | - Enrico N. De Toni
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Changhua Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
| | - Florian P. Reiter
- Department of Medicine II, University Hospital, LMU Munich, Germany.
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany.
| |
Collapse
|
|
15
|
Carter LE, Bugiel S, Nunnikhoven A, Verster AJ, Petronella N, Gill S, Curran IHA. Comparative genomic analysis of Fischer F344 rat livers exposed for 90 days to 3-methylfuran or its parental compound furan. Food Chem Toxicol 2024; 184:114426. [PMID: 38160780 DOI: 10.1016/j.fct.2023.114426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/22/2023] [Accepted: 12/23/2023] [Indexed: 01/03/2024]
Abstract
Furan is a naturally forming compound found in heat-processed foods such as coffee, canned meats, and jarred baby food. It is concurrently found with analogues including 2-methylfuran (2-MF) and 3-methylfuran (3-MF), and toxicity studies demonstrate all are potent liver toxins. Toxicity studies found 3-MF is more toxic than either furan, or 2-MF. The present analysis assesses the transcriptional response in liver samples taken from male Fischer (F344) rats exposed to furan or 3-MF from 0 to 2.0 and 0-1.0 mg/kg bw/day, respectively, for 90 days. Transcriptional analyses found decreased liver function and fatty acid metabolism are common responses to both furan and 3-MF exposure. Furan liver injury promotes a ductular reaction through Hippo and TGFB signalling, which combined with increased immune response results in ameliorating perturbed bile acid homeostasis in treated rats. Failure to activate these pathways in 3-MF exposed rats and decreased p53 activity leads to cholestasis, and increased toxicity. Finally, BMD analysis indicate many of the most sensitive pathways affected by furan and 3-MF exposure relate to metabolism - malate dehydrogenase and glucose metabolism with BMDLs of 0.03 and 0.01 mg/kg bw/day for furan and 3-MF exposure, respectively, which agrees with BMDLs previously reported for apical and microarray data.
Collapse
Affiliation(s)
- L E Carter
- Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, K1A 0K9, Canada.
| | - S Bugiel
- Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, K1A 0K9, Canada
| | - A Nunnikhoven
- Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, K1A 0K9, Canada
| | - A J Verster
- Bureau of Food Surveillance and Science Integration, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, K1A 0K9, Canada
| | - N Petronella
- Bureau of Food Surveillance and Science Integration, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, K1A 0K9, Canada
| | - S Gill
- Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, K1A 0K9, Canada
| | - I H A Curran
- Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, K1A 0K9, Canada
| |
Collapse
|
|
16
|
Loe AKH, Rao-Bhatia A, Wei Z, Kim JE, Guan B, Qin Y, Hong M, Kwak HS, Liu X, Zhang L, Wrana JL, Guo H, Kim TH. YAP targetome reveals activation of SPEM in gastric pre-neoplastic progression and regeneration. Cell Rep 2023; 42:113497. [PMID: 38041813 DOI: 10.1016/j.celrep.2023.113497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 06/25/2023] [Accepted: 11/09/2023] [Indexed: 12/04/2023] Open
Abstract
Peptic ulcer disease caused by environmental factors increases the risk of developing gastric cancer (GC), one of the most common and deadly cancers in the world. However, the mechanisms underlying this association remain unclear. A major type of GC uniquely undergoes spasmolytic polypeptide-expressing metaplasia (SPEM) followed by intestinal metaplasia. Notably, intestinal-type GC patients with high levels of YAP signaling exhibit a lower survival rate and poor prognosis. YAP overexpression in gastric cells induces atrophy, metaplasia, and hyperproliferation, while its deletion in a Notch-activated gastric adenoma model suppresses them. By defining the YAP targetome genome-wide, we demonstrate that YAP binds to active chromatin elements of SPEM-related genes, which correlates with the activation of their expression in both metaplasia and ulcers. Single-cell analysis combined with our YAP signature reveals that YAP signaling is activated during SPEM, demonstrating YAP as a central regulator of SPEM in gastric neoplasia and regeneration.
