|
1
|
Du W, Chen C, Liu Y, Quan H, Xu M, Liu J, Song P, Fang Z, Yue Z, Xu H, Ling Y, Duan J, He F, Wang L. A combined "eat me/don't eat me" strategy based on exosome for acute liver injury treatment. Cell Rep Med 2025:102033. [PMID: 40120577 DOI: 10.1016/j.xcrm.2025.102033] [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: 07/04/2024] [Revised: 12/09/2024] [Accepted: 02/24/2025] [Indexed: 03/25/2025]
Abstract
Drug-induced liver injury (DILI) involves multifaceted pathogenesis, necessitating effective therapeutic strategies. Wnt2, secreted by liver sinusoidal endothelial cell (LSEC), activates the Wnt/β-catenin signaling pathway to promote hepatocyte proliferation after injury. To address the dual challenges of targeted delivery and phagocytosis evasion, we develop a combined "eat me/don't eat me" strategy. RLTRKRGLK (RLTR) peptide-functionalized exosomes are engineered by inserting DMPE-PEG2000-CRLTRKRGLK into the lipid membrane of exosome derived from bEnd.3 cell. Surface-displayed RLTR mediates exosomal enrichment in LSEC, while CD47 engineering reduces macrophage clearance via "don't eat me" signaling. Then, lentiviral transfection enables stable encapsulation of functional Wnt2 mRNA into ExoCD47 (designated Wnt2@ExoCD47). In both acetaminophen (APAP) and dimethylnitrosamine (DMN)-induced murine liver injury models, RLTR-Wnt2@ExoCD47 demonstrates LSEC-specific targeting and significant hepatoprotection. This engineered exosome platform provides a therapeutic strategy for DILI.
Collapse
Affiliation(s)
- Wei Du
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Chen Chen
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - YingYing Liu
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Huiyi Quan
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Ming Xu
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - JingJing Liu
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Ping Song
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - ZhiQiang Fang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - ZhenSheng Yue
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Hao Xu
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - YuWei Ling
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - JuanLi Duan
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
| | - Fei He
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
| |
Collapse
|
|
2
|
Gao L, Ding YN, Zhou PC, Dong LL, Peng XY, Tang YR, Zhu QX, Zhang JX. Wnt5a promotes Kupffer cell activation in trichloroethylene-induced immune liver injury. Toxicol Ind Health 2025; 41:83-96. [PMID: 39588578 DOI: 10.1177/07482337241300953] [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] [Indexed: 11/27/2024]
Abstract
Trichloroethylene (TCE) is a volatile, colorless liquid that is widely used as a chlorinated organic vehicle in industrial production and processing industries. Many workers exposed to trichloroethylene may develop trichloroethylene hypersensitivity syndrome (THS). However, the underlying mechanism of THS is still unclear, especially liver injury. The present study aimed to investigate whether Wnt5a/c-Jun N-terminal kinase (JNK) is involved in and regulates liver injury caused by TCE exposure and to provide new directions for the prevention and treatment in clinical settings of liver injury caused by TCE exposure. We used 6- to 8-week-old SPF-grade BALB/c female mice to establish a TCE sensitization model and explored the mechanism through inhibitor intervention. We found that the expression of Wnt5a/JNK was significantly elevated in the liver of TCE sensitization-positive mice. Inhibitors of Wnt Production 2 (IWP-2) are known antagonists of the Wnt pathway. TCE-sensitization mice treated with IWP-2 showed downregulated Wnt5a/JNK expression, reduced Kupffer cell activation, and decreased liver injury. At the same time, we found that phosphorylated JNK in TCE-sensitization mouse livers and extracted Kupffer cells showed a significant downward trend after inhibition of Wnt5a function. We also found that a specific JNK inhibitor, SP600125, decreased the secretion of cytokines and chemokines and decreased Kupffer cell activation. We demonstrated that Wnt5a/JNK was involved in the regulation of liver injury in TCE-sensitization mice and that it exacerbated liver injury by activating Kupffer cells and releasing chemokines. We therefore hypothesized that Kupffer cell activation was affected by JNK, which reduced chemokine and cytokine secretion and attenuated liver injury in TCE-sensitization mice.
Collapse
Affiliation(s)
- Lei Gao
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, China
| | - Ya-Ni Ding
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, China
| | - Peng-Cheng Zhou
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, China
| | - Luo-Lun Dong
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, China
| | - Xin-Yu Peng
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, China
| | - Yi-Ru Tang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, China
| | - Qi-Xing Zhu
- Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China
- Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jia-Xiang Zhang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, China
- Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China
| |
Collapse
|
|
3
|
Rutt LN, Orlicky DJ, McCullough RL. Investigating the role of Wnt3a and Wnt5a as critical factors of hepatic stellate cell activation in acute toxicant-induced liver injury. Cell Biol Toxicol 2024; 41:5. [PMID: 39707064 PMCID: PMC11662040 DOI: 10.1007/s10565-024-09956-4] [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: 06/07/2024] [Accepted: 11/20/2024] [Indexed: 12/23/2024]
Abstract
Toxicant exposure can lead to acute liver injury, characterized by hepatic reprogramming and wound healing. Hepatic stellate cells (HSC) play a key role in liver regeneration during wound healing by secreting fibrogenic factors and production of extracellular matrix (ECM). However, repetitive injury to the liver can lead to extensive scarring and liver fibrosis, indicating HSCs coordinate both regeneration and disease. Because the factors contributing to HSC reprogramming during wound healing are not fully defined, we sought to further characterize morphogenic pathways of regeneration in an acute model of toxicant-induced liver injury1. Wnt/β-catenin signaling has been recently associated with progressive liver fibrosis, but its role in HSC reprogramming is not well defined. Here, we investigated the canonical role of Wnt3a/Wnt5a on β-catenin-dependent HSC transdifferentiation and find that hepatic ECM gene expression is increased and associated with Wnt3a, Wnt5a, and their transducers (Frizzled-2 and Frizzled-7) after an acute exposure of the hepatotoxin, carbon tetrachloride(CCl4). Moreover, we find exogenous Wnt3a and Wnt5a can accelerate spontaneous, culture-induced HSC activation in vitro as evidenced by increased total expression of fibrogenic factors, including Col1a1 and α-SMA. Challenge with Wnt3a induced canonical β-catenin-dependent transcription of axin2, which was attenuated by the Wnt coreceptor antagonist, Dickkopf-1 (DKK-1). These data support a role for canonical Wnt signaling as an additional mechanism by which HSCs dynamically respond to liver injury during the early wound healing response. New & noteworthy. This study elucidates novel mechanisms of fibrotic gene reprogramming in the liver. Specifically, we describe that Wnts and their transducers are increased during early liver injury which are associated with early fibrogenic responses and for the first time, causally link Wnts as direct inducers of HSC activation in the liver.
Collapse
Affiliation(s)
- Lauren N Rutt
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 13850 E. Montview Blvd, Box C238/V20-3128, Aurora, CO, 80045, USA
| | - David J Orlicky
- Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Rebecca L McCullough
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 13850 E. Montview Blvd, Box C238/V20-3128, Aurora, CO, 80045, USA.
| |
Collapse
|
|
4
|
Zheng S, Xue C, Li S, Qi W, Zao X, Li X, Wang W, Liu Q, Cao X, Zhang P, Ye Y. Research Progress of Chinese Medicine in the Regulation of Liver Fibrosis-Related Signaling Pathways. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2024; 52:1693-1728. [PMID: 39343991 DOI: 10.1142/s0192415x24500666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Liver fibrosis is a common complication of chronic liver disease, significantly affecting patients' quality of life and potentially leading to cirrhosis and hepatocellular carcinoma. Despite advancements in modern medicine, the treatment of liver fibrosis remains limited and challenging. Thus, identifying new therapeutic strategies is of great clinical importance. Signaling pathways related to liver fibrosis play a crucial regulatory role in immune response and inflammation. Aberrant activation of specific pathways, such as the NF-κB signaling pathway, results in the overexpression of genes associated with liver inflammation and fibrosis, thereby promoting the progression of liver fibrosis. Chinese medicine offers unique potential advantages as a therapeutic approach. Recent studies have increasingly demonstrated that certain Chinese medicines can effectively treat liver fibrosis by regulating relevant signaling pathways. The active ingredients in these medicines can inhibit hepatic inflammatory responses and fibrotic processes by interfering with these pathways, thus reducing the severity of liver fibrosis. This paper aims to investigate the mechanisms of Chinese medicine in treating liver fibrosis and its modulation of related signaling pathways. Additionally, it discusses the prospects of the clinical application of these treatments and provides valuable references for further research and clinical practice.
Collapse
Affiliation(s)
- Shihao Zheng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Chengyuan Xue
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Size Li
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Wenying Qi
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Xiaobin Zao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine Beijing, P. R. China
| | - Xiaoke Li
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Wei Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Qiyao Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Xu Cao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Peng Zhang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Yongan Ye
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P. R. China
| |
Collapse
|
|
5
|
de Haan LR, van Golen RF, Heger M. Molecular Pathways Governing the Termination of Liver Regeneration. Pharmacol Rev 2024; 76:500-558. [PMID: 38697856 DOI: 10.1124/pharmrev.123.000955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/24/2024] [Accepted: 02/08/2024] [Indexed: 05/05/2024] Open
Abstract
The liver has the unique capacity to regenerate, and up to 70% of the liver can be removed without detrimental consequences to the organism. Liver regeneration is a complex process involving multiple signaling networks and organs. Liver regeneration proceeds through three phases: the initiation phase, the growth phase, and the termination phase. Termination of liver regeneration occurs when the liver reaches a liver-to-body weight that is required for homeostasis, the so-called "hepatostat." The initiation and growth phases have been the subject of many studies. The molecular pathways that govern the termination phase, however, remain to be fully elucidated. This review summarizes the pathways and molecules that signal the cessation of liver regrowth after partial hepatectomy and answers the question, "What factors drive the hepatostat?" SIGNIFICANCE STATEMENT: Unraveling the pathways underlying the cessation of liver regeneration enables the identification of druggable targets that will allow us to gain pharmacological control over liver regeneration. For these purposes, it would be useful to understand why the regenerative capacity of the liver is hampered under certain pathological circumstances so as to artificially modulate the regenerative processes (e.g., by blocking the cessation pathways) to improve clinical outcomes and safeguard the patient's life.
Collapse
Affiliation(s)
- Lianne R de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Rowan F van Golen
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| |
Collapse
|
|
6
|
Zhang X, Lu X, Shi J, Li Y, Li Y, Tao R, Huang L, Tang Y, Zhu X, Li M, Gao Y, Feng H, Yu Z. Bufalin suppresses hepatocellular carcinogenesis by targeting M2 macrophage-governed Wnt1/β-catenin signaling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 126:155395. [PMID: 38340578 DOI: 10.1016/j.phymed.2024.155395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 10/28/2023] [Accepted: 01/24/2024] [Indexed: 02/12/2024]
Abstract
BACKGROUND The interplay of tumor-associated macrophages (TAMs) and tumor cells plays a key role in the development of hepatocellular carcinoma (HCC) and provides an important target for HCC therapy. The communication between them is still on the investigation. Bufalin, the active component derived from the traditional Chinese medicine (TCM) Chansu, has been evidenced to possess anti-HCC activity by directly suppressing tumor cells, while its immunomodulatory effect on the tumor microenvironment (TME) is unclear. PURPOSE To explore the mechanism of M2 TAM-governed tumor cell proliferation and the inhibitory effect of bufalin on HCC growth by targeting M2 macrophages. METHODS Morphology and marker proteins were detected to evaluate macrophage polarization via microscopy and flow cytometry. Cellular proliferation and malignant transformation of HCC cells cultured with macrophage conditioned medium (CM) or bufalin-primed M2-CM, were assessed by cell viability, colony formation and soft agar assays. Regulations of gene transcription and protein expression and release were determined by RT-qPCR, immunoblotting, immunoprecipitation, ELISA and immunofluorescence. Tumorigenicity upon bufalin treatment was verified in orthotopic and diethylnitrosamine-induced HCC mouse model. RESULTS In this study, we first verified that M2 macrophages secreted Wnt1, which acted as a mediator to trigger β-catenin activation in HCC cells, leading to cellular proliferation. Bufalin suppressed HCC cell proliferation and malignant transformation by inhibiting Wnt1 release in M2 macrophages, and dose-dependently inhibited HCC progression in mice. Mechanistically, bufalin specially targeted to block Wnt1 transcription, thus inactivating β-catenin signaling cascade in HCC cells and leading to tumor regression in HCC mouse model. CONCLUSION These results clearly reveal a novel potential of bufalin to suppress HCC through immunomodulation, and shed light on a new M2 macrophage-based modality of HCC immunotherapy, which additively enhances direct tumor-inhibitory efficacy of bufalin.
Collapse
Affiliation(s)
- Xuemei Zhang
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaona Lu
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jia Shi
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yuyao Li
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yue Li
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ru Tao
- Department of Nursing, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lingying Huang
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yifei Tang
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaojun Zhu
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Man Li
- Laboratoy of Cellular Immunity, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yueqiu Gao
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Hai Feng
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Zhuo Yu
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| |
Collapse
|
|
7
|
Plata-Gómez AB, de Prado-Rivas L, Sanz A, Deleyto-Seldas N, García F, de la Calle Arregui C, Silva C, Caleiras E, Graña-Castro O, Piñeiro-Yáñez E, Krebs J, Leiva-Vega L, Muñoz J, Jain A, Sabio G, Efeyan A. Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver. Nat Commun 2024; 15:1878. [PMID: 38499523 PMCID: PMC10948770 DOI: 10.1038/s41467-024-46032-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 02/09/2024] [Indexed: 03/20/2024] Open
Abstract
The metabolic functions of the liver are spatially organized in a phenomenon called zonation, linked to the differential exposure of portal and central hepatocytes to nutrient-rich blood. The mTORC1 signaling pathway controls cellular metabolism in response to nutrients and insulin fluctuations. Here we show that simultaneous genetic activation of nutrient and hormone signaling to mTORC1 in hepatocytes results in impaired establishment of postnatal metabolic and zonal identity of hepatocytes. Mutant hepatocytes fail to upregulate postnatally the expression of Frizzled receptors 1 and 8, and show reduced Wnt/β-catenin activation. This defect, alongside diminished paracrine Wnt2 ligand expression by endothelial cells, underlies impaired postnatal maturation. Impaired zonation is recapitulated in a model of constant supply of nutrients by parenteral nutrition to piglets. Our work shows the role of hepatocyte sensing of fluctuations in nutrients and hormones for triggering a latent metabolic zonation program.