Collapse
Affiliation(s)
- Adrian K H Loe
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Abilasha Rao-Bhatia
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Zhao Wei
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, China
| | - Jung-Eun Kim
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Bingxin Guan
- Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong, China
| | - Yan Qin
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Minji Hong
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Hyo Sang Kwak
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Xiaoyu Liu
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong, China; Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, Shandong, China; Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, Shandong, China
| | - Leyi Zhang
- Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Jeffrey L Wrana
- Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Haiyang Guo
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong, China; Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, Shandong, China; Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, Shandong, China.
| | - Tae-Hee Kim
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
| |
Collapse
|
|
17
|
Liu K, Chen R, Wang X, Gong Y, Shi J, Gu B, Zhou Y, Cai W. Biallelic ANKS6 null variants cause notable extrarenal phenotypes in a nephronophthisis patient and lead to hepatobiliary abnormalities by YAP1 deficiency. Clin Genet 2023; 104:625-636. [PMID: 37525964 DOI: 10.1111/cge.14412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 07/17/2023] [Accepted: 07/20/2023] [Indexed: 08/02/2023]
Abstract
The ankyrin repeat and sterile alpha motif domain containing 6 (ANKS6) gene, encoding an inversin compartment protein of the primary cilium, was recently reported as a pathogenic gene of nephronophthisis (MIM PS256100). Extrarenal manifestations are frequently observed in this disease, however, potential genotype-phenotype correlations and the underlying mechanisms remain poorly understood. Here we described an infant with kidney failure, hepatobiliary abnormalities, and heart disease, in whom whole exome sequencing identified compound heterozygous variants in ANKS6, including a novel nonsense variant p.Trp458* and a recurrent splicing variant c.2394+1G > A. mRNA expression studies showed that the splicing variant caused aberrant mRNA splicing with exon 13 skipping and the biallelic variants were predicted to cause loss of ANKS6 function. We systematically characterized the clinical and genetic spectra of the disease and revealed that biallelic null variants in ANKS6 cause more severe kidney disease and more extrarenal manifestations, thus establishing a clear genotype-phenotype correlation for the disease. Further evaluations showed that ANKS6 deficiency reduced YAP1 expression in the patient's bile duct epithelium and ANKS6 promotes YAP1 transcriptional activity in a dose-dependent manner, indicating that loss of ANKS6 function causes hepatobiliary abnormalities through YAP1 deficiency during biliary morphogenesis and development, which may offer new therapeutic targets.
Collapse
Affiliation(s)
- Keqiang Liu
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
- Shanghai Institute for Pediatric Research, Shanghai, China
| | - Ru Chen
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoying Wang
- Department of Pathology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiming Gong
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jia Shi
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Beilin Gu
- Shanghai Institute for Pediatric Research, Shanghai, China
| | - Ying Zhou
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Cai
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
- Shanghai Institute for Pediatric Research, Shanghai, China
| |
Collapse
|
|
18
|
Mokhtari RB, Ashayeri N, Baghaie L, Sambi M, Satari K, Baluch N, Bosykh DA, Szewczuk MR, Chakraborty S. The Hippo Pathway Effectors YAP/TAZ-TEAD Oncoproteins as Emerging Therapeutic Targets in the Tumor Microenvironment. Cancers (Basel) 2023; 15:3468. [PMID: 37444578 DOI: 10.3390/cancers15133468] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/21/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Various cancer cell-associated intrinsic and extrinsic inputs act on YAP/TAZ proteins to mediate the hyperactivation of the TEAD transcription factor-based transcriptome. This YAP/TAZ-TEAD activity can override the growth-limiting Hippo tumor-suppressor pathway that maintains normal tissue homeostasis. Herein, we provide an integrated summary of the contrasting roles of YAP/TAZ during normal tissue homeostasis versus tumor initiation and progression. In addition to upstream factors that regulate YAP/TAZ in the TME, critical insights on the emerging functions of YAP/TAZ in immune suppression and abnormal vasculature development during tumorigenesis are illustrated. Lastly, we discuss the current methods that intervene with the YAP/TAZ-TEAD oncogenic signaling pathway and the emerging applications of combination therapies, gut microbiota, and epigenetic plasticity that could potentiate the efficacy of chemo/immunotherapy as improved cancer therapeutic strategies.