Collapse
Affiliation(s)
- Ana Belén Plata-Gómez
- Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid, 28029, Spain
| | - Lucía de Prado-Rivas
- Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid, 28029, Spain
| | - Alba Sanz
- Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid, 28029, Spain
| | - Nerea Deleyto-Seldas
- Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid, 28029, Spain
| | - Fernando García
- Proteomics Unit. Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Celia de la Calle Arregui
- Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid, 28029, Spain
| | - Camila Silva
- Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid, 28029, Spain
| | - Eduardo Caleiras
- Histopathology Unit. Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Osvaldo Graña-Castro
- Bioinformatics Unit. Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Department of Basic Medical Sciences, Institute of Applied Molecular Medicine (IMMA-Nemesio Díez), School of Medicine, San Pablo-CEU University, CEU Universities, Boadilla del Monte, Madrid, Spain
| | - Elena Piñeiro-Yáñez
- Bioinformatics Unit. Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Joseph Krebs
- Department of Pediatrics, Saint Louis University, Saint Louis, MO, USA
| | - Luis Leiva-Vega
- Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Javier Muñoz
- Proteomics Unit. Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Cell Signalling and Clinical Proteomics Group, Biocruces Bizkaia Health Research Institute & Ikerbasque Basque Foundation for Science, Bilbao, Spain
| | - Ajay Jain
- Department of Pediatrics, Saint Louis University, Saint Louis, MO, USA
| | - Guadalupe Sabio
- Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Alejo Efeyan
- Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid, 28029, Spain.
| |
Collapse
|
|
8
|
Tai Y, Shang J. Wnt/β-catenin signaling pathway in the tumor progression of adrenocortical carcinoma. Front Endocrinol (Lausanne) 2024; 14:1260701. [PMID: 38269250 PMCID: PMC10806569 DOI: 10.3389/fendo.2023.1260701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 12/20/2023] [Indexed: 01/26/2024] Open
Abstract
Adrenocortical carcinoma (ACC) is an uncommon, aggressive endocrine malignancy with a high rate of recurrence, a poor prognosis, and a propensity for metastasis. Currently, only mitotane has received certification from both the US Food and Drug Administration (FDA) and the European Medicines Agency for the therapy of advanced ACC. However, treatment in the advanced periods of the disorders is ineffective and has serious adverse consequences. Completely surgical excision is the only cure but has failed to effectively improve the survival of advanced patients. The aberrantly activated Wnt/β-catenin pathway is one of the catalysts for adrenocortical carcinogenesis. Research has concentrated on identifying methods that can prevent the stimulation of the Wnt/β-catenin pathway and are safe and advantageous for patients in view of the absence of effective treatments and the frequent alteration of the Wnt/β-catenin pathway in ACC. Comprehending the complex connection between the development of ACC and Wnt/β-catenin signaling is essential for accurate pharmacological targets. In this review, we summarize the potential targets between adrenocortical carcinoma and the Wnt/β-catenin signaling pathway. We analyze the relevant targets of drugs or inhibitors that act on the Wnt pathway. Finally, we provide new insights into how drugs or inhibitors may improve the treatment of ACC.
Collapse
Affiliation(s)
- Yanghao Tai
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
| | - Jiwen Shang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
- Department of Ambulatory Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| |
Collapse
|
|
9
|
Li N, Ge Q, Guo Q, Tao Y. Identification and functional validation of FZD8-specific antibodies. Int J Biol Macromol 2024; 254:127846. [PMID: 37926311 DOI: 10.1016/j.ijbiomac.2023.127846] [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: 10/05/2023] [Revised: 10/31/2023] [Accepted: 10/31/2023] [Indexed: 11/07/2023]
Abstract
The Wnt pathway is an evolutionarily conserved pathway involved in stem cell homeostasis and tissue regeneration. Aberrant signaling in the Wnt pathway is highly associated with cancer. Developing antibodies to block overactivation of Frizzled receptors (FZDs), the main receptors in the Wnt pathway, is one of the viable options for treating cancer. However, obtaining isoform-specific antibodies is often challenging due to the high degree of homology among the ten FZDs. In this study, by using a synthetic library, we identified an antibody named pF8_AC3 that preferentially binds to FZD8. Guided by the structure of the complex of pF8_AC3 and FZD8, a second-generation targeted library was further constructed, and finally, the FZD8-specific antibody sF8_AG6 was obtained. Cell-based assays showed that these antibodies could selectively block FZD8-mediated signaling activation. Taken together, these antibodies have the potential to be developed into therapeutic drugs in the future.
Collapse
Affiliation(s)
- Na Li
- MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China
| | - Qiangqiang Ge
- MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China
| | - Qiong Guo
- MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China.
| | - Yuyong Tao
- MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China.
| |
Collapse
|
|
10
|
Sharma N, Sistla R, Andugulapati SB. Yohimbine ameliorates liver inflammation and fibrosis by regulating oxidative stress and Wnt/β-catenin pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 123:155182. [PMID: 37952411 DOI: 10.1016/j.phymed.2023.155182] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 10/17/2023] [Accepted: 11/01/2023] [Indexed: 11/14/2023]
Abstract
BACKGROUND AND PURPOSE Chronic liver injury, caused by various aetiologies, causes recurrent tissue damage, culminating in decreased liver regenerative ability and resulting in fibrosis followed by cirrhosis. In this study, the anti-fibrotic activity of Yohimbine hydrochloride (YHC) was investigated using various in vitro models and in vivo models. METHODS To assess the anti-inflammatory, antioxidant, and anti-fibrotic effects of YHC, lipopolysaccharide or TGF-β induced differentiation or lipid-induced oxidative-stress models were employed using HLECs, HSC-LX2, and HepG2 cells. Further, thioacetamide (TAA) induced hepatic inflammation/fibrosis models were utilized to validate the YHC's anti-fibrotic activity in rats. RESULTS Inflammation/differentiation experiments in HLECs and HSC-LX2 revealed that YHC treatment significantly (p < 0.001) mitigated the lipopolysaccharide or TGF-β induced upregulation of inflammatory and fibrotic markers expression respectively. In addition, YHC dose-dependently reduced the TGF-β induced migration and palmitic acid-induced oxidative stress in HepG2 cells. Further, TAA administration (5 weeks) in vivo rat model showed increased inflammatory marker levels/expression, oxidative stress, and pathological abnormalities. Additionally, TAA administration (9 weeks) elevated the fibrotic marker expression, collagen deposition in liver tissues, and shortened longevity in rats. Treatment with YHC dose-dependently mitigated the TAA-induced abnormalities in both inflammation and fibrosis models and improved the survival of the rats. Further mechanistic approaches revealed that TAA administration elevated the JNK, Wnt components and β-catenin expression in hepatic stellate cells and animal tissues. Further treatment with YHC significantly modulated the JNK/Wnt/β-catenin signaling. Moreover, the β-catenin nuclear translocation results showed that β-catenin levels were significantly elevated in the nuclear fraction of TAA control samples and reduced in YHC-treated samples. CONCLUSION Yohimbine treatment significantly improved inflammation and fibrosis by inhibiting differentiation, oxidative stress, and collagen deposition by partly modulating the JNK/Wnt/β-catenin pathway. These results might serve as a foundation for proposing yohimbine as a potential lead compound for liver fibrosis.