Collapse
Affiliation(s)
- Reza Bayat Mokhtari
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Neda Ashayeri
- Division of Hematology and Oncology, Department of Pediatrics, Ali-Asghar Children Hospital, Iran University of Medical Science, Tehran 1449614535, Iran
| | - Leili Baghaie
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Manpreet Sambi
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Kosar Satari
- Division of Hematology and Oncology, Department of Pediatrics, Ali-Asghar Children Hospital, Iran University of Medical Science, Tehran 1449614535, Iran
| | - Narges Baluch
- Department of Immunology and Allergy, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Dmitriy A Bosykh
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Myron R Szewczuk
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Sayan Chakraborty
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| |
Collapse
|
|
19
|
Zhang J, Lyu Z, Li B, You Z, Cui N, Li Y, Li Y, Huang B, Chen R, Chen Y, Peng Y, Fang J, Wang Q, Miao Q, Tang R, Gershwin ME, Lian M, Xiao X, Ma X. P4HA2 induces hepatic ductular reaction and biliary fibrosis in chronic cholestatic liver diseases. Hepatology 2023; 78:10-25. [PMID: 36799463 DOI: 10.1097/hep.0000000000000317] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 01/06/2023] [Indexed: 02/18/2023]
Abstract
BACKGROUNDS Prolyl-4-hydroxylases (P4Hs) are key enzymes in collagen synthesis. The P4HA subunit (P4HA1, P4HA2, and P4HA3) contains a substrate binding and catalyzation domain. We postulated that P4HA2 would play a key role in the cholangiocyte pathology of cholestatic liver diseases. METHODS We studied humans with primary biliary cholangitis (PBC) and Primary sclerosing cholangitis (PSC), P4HA2 -/- mice injured by DDC, and P4HA2 -/- /MDR2 -/- double knockout mice. A parallel study was performed in patients with PBC, PSC, and controls using immunohistochemistry and immunofluorescence. In the murine model, the level of ductular reaction and biliary fibrosis were monitored by histology, qPCR, immunohistochemistry, and Western blotting. Expression of Yes1 Associated Transcriptional Regulator (YAP) phosphorylation was measured in isolated mouse cholangiocytes. The mechanism of P4HA2 was explored in RBE and 293T cell lines by using qPCR, Western blot, immunofluorescence, and co-immunoprecipitation. RESULTS The hepatic expression level of P4HA2 was highly elevated in patients with PBC or PSC. Ductular reactive cholangiocytes predominantly expressed P4HA2. Cholestatic patients with more severe liver injury correlated with levels of P4HA2 in the liver. In P4HA2 -/- mice, there was a significantly reduced level of ductular reaction and fibrosis compared with controls in the DDC-induced chronic cholestasis. Decreased liver fibrosis and ductular reaction were observed in P4HA2 -/- /MDR2 -/- mice compared with MDR2 -/- mice. Cholangiocytes isolated from P4HA2 -/- /MDR2 -/- mice displayed a higher level of YAP phosphorylation, resulting in cholangiocytes proliferation inhibition. In vitro studies showed that P4HA2 promotes RBE cell proliferation by inducing SAV1 degradation, eventually resulting in the activation of YAP. CONCLUSIONS P4HA2 promotes hepatic ductular reaction and biliary fibrosis by regulating the SAV1-mediated Hippo signaling pathway. P4HA2 is a potential therapeutic target for PBC and PSC.
Collapse
Affiliation(s)
- Jun Zhang
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Zhuwan Lyu
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Bo Li
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Zhengrui You
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Nana Cui
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - You Li
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Yikang Li
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Bingyuan Huang
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Ruiling Chen
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Yong Chen
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Yanshen Peng
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Jingyuan Fang
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Qi Miao
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, California, USA
| | - Min Lian
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Xiao Xiao
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| |
Collapse
|
|
20
|
Bay S, Öztürk G, Emekli N, Demircan T. Downregulation of Yap1 during limb regeneration results in defective bone formation in axolotl. Dev Biol 2023:S0012-1606(23)00094-5. [PMID: 37271360 DOI: 10.1016/j.ydbio.2023.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 05/25/2023] [Accepted: 06/01/2023] [Indexed: 06/06/2023]
Abstract
The Hippo pathway plays an imperative role in cellular processes such as differentiation, regeneration, cell migration, organ growth, apoptosis, and cell cycle. Transcription coregulator component of Hippo pathway, YAP1, promotes transcription of genes involved in cell proliferation, migration, differentiation, and suppressing apoptosis. However, its role in epimorphic regeneration has not been fully explored. The axolotl is a well-established model organism for developmental biology and regeneration studies. By exploiting its remarkable regenerative capacity, we investigated the role of Yap1 in the early blastema stage of limb regeneration. Depleting Yap1 using gene-specific morpholinos attenuated the competence of axolotl limb regeneration evident in bone formation defects. To explore the affected downstream pathways from Yap1 down-regulation, the gene expression profile was examined by employing LC-MS/MS technology. Based on the generated data, we provided a new layer of evidence on the putative roles of increased protease inhibition and immune system activities and altered ECM composition in diminished bone formation capacity during axolotl limb regeneration upon Yap1 deficiency. We believe that new insights into the roles of the Hippo pathway in complex structure regeneration were granted in this study.
Collapse
Affiliation(s)
- Sadık Bay
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, 34810, Turkey; Graduate School of Health Sciences, İstanbul Medipol University, İstanbul, Turkey.
| | - Gürkan Öztürk
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, 34810, Turkey; Department of Physiology, International School of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Nesrin Emekli
- Department of Medical Biochemistry, Faculty of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Turan Demircan
- Department of Medical Biology, School of Medicine, Muğla Sıtkı Koçman University, Muğla, Turkey; Department of Bioinformatics, Muğla Sıtkı Koçman University, Muğla, Turkey.
| |
Collapse
|
|
21
|
An involvement of Hippo-yes-associated protein pathway in biliary epithelial senescence in primary biliary cholangitis. Clin Res Hepatol Gastroenterol 2023; 47:102106. [PMID: 36849079 DOI: 10.1016/j.clinre.2023.102106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 02/03/2023] [Accepted: 02/24/2023] [Indexed: 03/01/2023]
Abstract
BACKGROUND & AIMS Accumulating evidence suggest that Hippo-yes-associated protein (YAP) pathway plays important roles in development and repair after injuries in biliary system. We disclosed that senescent biliary epithelial cells (BECs) participate in the pathogenesis of primary biliary cholangitis (PBC). We hypothesized that dysregulation of Hippo-YAP pathway may be associated with biliary epithelial senescence in pathogenesis of PBC. APPROACH & RESULTS Cellular senescence was induced in cultured BECs by treatment with serum depletion or glycochenodeoxycholic acid. The expression and activity of YAP1 were significantly decreased in senescent BECs (p<0.01). Cellular senescence and apoptosis were significantly increased (p<0.01) and a proliferation activity and a 3D-cyst formation activity were significantly decreased (p<0.01) by a knockdown of YAP1 in BECs. The expression of YAP1 were immunohistochemically determined in livers taken from the patients with PBC (n = 79) and 79 control diseased and normal livers and its association with senescent markers p16INK4a and p21WAF1/Cip1 was analyzed. The nuclear expression of YAP1, which indicates activation of YAP1, was significantly decreased in BECs in small bile ducts involved in cholangitis and ductular reactions in PBC, compared to control livers (p<0.01). The decreased expression of YAP1 was seen in senescent BECs showing expression of p16INK4a and p21WAF1/Cip1 in bile duct lesions. CONCLUSION Dysregulation of Hippo-YAP1 pathway may be involved in the pathogenesis of PBC in association with biliary epithelial senescence.
Collapse
|
|
22
|
Piccolo S, Panciera T, Contessotto P, Cordenonsi M. YAP/TAZ as master regulators in cancer: modulation, function and therapeutic approaches. NATURE CANCER 2023; 4:9-26. [PMID: 36564601 PMCID: PMC7614914 DOI: 10.1038/s43018-022-00473-z] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 10/31/2022] [Indexed: 12/24/2022]
Abstract
Our understanding of the function of the transcriptional regulators YAP and TAZ (YAP/TAZ) in cancer is advancing. In this Review, we provide an update on recent progress in YAP/TAZ biology, their regulation by Hippo signaling and mechanotransduction and highlight open questions. YAP/TAZ signaling is an addiction shared by multiple tumor types and their microenvironments, providing many malignant attributes. As such, it represents an important vulnerability that may offer a broad window of therapeutic efficacy, and here we give an overview of the current treatment strategies and pioneering clinical trials.
Collapse
Affiliation(s)
- Stefano Piccolo
- Department of Molecular Medicine, University of Padua, Padua, Italy.