Collapse
Affiliation(s)
- Nidhi Sharma
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, Telangana, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh-201 002, India
| | - Ramakrishna Sistla
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, Telangana, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh-201 002, India
| | - Sai Balaji Andugulapati
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, Telangana, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh-201 002, India.
| |
Collapse
|
|
11
|
Lehrich BM, Monga SP. Learning human liver biology in humanized mice. Cell Res 2024; 34:9-10. [PMID: 37730939 PMCID: PMC10770126 DOI: 10.1038/s41422-023-00877-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/22/2023] Open
Affiliation(s)
- Brandon M Lehrich
- Division of Experimental Pathology, Department of Pathology and Pittsburgh Liver Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Satdarshan P Monga
- Division of Experimental Pathology, Department of Pathology and Pittsburgh Liver Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| |
Collapse
|
|
12
|
Kaffe E, Roulis M, Zhao J, Qu R, Sefik E, Mirza H, Zhou J, Zheng Y, Charkoftaki G, Vasiliou V, Vatner DF, Mehal WZ, Yuval Kluger, Flavell RA. Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions. Cell 2023; 186:3793-3809.e26. [PMID: 37562401 PMCID: PMC10544749 DOI: 10.1016/j.cell.2023.07.017] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 04/24/2023] [Accepted: 07/12/2023] [Indexed: 08/12/2023]
Abstract
Hepatocytes, the major metabolic hub of the body, execute functions that are human-specific, altered in human disease, and currently thought to be regulated through endocrine and cell-autonomous mechanisms. Here, we show that key metabolic functions of human hepatocytes are controlled by non-parenchymal cells (NPCs) in their microenvironment. We developed mice bearing human hepatic tissue composed of human hepatocytes and NPCs, including human immune, endothelial, and stellate cells. Humanized livers reproduce human liver architecture, perform vital human-specific metabolic/homeostatic processes, and model human pathologies, including fibrosis and non-alcoholic fatty liver disease (NAFLD). Leveraging species mismatch and lipidomics, we demonstrate that human NPCs control metabolic functions of human hepatocytes in a paracrine manner. Mechanistically, we uncover a species-specific interaction whereby WNT2 secreted by sinusoidal endothelial cells controls cholesterol uptake and bile acid conjugation in hepatocytes through receptor FZD5. These results reveal the essential microenvironmental regulation of hepatic metabolism and its human-specific aspects.
Collapse
Affiliation(s)
- Eleanna Kaffe
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Manolis Roulis
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Jun Zhao
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA; Computational Biology and Bioinformatics Program, Yale University, New Haven, CT 06511, USA
| | - Rihao Qu
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA; Computational Biology and Bioinformatics Program, Yale University, New Haven, CT 06511, USA
| | - Esen Sefik
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Haris Mirza
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Jing Zhou
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Yunjiang Zheng
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Georgia Charkoftaki
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06520, USA
| | - Vasilis Vasiliou
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06520, USA
| | - Daniel F Vatner
- Department of Internal Medicine, Section of Endocrinology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Wajahat Z Mehal
- Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA; Veterans Affairs Medical Center, West Haven, CT 06516, USA
| | - Yuval Kluger
- Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA; Computational Biology and Bioinformatics Program, Yale University, New Haven, CT 06511, USA; Program of Applied Mathematics, Yale University, New Haven, CT 06511, USA
| | - Richard A Flavell
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06519, USA.
| |
Collapse
|
|
13
|
Shree Harini K, Ezhilarasan D. Wnt/beta-catenin signaling and its modulators in nonalcoholic fatty liver diseases. Hepatobiliary Pancreat Dis Int 2023; 22:333-345. [PMID: 36448560 DOI: 10.1016/j.hbpd.2022.10.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 10/13/2022] [Indexed: 11/04/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global health concern associated with significant morbidity and mortality. NAFLD is a spectrum of diseases originating from simple steatosis, progressing through nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis that may lead to hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is mediated by the triglyceride accumulation followed by proinflammatory cytokines expression leading to inflammation, oxidative stress, and mitochondrial dysfunction denoted as "two-hit hypothesis", advancing with a "third hit" of insufficient hepatocyte proliferation, leading to the increase in hepatic progenitor cells contributing to fibrosis and HCC. Wnt/β-catenin signaling is responsible for normal liver development, regeneration, hepatic metabolic zonation, ammonia and drug detoxification, hepatobiliary development, etc., maintaining the overall liver homeostasis. The key regulators of canonical Wnt signaling such as LRP6, Wnt1, Wnt3a, β-catenin, GSK-3β, and APC are abnormally regulated in NAFLD. Many experimental studies have shown the aberrated Wnt/β-catenin signaling during the NAFLD progression and NASH to hepatic fibrosis and HCC. Therefore, in this review, we have emphasized the role of Wnt/β-catenin signaling and its modulators that can potentially aid in the inhibition of NAFLD.
Collapse
Affiliation(s)
- Karthik Shree Harini
- Department of Pharmacology, Molecular Medicine and Toxicology Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu 600 077, India
| | - Devaraj Ezhilarasan
- Department of Pharmacology, Molecular Medicine and Toxicology Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu 600 077, India.
| |
Collapse
|
|
14
|
Gayden J, Hu S, Joseph PN, Delgado E, Liu S, Bell A, Puig S, Monga SP, Freyberg Z. A Spatial Atlas of Wnt Receptors in Adult Mouse Liver. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:558-566. [PMID: 36773785 PMCID: PMC10155265 DOI: 10.1016/j.ajpath.2023.01.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/13/2023] [Accepted: 01/30/2023] [Indexed: 02/12/2023]
Abstract
Hepatic zonation is critical for most metabolic functions in liver. Wnt signaling plays an important role in establishing and maintaining liver zonation. Yet, the anatomic expression of Wnt signaling components, especially all 10 Frizzled (Fzd) receptors, has not been characterized in adult liver. To address this, the spatial expression of Fzd receptors was quantitatively mapped in adult mouse liver via multiplex fluorescent in situ hybridization. Although all 10 Fzd receptors were expressed within a metabolic unit, Fzd receptors 1, 4, and 6 were the highest expressed. Although most Wnt signaling occurs in zone 3, expression of most Fzd receptors was not zonated. In contrast, Fzd receptor 6 was preferentially expressed in zone 1. Wnt2 and Wnt9b expression was highly zonated and primarily found in zone 3. Therefore, the current results suggest that zonated Wnt/β-catenin signaling at baseline occurs primarily due to Wnt2 and Wnt9b rather than zonation of Fzd mRNA expression. Finally, the study showed that Fzd receptors and Wnts are not uniformly expressed by all hepatic cell types. Instead, there is broad distribution among both hepatocytes and nonparenchymal cells, including endothelial cells. Overall, this establishment of a definitive mRNA expression atlas, especially of Fzd receptors, opens the door to future functional characterization in healthy and diseased liver states.
Collapse
Affiliation(s)
- Jenesis Gayden
- Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Shikai Hu
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Paul N Joseph
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Evan Delgado
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Silvia Liu
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Aaron Bell
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Stephanie Puig
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
| | - Satdarshan P Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania; Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania.
| | - Zachary Freyberg
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
| |
Collapse
|
|
15
|
Zou G, Park JI. Wnt signaling in liver regeneration, disease, and cancer. Clin Mol Hepatol 2023; 29:33-50. [PMID: 35785913 PMCID: PMC9845677 DOI: 10.3350/cmh.2022.0058] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 06/30/2022] [Indexed: 02/02/2023] Open
Abstract
The liver exhibits the highest recovery rate from acute injuries. However, in chronic liver disease, the long-term loss of hepatocytes often leads to adverse consequences such as fibrosis, cirrhosis, and liver cancer. The Wnt signaling plays a pivotal role in both liver regeneration and tumorigenesis. Therefore, manipulating the Wnt signaling has become an attractive approach to treating liver disease, including cancer. Nonetheless, given the crucial roles of Wnt signaling in physiological processes, blocking Wnt signaling can also cause several adverse effects. Recent studies have identified cancer-specific regulators of Wnt signaling, which would overcome the limitation of Wnt signaling target approaches. In this review, we discussed the role of Wnt signaling in liver regeneration, precancerous lesion, and liver cancer. Furthermore, we summarized the basic and clinical approaches of Wnt signaling blockade and proposed the therapeutic prospects of cancer-specific Wnt signaling blockade for liver cancer treatment.
Collapse
Affiliation(s)
- Gengyi Zou
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,Corresponding author : Gengyi Zou Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd Unit 1054, Houston, TX 77030, USA Tel: +1-713-792-3659, Fax: +1-713-794-5369, E-mail:
| | - Jae-Il Park
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,Genetics and Epigenetics Program, The University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences, Houston, TX, USA,Jae-Il Park Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd. Unit 1052, Houston, TX 77030, USA Tel: +1-713-792-3659, Fax: +1-713-794-5369, E-mail:
| |
Collapse
|
|
16
|
Hu S, Liu S, Bian Y, Poddar M, Singh S, Cao C, McGaughey J, Bell A, Blazer LL, Adams JJ, Sidhu SS, Angers S, Monga SP. Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b. Cell Rep Med 2022; 3:100754. [PMID: 36220068 PMCID: PMC9588996 DOI: 10.1016/j.xcrm.2022.100754] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 07/04/2022] [Accepted: 09/08/2022] [Indexed: 11/16/2022]
Abstract
The conclusive identity of Wnts regulating liver zonation (LZ) and regeneration (LR) remains unclear despite an undisputed role of β-catenin. Using single-cell analysis, we identified a conserved Wnt2 and Wnt9b expression in endothelial cells (ECs) in zone 3. EC-elimination of Wnt2 and Wnt9b led to both loss of β-catenin targets in zone 3, and re-appearance of zone 1 genes in zone 3, unraveling dynamicity in the LZ process. Impaired LR observed in the knockouts phenocopied models of defective hepatic Wnt signaling. Administration of a tetravalent antibody to activate Wnt signaling rescued LZ and LR in the knockouts and induced zone 3 gene expression and LR in controls. Administration of the agonist also promoted LR in acetaminophen overdose acute liver failure (ALF) fulfilling an unmet clinical need. Overall, we report an unequivocal role of EC-Wnt2 and Wnt9b in LZ and LR and show the role of Wnt activators as regenerative therapy for ALF.
Collapse
Affiliation(s)
- Shikai Hu
- School of Medicine, Tsinghua University, Beijing, China; Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Silvia Liu
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Yu Bian
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Minakshi Poddar
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sucha Singh
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Catherine Cao
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jackson McGaughey
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Aaron Bell
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Levi L Blazer
- Donnelly Centre, University of Toronto, Toronto, ON, Canada
| | - Jarret J Adams
- Donnelly Centre, University of Toronto, Toronto, ON, Canada
| | | | - Stephane Angers
- Donnelly Centre, University of Toronto, Toronto, ON, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada
| | - Satdarshan P Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| |
Collapse
|
|
17
|
Eguchi A, Iwasa M, Sugimoto R, Tempaku M, Yoshikawa K, Yoshizawa N, Povero D, Sugimoto K, Hasegawa H, Takei Y, Nakagawa H. Complement complex 1 subunit q-mediated hepatic stellate cell activation with connective tissue growth factor elevation is a prognostic factor for survival in rat and human chronic liver diseases. Hepatol Commun 2022; 6:3515-3527. [PMID: 36199236 PMCID: PMC9701491 DOI: 10.1002/hep4.2097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 08/23/2022] [Accepted: 09/01/2022] [Indexed: 01/21/2023] Open
Abstract
Complement complex 1 subunit q (C1q) has multiple functions, including cell migration, in addition to its traditional complement-activating effect. Research shows C1q is a ligand for frizzled receptors (FZDs). FZD-induced yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) alternate Wnt signaling activation induces connective tissue growth factor (CTGF) production and hepatic stellate cell (HSC) activation. However, no study exists in which C1q directly induces CTGF in HSCs. Here, we investigated the role of C1q in HSC activation. Human HSCs (LX2) were incubated with C1q to assess HSC activation. C1q and fibrotic markers were assessed using immunohistochemistry, immunoblotting, and quantitative reverse-transcription polymerase chain reaction in cirrhotic rats administered CCl4 for 21 weeks. Serum C1q, liver function, and fibrosis score were measured in 91 patients with chronic liver disease. The correlations between serum C1q and liver function, fibrosis score, and survival prognosis were examined. C1q-activated LX2s showed morphologic changes, up-regulation of CTGF, tissue inhibitors of metalloproteinases (TIMP-1), and alternate Wnt signal genes FZD2, TAZ, and cysteine-rich angiogenic inducer 61 (Cyr61). Cirrhotic rat liver C1q expression correlated with the Azan-positive area and expression of CTGF, TIMP-1, hyaluronan synthase (HAS)1, HAS3, and CD44. Expression of C1q protein and C1q, CTGF, and TIMP-1 genes were higher in deceased cirrhotic rat livers compared to surviving rats. Human serum C1q levels increased in liver cirrhosis compared to chronic hepatitis and correlated with liver fibrosis and functional markers. Ten patients suffered liver-related death over a 66-month observation period. The C1q cut-off value (11 mg/dl) showed patients with serum values < 11 mg/dl had longer rates of survival compared to C1q ≥ 11 mg/dl. Conclusion: C1q-mediated HSC activation in liver fibrosis is associated with CTGF elevation. Additionally, serum C1q may be diagnostic for survival in human chronic liver diseases.
Collapse
Affiliation(s)
- Akiko Eguchi
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Motoh Iwasa
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Ryosuke Sugimoto
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Mina Tempaku
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Kyoko Yoshikawa
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Naohiko Yoshizawa
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Davide Povero
- Department of Biochemistry and Molecular BiologyMayo ClinicRochesterMinnesotaUSA
| | - Kazushi Sugimoto
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Hiroshi Hasegawa
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Hayato Nakagawa
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| |
Collapse
|
|
18
|
Sun HY, Gu AX, Huang BY, Zhang T, Li JP, Shan AS. Dietary Grape Seed Proanthocyanidin Alleviates the Liver Injury Induced by Long-Term High-Fat Diets in Sprague Dawley Rats. Front Vet Sci 2022; 9:959906. [PMID: 35990272 PMCID: PMC9382112 DOI: 10.3389/fvets.2022.959906] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 06/16/2022] [Indexed: 12/03/2022] Open
Abstract
In mammals, the liver is the most important organ that plays a vital function in lipid metabolism. Grape seed proanthocyanidin (GSPE) is a kind of natural polyphenolic compound primarily obtained from grape skin and seeds. Recent research found it had high bioavailability in defending against obesity, hyperlipidemia, inflammatory, oxidative stress, and targeting liver tissue. However, the mechanism of GSPE in regulating obesity induced by dietary high-fat (HF) was not fully understood, particularly the influences on liver functions. Therefore, this study aimed to investigate the effects of GSPE supplementation on the liver function and lipid metabolic parameters in rats fed HF diets long-term. A total of 40 healthy female Sprague Dawley rats were selected. After 8 weeks of obesity model feeding, the rats were randomly divided into four treatments: NC, standard diet; NC + GSPE, standard diet + 500 mg/kg body weight GSPE; HF, high-fat diet; HG + GSPE, high fat diet + 500 mg/kg body weight GSPE. Results indicated that long-term HF feeding caused severe liver problems including megalohepatia, steatosis, inflammation, and hepatocyte apoptosis. The supplementation of GSPE alleviated these symptoms. The results of the current experiment confirmed that GSPE addition up-regulated the expression of the Wnt3a/β-catenin signaling pathway, thereby restraining the liver cell endoplasmic reticulum stress and hepatocyte apoptosis. Furthermore, the microRNA-103 may play a role in this signal-regulated pathway. In summary, GSPE had a protective effect on the liver and the current experiment provided a reference for the application of GSPE in animal nutrition as a kind of natural feed additive.