- IFOM-ETS, the AIRC Institute of Molecular Oncology, Milan, Italy.
| | - Tito Panciera
- Department of Molecular Medicine, University of Padua, Padua, Italy
| | | | | |
Collapse
|
|
23
|
Pibiri M, Simbula G. Role of the Hippo pathway in liver regeneration and repair: recent advances. Inflamm Regen 2022; 42:59. [PMID: 36471376 PMCID: PMC9720992 DOI: 10.1186/s41232-022-00235-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 11/09/2022] [Indexed: 12/12/2022] Open
Abstract
Although the signaling pathways involved in normal liver regeneration have been well characterized, less has been done for livers affected by chronic tissue damage. These "abnormal livers" have an impaired regenerative response that leads to liver repair and fibrosis. The tumor suppressor Hippo pathway plays a key role in liver regeneration and repair. On this basis, this review discusses recent studies focusing on the involvement of the Hippo signaling pathway during "normal healthy liver regeneration" (i.e., in a normal liver after 2/3 partial hepatectomy) and "abnormal liver regeneration" (i.e., in a liver damaged by chronic disease). This could be an important question to address with respect to new therapies aimed at improving impaired liver regenerative responses. The studies reported here have shown that activation of the Hippo coactivators YAP/TAZ during normal liver regeneration promotes the formation of a new bile duct network through direct BEC proliferation or/and hepatocyte dedifferentiation to HPCs which can trans-differentiate to BECs. Moreover, YAP/TAZ signaling interaction with other signaling pathways mediates the recruitment and activation of Kupffer cells, which release mitogenic cytokines for parenchymal and/or non-parenchymal cells and engage in phagocytosis of cellular debris. In addition, YAP-mediated activation of stellate cells (HSCs) promotes liver regeneration through the synthesis of extracellular matrix. However, in chronically diseased livers, where the predetermined threshold for proper liver regeneration is exceeded, YAP/TAZ activation results in a reparative process characterized by liver fibrosis. In this condition, YAP/TAZ activation in parenchymal and non-parenchymal cells results in (i) differentiation of quiescent HSCs into myofibroblastic HSCs; (ii) recruitment of macrophages releasing inflammatory cytokines; (iii) polarization of macrophages toward the M2 phenotype. Since accumulation of damaged hepatocytes in chronic liver injury represent a significant risk factor for the development of hepatocarcinoma, this review also discussed the involvement of the Hippo pathway in the clearance of damaged cells.
Collapse
Affiliation(s)
- Monica Pibiri
- grid.7763.50000 0004 1755 3242Department of Biomedical Sciences, Oncology and Molecular Pathology Unit, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. Monserrato-Sestu km 0.700, Blocco A. 09042 Monserrato, Cagliari, Italy
| | - Gabriella Simbula
- grid.7763.50000 0004 1755 3242Department of Biomedical Sciences, Oncology and Molecular Pathology Unit, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. Monserrato-Sestu km 0.700, Blocco A. 09042 Monserrato, Cagliari, Italy
| |
Collapse
|
|
24
|
Lou J, Lu Y, Cheng J, Zhou F, Yan Z, Zhang D, Meng X, Zhao Y. A chemical perspective on the modulation of TEAD transcriptional activities: Recent progress, challenges, and opportunities. Eur J Med Chem 2022; 243:114684. [DOI: 10.1016/j.ejmech.2022.114684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/02/2022] [Accepted: 08/11/2022] [Indexed: 11/30/2022]
|
|
25
|
Xie Y, Hu B, Gao Y, Tang Y, Chen G, Shen J, Jiang Z, Jiang H, Han J, Yan J, Jin L. Yap signalling regulates ductular reactions in mice with CRISPR/Cas9-induced glycogen storage disease type Ia. Anim Cells Syst (Seoul) 2022; 26:300-309. [PMID: 36605584 PMCID: PMC9809376 DOI: 10.1080/19768354.2022.2139755] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in the glucose-6-phosphatase (G6Pase, G6pc) enzyme, which catalyses the final step of gluconeogenesis and glycogenolysis. Accumulation of G6pc can lead to an increase in glycogen and development of fatty liver. Ductular reactions refer to the proliferation of cholangiocytes and hepatic progenitors, which worsen fatty liver progress. To date, however, ductular reactions in GSD-Ia remain poorly understood. Here, we studied the development and potential underlying mechanism of ductular reactions in GSD-Ia in mice. We first generated GSD-Ia mice using CRISPR/Cas9 to target the exon 3 region of the G6pc gene. The typical GSD-Ia phenotype in G6pc -/- mice was then analysed using biochemical and histological assays. Ductular reactions in G6pc -/- mice were tested based on the expression of cholangiocytic markers cytokeratin 19 (CK19) and epithelial cell adhesion molecule (EpCAM). Yes-associated protein 1 (Yap) signalling activity was measured using western blot (WB) analysis and quantitative real-time polymerase chain reaction (qRT-PCR). Verteporfin was administered to the G6pc -/- mice to inhibit Yap signalling. The CRISPR/Cas9 system efficiently generated G6pc -/- mice, which exhibited typical GSD-Ia characteristics, including retarded growth, hypoglycaemia, and fatty liver disease. In addition, CK19- and EpCAM-positive cells as well as Yap signalling activity were increased in the livers of G6pc -/- mice. However, verteporfin treatment ameliorated ductular reactions and decreased Yap signalling activity. This study not only improves our understanding of GSD-Ia pathophysiology, but also highlights the potential of novel therapeutic approaches for GSD-Ia such as drug targeting of ductular reactions.