Collapse
Affiliation(s)
| | | | | | | | - Jian Ping Li
- College of Animal Science and Technology, Institute of Animal Nutrition, Northeast Agricultural University, Harbin, China
| | - An Shan Shan
- College of Animal Science and Technology, Institute of Animal Nutrition, Northeast Agricultural University, Harbin, China
| |
Collapse
|
|
19
|
Feng Y, Wang Y, Guo K, Feng J, Shao C, Pan M, Ding P, Liu H, Duan H, Lu D, Wang Z, Zhang Y, Zhang Y, Han J, Li X, Yan X. The value of WNT5A as prognostic and immunological biomarker in pan-cancer. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:466. [PMID: 35571400 PMCID: PMC9096401 DOI: 10.21037/atm-22-1317] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/13/2022] [Indexed: 11/25/2022]
Abstract
Background Finding new immune-related biomarkers is one of the promising research directions for tumor immunotherapy. The WNT5A gene could stimulate the WNT pathway and regulate the progression of various tumors. Recent studies have partially revealed the relationship between WNT5A and tumor immunity, but the correlation and underlying mechanisms in pan-cancer remain obscure. Thus, we conducted this study aiming to characterize the prognostic value and immunological portrait of WNT5A in cancer. Methods The data obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases was utilized to analyze WNT5A expression levels by Kruskal-Wallis test and correlation to prognosis by Cox regression test and Kaplan-Meier test, while the data was also used to study the association between WNT5A expression and immune microenvironment, immune neoantigens, immune checkpoints, tumor mutational burden (TMB), and microsatellite instability (MSI) in pan-cancer. Gene set enrichment analysis (GSEA) was used to clarify the relevant signaling pathways. The R package was used for data analysis and to create the plots. Results The pan-cancer analysis revealed that the expression level of WNT5A is generally elevated in most tumors (19/34, 55.88%), and high WNT5A expression was correlated with poor prognosis in esophageal carcinoma (ESCA, P<0.05), low-grade glioma (LGG, P<0.01), adrenocortical carcinoma (ACC, P<0.01), pancreatic adenocarcinoma (PAAD, P<0.01), and head and neck squamous cell carcinoma (HNSC, P<0.05). In addition, WNT5A expression was positively associated with immune infiltration, stromal score, and immune checkpoints in most cancers, and correlated to immune neoantigens, TMB, and MSI. Finally, GSEA indicated that WNT5A is implicated in the transforming growth factor β (TGFβ), Notch, and Hedgehog signaling pathways, which may be related to tumor immunity. Conclusions The expression of WNT5A is elevated in most tumors and associated with tumor prognosis. Furthermore, WNT5A is associated with tumor immunity and may be an immunological biomarker in cancer.
Collapse
Affiliation(s)
- Yingtong Feng
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, China.,Department of Cardiothoracic Surgery, The 71st Group Army Hospital of PLA/The Affiliated Huaihai Hospital of Xuzhou Medical University, Xuzhou, China
| | - Yuanyong Wang
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, China
| | - Kai Guo
- Department of Thoracic Surgery, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Junjun Feng
- Department of Human Resource Management, The 71st Group Army Hospital of PLA/The Affiliated Huaihai Hospital of Xuzhou Medical University, Xuzhou, China
| | - Changjian Shao
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, China
| | - Minghong Pan
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, China
| | - Peng Ding
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, China
| | - Honggang Liu
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, China
| | - Hongtao Duan
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, China
| | - Di Lu
- Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Zhaoyang Wang
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, China
| | - Yimeng Zhang
- Department of Ophthalmology, Tangdu Hospital, The Air Force Military Medical University, Xi'an, China
| | - Yujing Zhang
- Department of Cardiothoracic Surgery, The 71st Group Army Hospital of PLA/The Affiliated Huaihai Hospital of Xuzhou Medical University, Xuzhou, China
| | - Jing Han
- Department of Ophthalmology, Tangdu Hospital, The Air Force Military Medical University, Xi'an, China
| | - Xiaofei Li
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, China
| | - Xiaolong Yan
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, China
| |
Collapse
|
|
20
|
Camaya I, Donnelly S, O'Brien B. Targeting the PI3K/Akt signaling pathway in pancreatic β-cells to enhance their survival and function: An emerging therapeutic strategy for type 1 diabetes. J Diabetes 2022; 14:247-260. [PMID: 35191175 PMCID: PMC9060113 DOI: 10.1111/1753-0407.13252] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 01/11/2022] [Indexed: 12/16/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of the insulin-producing β-cells within the pancreas. Islet transplantation represents one cure; however, during islet preparation and post transplantation significant amounts of β-cell death occur. Therefore, prevention and cure of T1D is dependent upon the preservation of β-cell function and the prevention of β-cell death. Phosphoinositide 3-kinase (PI3K)/Akt signaling represents a promising therapeutic target for T1D due to its pronounced effects on cellular survival, proliferation, and metabolism. A growing amount of evidence indicates that PI3K/Akt signaling is a critical determinant of β-cell mass and function. Modulation of the PI3K/Akt pathway, directly (via the use of highly specific protein and peptide-based biologics, excretory/secretory products of parasitic worms, and complex constituents of plant extracts) or indirectly (through microRNA interactions) can regulate the β-cell processes to ultimately determine the fate of β-cell mass. An important consideration is the identification of the specific PI3K/Akt pathway modulators that enhance β-cell function and prevent β-cell death without inducing excessive β-cell proliferation, which may carry carcinogenic side effects. Among potential PI3K/Akt pathway agonists, we have identified a novel parasite-derived protein, termed FhHDM-1 (Fasciola hepatica helminth defense molecule 1), which efficiently stimulates the PI3K/Akt pathway in β-cells to enhance function and prevent death without concomitantly inducing proliferation unlike several other identified stimulators of PI3K/Akt signaling . As such, FhHDM-1 will inform the design of biologics aimed at targeting the PI3K/Akt pathway to prevent/ameliorate not only T1D but also T2D, which is now widely recognized as an inflammatory disease characterized by β-cell dysfunction and death. This review will explore the modulation of the PI3K/Akt signaling pathway as a novel strategy to enhance β-cell function and survival.
Collapse
Affiliation(s)
- Inah Camaya
- School of Life Sciences, Faculty of ScienceThe University of Technology SydneyUltimoNew South WalesAustralia
| | - Sheila Donnelly
- School of Life Sciences, Faculty of ScienceThe University of Technology SydneyUltimoNew South WalesAustralia
| | - Bronwyn O'Brien
- School of Life Sciences, Faculty of ScienceThe University of Technology SydneyUltimoNew South WalesAustralia
| |
Collapse
|
|
21
|
Xu C, Xu Z, Zhang Y, Evert M, Calvisi DF, Chen X. β-Catenin signaling in hepatocellular carcinoma. J Clin Invest 2022; 132:154515. [PMID: 35166233 PMCID: PMC8843739 DOI: 10.1172/jci154515] [Citation(s) in RCA: 134] [Impact Index Per Article: 44.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Deregulated Wnt/β-catenin signaling is one of the main genetic alterations in human hepatocellular carcinoma (HCC). Comprehensive genomic analyses have revealed that gain-of-function mutation of CTNNB1, which encodes β-catenin, and loss-of-function mutation of AXIN1 occur in approximately 35% of human HCC samples. Human HCCs with activation of the Wnt/β-catenin pathway demonstrate unique gene expression patterns and pathological features. Activated Wnt/β-catenin synergizes with multiple signaling cascades to drive HCC formation, and it functions through its downstream effectors. Therefore, strategies targeting Wnt/β-catenin have been pursued as possible therapeutics against HCC. Here, we review the genetic alterations and oncogenic roles of aberrant Wnt/β-catenin signaling during hepatocarcinogenesis. In addition, we discuss the implication of this pathway in HCC diagnosis, classification, and personalized treatment.
Collapse
Affiliation(s)
- Chuanrui Xu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhong Xu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yi Zhang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, UCSF, San Francisco, California, USA
| |
Collapse
|
|
22
|
Panday R, Monckton CP, Khetani SR. The Role of Liver Zonation in Physiology, Regeneration, and Disease. Semin Liver Dis 2022; 42:1-16. [PMID: 35120381 DOI: 10.1055/s-0041-1742279] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
As blood flows from the portal triad to the central vein, cell-mediated depletion establishes gradients of soluble factors such as oxygen, nutrients, and hormones, which act through molecular pathways (e.g., Wnt/β-catenin, hedgehog) to spatially regulate hepatocyte functions along the sinusoid. Such "zonation" can lead to the compartmentalized initiation of several liver diseases, including alcoholic/non-alcoholic fatty liver diseases, chemical/drug-induced toxicity, and hepatocellular carcinoma, and can also modulate liver regeneration. Transgenic rodent models provide valuable information on the key molecular regulators of zonation, while in vitro models allow for subjecting cells to precisely controlled factor gradients and elucidating species-specific differences in zonation. Here, we discuss the latest advances in both in vivo and in vitro models of liver zonation and pending questions to be addressed moving forward. Ultimately, obtaining a deeper understanding of zonation can lead to the development of more effective therapeutics for liver diseases, microphysiological systems, and scalable cell-based therapies.
Collapse
Affiliation(s)
- Regeant Panday
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, Illinois
| | - Chase P Monckton
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, Illinois
| | - Salman R Khetani
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, Illinois
| |
Collapse
|
|
23
|
Yin C, Ye Z, Wu J, Huang C, Pan L, Ding H, Zhong L, Guo L, Zou Y, Wang X, Wang Y, Gao P, Jin X, Yan X, Zou Y, Huang R, Gong H. Elevated Wnt2 and Wnt4 activate NF-κB signaling to promote cardiac fibrosis by cooperation of Fzd4/2 and LRP6 following myocardial infarction. EBioMedicine 2021; 74:103745. [PMID: 34911029 PMCID: PMC8669316 DOI: 10.1016/j.ebiom.2021.103745] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 11/25/2021] [Accepted: 11/26/2021] [Indexed: 11/29/2022] Open
Abstract
Background Acute myocardial infarction (AMI)-induced excessive myocardial fibrosis exaggerates cardiac dysfunction. However, serum Wnt2 or Wnt4 level in AMI patients, and the roles in cardiac fibrosis are largely unkown. Methods AMI and non-AMI patients were enrolled to examine serum Wnt2 and Wnt4 levels by ELISA analysis. The AMI patients were followed-up for one year. MI mouse model was built by ligation of left anterior descending branch (LAD). Findings Serum Wnt2 or Wnt4 level was increased in patients with AMI, and the elevated Wnt2 and Wnt4 were correlated to adverse outcome of these patients. Knockdown of Wnt2 and Wnt4 significantly attenuated myocardial remodeling and cardiac dysfunction following experimental MI. In vitro, hypoxia enhanced the secretion and expression of Wnt2 and Wnt4 in neonatal rat cardiac myocytes (NRCMs) or fibroblasts (NRCFs). Mechanistically, the elevated Wnt2 or Wnt4 activated β-catenin /NF-κB signaling to promote pro-fibrotic effects in cultured NRCFs. In addition, Wnt2 or Wnt4 upregulated the expression of these Wnt co-receptors, frizzled (Fzd) 2, Fzd4 and (ow-density lipoprotein receptor-related protein 6 (LRP6). Further analysis revealed that Wnt2 or Wnt4 activated β-catenin /NF-κB by the co-operation of Fzd4 or Fzd2 and LRP6 signaling, respectively. Interpretation Elevated Wnt2 and Wnt4 activate β-catenin/NF-κB signaling to promote cardiac fibrosis by cooperation of Fzd4/2 and LRP6 in fibroblasts, which contributes to adverse outcome of patients with AMI, suggesting that systemic inhibition of Wnt2 and Wnt4 may improve cardiac dysfunction after MI.
Collapse
Affiliation(s)
- Chao Yin
- NHC Key Laboratory of Viral Heart Diseases, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Zhishuai Ye
- Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100053, China
| | - Jian Wu
- NHC Key Laboratory of Viral Heart Diseases, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Chenxing Huang
- NHC Key Laboratory of Viral Heart Diseases, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Le Pan
- NHC Key Laboratory of Viral Heart Diseases, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Huaiyu Ding
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Lei Zhong
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Lei Guo
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Yan Zou
- NHC Key Laboratory of Viral Heart Diseases, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Xiang Wang
- NHC Key Laboratory of Viral Heart Diseases, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Ying Wang
- NHC Key Laboratory of Viral Heart Diseases, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Pan Gao
- NHC Key Laboratory of Viral Heart Diseases, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Xuejuan Jin
- NHC Key Laboratory of Viral Heart Diseases, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Xiaoxiang Yan
- Department of Vascular and Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yunzeng Zou
- NHC Key Laboratory of Viral Heart Diseases, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Rongchong Huang
- Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100053, China.
| | - Hui Gong
- NHC Key Laboratory of Viral Heart Diseases, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
| |
Collapse
|
|
24
|
Tian L, Wang Y, Jang YY. Wnt signaling in biliary development, proliferation, and fibrosis. Exp Biol Med (Maywood) 2021; 247:360-367. [PMID: 34861115 DOI: 10.1177/15353702211061376] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Biliary fibrosis is an important pathological indicator of hepatobiliary damage. Cholangiocyte is the key cell type involved in this process. To reveal the pathogenesis of biliary fibrosis, it is essential to understand the normal development as well as the aberrant generation and proliferation of cholangiocytes. Numerous reports suggest that the Wnt signaling pathway is implicated in the physiological and pathological processes of cholangiocyte development and ductular reaction. In this review, we summarize the effects of Wnt pathway in cholangiocyte development from embryonic stem cells, as well as the underlying mechanisms of cholangiocyte responses to adult ductal damage. Wnt signaling pathway is regulated in a step-wise manner during each of the liver differentiation stages from embryonic stem cells to functional mature cholangiocytes. With the modulation of Wnt pathway, cholangiocytes can also be generated from adult liver progenitor cells and mature hepatocytes to repair liver damage. Non-canonical Wnt signaling is triggered in the active ductal cells during biliary fibrosis. Targeted control of the Wnt signaling may hold the great potential to reduce and/or reverse the biliary fibrogenic process.