Collapse
Affiliation(s)
- Yixia Xie
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China,Shaoxing Academy of Biomedicine of Zhejiang Sci-Tech University, Shaoxing, Zhejiang, China
| | - Baowei Hu
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | - Yue Gao
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | - Yaxin Tang
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | - Guohe Chen
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | - Jiayuan Shen
- Department of Pathology, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China
| | - Zhikai Jiang
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - He Jiang
- The First Clinical Medical School of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jiwei Han
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | - Junyan Yan
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China, Junyan Yan School of Life Science, Shaoxing University, Shaoxing, Zhejiang312000, People’s Republic of China
| | - Lifang Jin
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China,Shaoxing Academy of Biomedicine of Zhejiang Sci-Tech University, Shaoxing, Zhejiang, China,Lifang Jin School of Life Science, Shaoxing University, Shaoxing, Zhejiang312000, People’s Republic of China
| |
Collapse
|
|
26
|
Cai J, Choi K, Li H, Pulgar Prieto KD, Zheng Y, Pan D. YAP-VGLL4 antagonism defines the major physiological function of the Hippo signaling effector YAP. Genes Dev 2022; 36:1119-1128. [PMID: 36522128 PMCID: PMC9851404 DOI: 10.1101/gad.350127.122] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022]
Abstract
The Hippo-YAP signaling pathway plays a critical role in development, homeostasis, regeneration, and tumorigenesis by converging on YAP, a coactivator for the TEAD family DNA-binding transcription factors, to regulate downstream transcription programs. Given its pivotal role as the nuclear effector of the Hippo pathway, YAP is indispensable in multiple developmental and tissue contexts. Here we report that the essentiality of YAP in liver and lung development can be genetically bypassed by simultaneous inactivation of the TEAD corepressor VGLL4. This striking antagonistic epistasis suggests that the major physiological function of YAP is to antagonize VGLL4. We further show that the YAP-VGLL4 antagonism plays a widespread role in regulating Hippo pathway output beyond normal development, as inactivation of Vgll4 dramatically enhanced intrahepatic cholangiocarcinoma formation in Nf2-deficient livers and ameliorated CCl4-induced damage in normal livers. Interestingly, Vgll4 expression is temporally regulated in development and regeneration and, in certain contexts, provides a better indication of overall Hippo pathway output than YAP phosphorylation. Together, these findings highlight the central importance of VGLL4-mediated transcriptional repression in Hippo pathway regulation and inform potential strategies to modulate Hippo signaling in cancer and regenerative medicine.
Collapse
Affiliation(s)
- Jing Cai
- Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Kyungsuk Choi
- Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Hongde Li
- Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Katiuska Daniela Pulgar Prieto
- Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Yonggang Zheng
- Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Duojia Pan
- Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| |
Collapse
|
|
27
|
Lu X, Yu H, Ma J, Wang K, Guo L, Zhang Y, Li B, Zhao Z, Li H, Sun S. Loss of Mst1/2 activity promotes non-mitotic hair cell generation in the neonatal organ of Corti. NPJ Regen Med 2022; 7:64. [PMID: 36280668 PMCID: PMC9592590 DOI: 10.1038/s41536-022-00261-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 10/10/2022] [Indexed: 11/09/2022] Open
Abstract
Mammalian sensory hair cells (HCs) have limited capacity for regeneration, which leads to permanent hearing loss after HC death. Here, we used in vitro RNA-sequencing to show that the Hippo signaling pathway is involved in HC damage and self-repair processes. Turning off Hippo signaling through Mst1/2 inhibition or Yap overexpression induces YAP nuclear accumulation, especially in supporting cells, which induces supernumerary HC production and HC regeneration after injury. Mechanistically, these effects of Hippo signaling work synergistically with the Notch pathway. Importantly, the supernumerary HCs not only express HC markers, but also have cilia structures that are able to form neural connections to auditory regions in vivo. Taken together, regulating Hippo suggests new strategies for promoting cochlear supporting cell proliferation, HC regeneration, and reconnection with neurons in mammals.
Collapse
Affiliation(s)
- Xiaoling Lu
- grid.8547.e0000 0001 0125 2443ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, NHC Key Laboratory of Hearing Medicine (Fudan University), Fudan University, 200031 Shanghai, P. R. China
| | - Huiqian Yu
- grid.8547.e0000 0001 0125 2443ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, NHC Key Laboratory of Hearing Medicine (Fudan University), Fudan University, 200031 Shanghai, P. R. China
| | - Jiaoyao Ma
- grid.8547.e0000 0001 0125 2443ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, NHC Key Laboratory of Hearing Medicine (Fudan University), Fudan University, 200031 Shanghai, P. R. China
| | - Kunkun Wang
- grid.8547.e0000 0001 0125 2443ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, NHC Key Laboratory of Hearing Medicine (Fudan University), Fudan University, 200031 Shanghai, P. R. China
| | - Luo Guo
- grid.8547.e0000 0001 0125 2443ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, NHC Key Laboratory of Hearing Medicine (Fudan University), Fudan University, 200031 Shanghai, P. R. China
| | - Yanping Zhang
- grid.8547.e0000 0001 0125 2443ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, NHC Key Laboratory of Hearing Medicine (Fudan University), Fudan University, 200031 Shanghai, P. R. China
| | - Boan Li
- grid.12955.3a0000 0001 2264 7233Xiamen University School of Life Sciences, 361100 Xiamen, P. R. China
| | - Zehang Zhao
- grid.12955.3a0000 0001 2264 7233Xiamen University School of Life Sciences, 361100 Xiamen, P. R. China
| | - Huawei Li
- grid.8547.e0000 0001 0125 2443ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, NHC Key Laboratory of Hearing Medicine (Fudan University), Fudan University, 200031 Shanghai, P. R. China ,grid.8547.e0000 0001 0125 2443Institutes of Biomedical Sciences, Fudan University, 200032 Shanghai, P. R. China ,grid.8547.e0000 0001 0125 2443The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, 200032 Shanghai, China
| | - Shan Sun
- grid.8547.e0000 0001 0125 2443ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, NHC Key Laboratory of Hearing Medicine (Fudan University), Fudan University, 200031 Shanghai, P. R. China
| |
Collapse
|
|
28
|
[Changes of YAP activity at the early stage of nonalcoholic steatohepatitis and its spatiotemporal relationship with ductular reaction in mice]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2022; 42:1324-1334. [PMID: 36210705 PMCID: PMC9550545 DOI: 10.12122/j.issn.1673-4254.2022.09.08] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
OBJECTIVE To explore the changes in Yes-associated protein (YAP) activity at the early stage of nonalcoholic steatohepatitis (NASH) and the spatiotemporal relationship between YAP and ductular reaction (DR). METHODS Male C57BL/6J mouse models of NASH were established by feeding with a methionine- and choline-deficient (MCD) diet or a thioacetamide (TAA) diet for 12 weeks. At different time points during the feeding, liver histology of the mice was observed with HE and Masson trichrome staining. The mRNA expressions of YAP and its target genes (Ctgf, Cyr61, Acta2) were determined by qPCR, and the total protein expression level of YAP was measured with immunoblotting. The expression and distribution of YAP and the markers of DR (K19 and Sox9) were observed with immunohistochemical staining. RESULTS At the early stage of NASH induced by MCD diet (1 to 4 weeks), the mRNA expression of YAP and its target genes and the total protein expression of YAP increased significantly (P < 0.01). The number of YAP-positive hepatocytes reached the peak level of 90.8 (cells per ×400 field of view) at week 2 and then decreased to 30.8 at week 4 (P < 0.001); YAP-positive ductular cells appeared near the portal area, where DR began to occur. From 8 to 12 weeks, numerous K19/Sox9-positive DR cells were observed in the hepatic lobules around the central vein (P < 0.01), while only a few YAP-positive hepatocytes were present in the liver tissue (P > 0.05), and the number of YAP-positive ductular cells gradually increased with time (P < 0.001). At the early stage of NASH induced by TAA diet (3 days to 2 weeks), the mRNA expression of YAP and its target genes and the total protein expression of YAP increased significantly (P < 0.05), and the number of YAP-positive hepatocytes reached the peak of 69.2 at week 2 and then decreased to 55.2 at week 4 (P < 0.001); YAP-positive ductular cells first appeared at the initial location of DR near the central vein. From 6 to 12 weeks, numerous K19/Sox9-positive DR cells occurred in the hepatic lobules around the central vein (P < 0.01). While the number of YAP-positive hepatocytes decreased (P < 0.001), the number of YAP-positive ductular cells continued to increase (P < 0.001). CONCLUSION During the development of NASH, YAP activation occurs earlier than DR but they are spatiotemporally correlated. YAP activation in hepatocytes may participate in DR by promoting hepatocyte dedifferentiation.
Collapse
|
|
29
|
Biliary NIK promotes ductular reaction and liver injury and fibrosis in mice. Nat Commun 2022; 13:5111. [PMID: 36042192 PMCID: PMC9427946 DOI: 10.1038/s41467-022-32575-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 08/08/2022] [Indexed: 11/21/2022] Open
Abstract
Excessive cholangiocyte expansion (ductular reaction) promotes liver disease progression, but the underlying mechanism is poorly understood. Here we identify biliary NF-κB-inducing kinase (NIK) as a pivotal regulator of ductular reaction. NIK is known to activate the noncanonical IKKα/NF-κB2 pathway and regulate lymphoid tissue development. We find that cholangiocyte NIK is upregulated in mice with cholestasis induced by bile duct ligation (BDL), 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), or α-naphtyl-isothiocyanate (ANIT). DDC, ANIT, or BDL induces ductular reaction, liver injury, inflammation, and fibrosis in mice. Cholangiocyte-specific deletion of NIK, but not IKKα, blunts these pathological alterations. NIK inhibitor treatment similarly ameliorates DDC-induced ductular reaction, liver injury, and fibrosis. Biliary NIK directly increases cholangiocyte proliferation while suppressing cholangiocyte death, and it also promotes secretion of cholangiokines from cholangiocytes. Cholangiokines stimulate liver macrophages and hepatic stellate cells, augmenting liver inflammation and fibrosis. These results unveil a NIK/ductular reaction axis and a NIK/cholangiokine axis that promote liver disease progression. Excessive expansion of cholangiocytes in the liver leads to ductular reaction and liver disease. Here, the authors show that genetic ablation, or pharmacological inhibition, of biliary NIK blocks ductular reaction, liver inflammation, and liver fibrosis in mice by modulating secretion of cholangiokines that mediate liver inflammation and fibrosis.
Collapse
|
|
30
|
Shu W, Yang M, Yang J, Lin S, Wei X, Xu X. Cellular crosstalk during liver regeneration: unity in diversity. Cell Commun Signal 2022; 20:117. [PMID: 35941604 PMCID: PMC9358812 DOI: 10.1186/s12964-022-00918-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 06/08/2022] [Indexed: 11/27/2022] Open
Abstract
The liver is unique in its ability to regenerate from a wide range of injuries and diseases. Liver regeneration centers around hepatocyte proliferation and requires the coordinated actions of nonparenchymal cells, including biliary epithelial cells, liver sinusoidal endothelial cells, hepatic stellate cells and kupffer cells. Interactions among various hepatocyte and nonparenchymal cells populations constitute a sophisticated regulatory network that restores liver mass and function. In addition, there are two different ways of liver regeneration, self-replication of liver epithelial cells and transdifferentiation between liver epithelial cells. The interactions among cell populations and regenerative microenvironment in the two modes are distinct. Herein, we first review recent advances in the interactions between hepatocytes and surrounding cells and among nonparenchymal cells in the context of liver epithelial cell self-replication. Next, we discuss the crosstalk of several cell types in the context of liver epithelial transdifferentiation, which is also crucial for liver regeneration.
|