Collapse
Affiliation(s)
- Lipeng Tian
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Yichen Wang
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Yoon Young Jang
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| |
Collapse
|
|
25
|
Huang D, Yang B, Yao Y, Liao M, Zhang Y, Zeng Y, Zhang F, Wang N, Tong G. Autophagic Inhibition of Caveolin-1 by Compound Phyllanthus urinaria L. Activates Ubiquitination and Proteasome Degradation of β-catenin to Suppress Metastasis of Hepatitis B-Associated Hepatocellular Carcinoma. Front Pharmacol 2021; 12:659325. [PMID: 34168559 PMCID: PMC8217966 DOI: 10.3389/fphar.2021.659325] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 05/24/2021] [Indexed: 12/29/2022] Open
Abstract
Compound Phyllanthus urinaria L. (CP) is a traditional Chinese medicine (TCM) formula for cancer treatment in the clinic, particularly during progression of hepatitis B-associated hepatocellular carcinoma (HBV-associated HCC). Nevertheless, its anti-metastatic action and mechanisms are not well elucidated. In this study, CP was found to exert remarkable inhibitory effects on the proliferation, migration and invasion of HBV-associated HCC cells. The following network and biological analyses predicted that CP mainly targeted Caveolin-1 (Cav-1) to induce anti-metastatic effects, and Wnt/β-catenin pathway was one of the core mechanisms of CP action against HBV-associated HCC. Further experimental validation implied that Cav-1 overexpression promoted metastasis of HBV-associated HCC by stabilizing β-catenin, while CP administration induced autophagic degradation of Cav-1, activated the Akt/GSK3β-mediated proteasome degradation of β-catenin via ubiquitination activation, and subsequently attenuated the metastasis-promoting effect of Cav-1. In addition, the anti-cancer and anti-metastatic action of CP was further confirmed by in vivo and ex vivo experiments. It was found that CP inhibited the tumor growth and metastasis of HBV-associated HCC in both mice liver cancer xenograft and zebrafish xenotransplantation models. Taken together, our study not only highlights the novel function of CP formula in suppressing metastasis of HBV-associated HCC, but it also addresses the critical role of Cav-1 in mediating Akt/GSK3β/β-catenin axis to control the late-phase of cancer progression.
Collapse
Affiliation(s)
- Danping Huang
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Bowen Yang
- The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yaoyao Yao
- The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Mianmian Liao
- The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yu Zhang
- The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yihao Zeng
- The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fengxue Zhang
- The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Neng Wang
- The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Guangdong Tong
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| |
Collapse
|
|
26
|
Guan H, Zhang J, Luan J, Xu H, Huang Z, Yu Q, Gou X, Xu L. Secreted Frizzled Related Proteins in Cardiovascular and Metabolic Diseases. Front Endocrinol (Lausanne) 2021; 12:712217. [PMID: 34489867 PMCID: PMC8417734 DOI: 10.3389/fendo.2021.712217] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 07/23/2021] [Indexed: 11/13/2022] Open
Abstract
Abnormal gene expression and secreted protein levels are accompanied by extensive pathological changes. Secreted frizzled related protein (SFRP) family members are antagonistic inhibitors of the Wnt signaling pathway, and they were recently found to be involved in the pathogenesis of a variety of metabolic diseases, which has led to extensive interest in SFRPs. Previous reports highlighted the importance of SFRPs in lipid metabolism, obesity, type 2 diabetes mellitus and cardiovascular diseases. In this review, we provide a detailed introduction of SFRPs, including their structural characteristics, receptors, inhibitors, signaling pathways and metabolic disease impacts. In addition to summarizing the pathologies and potential molecular mechanisms associated with SFRPs, this review further suggests the potential future use of SFRPs as disease biomarkers therapeutic targets.
Collapse
Affiliation(s)
- Hua Guan
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anethesiology, School of Stomatology, Fourth Military Medical University, Xi’an, China
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi’an Medical University, Xi’an, China
| | - Jin Zhang
- Department of Preventive Medicine, School of Stomatology, Fourth Military Medical University, Xi’an, China
| | - Jing Luan
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anethesiology, School of Stomatology, Fourth Military Medical University, Xi’an, China
- Shaanxi Key Laboratory of Brain Disorders & Institute of Basic and Translational Medicine, Xi’an Medical University, Xi’an, China
| | - Hao Xu
- Institution of Basic Medical Science, Xi’an Medical University, Xi’an, China
| | - Zhenghao Huang
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi’an Medical University, Xi’an, China
| | - Qi Yu
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi’an Medical University, Xi’an, China
| | - Xingchun Gou
- Shaanxi Key Laboratory of Brain Disorders & Institute of Basic and Translational Medicine, Xi’an Medical University, Xi’an, China
- *Correspondence: Lixian Xu, ; Xingchun Gou,
| | - Lixian Xu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anethesiology, School of Stomatology, Fourth Military Medical University, Xi’an, China
- *Correspondence: Lixian Xu, ; Xingchun Gou,
| |
Collapse
|
|
27
|
Najafi SMA. The Canonical Wnt Signaling (Wnt/β-Catenin Pathway): A Potential Target for Cancer Prevention and Therapy. IRANIAN BIOMEDICAL JOURNAL 2020; 24:269-80. [PMID: 32429632 PMCID: PMC7392137 DOI: 10.29252/ibj.24.5.264] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Accepted: 11/27/2019] [Indexed: 11/15/2022]
Abstract
Precise regulation of signal transduction pathways is crucial for normal animal development and for maintaining cellular and tissue homeostasis in adults. The Wnt/Frizzled-mediated signaling includes canonical and non-canonical signal transduction pathways. Upregulation or downregulation of the canonical Wnt signaling (or the Wnt/β-Catenin signal transduction) leads to a variety of human diseases, including cancers, neurodegenerative disorders, skin and bone diseases, and heart deficiencies. Therefore, Wnt/β-Catenin signal transduction is a potential clinical target for the treatment of not only human cancers but also some other human chronic diseases. Here, some recent results including those from my laboratory highlighting the role of Wnt/β-Catenin signal transduction in human cancers will be reviewed. After a brief overview on canonical Wnt signaling and introducing some critical β-Catenin/T-cell factor-target genes, the interaction of canonical Wnt signaling with some common human cancers will be discussed. In the end, the different segments of the aforesaid signaling pathway, which have been considered as targets for clinical purposes, will be scrutinized.
Collapse
Affiliation(s)
- S Mahmoud A Najafi
- Department of Cell and Molecular Biology, School of Biology, College of Sciences, University of Tehran, P.O. Box 14155-6455, Tehran, Iran
| |
Collapse
|
|
28
|
Scheidecker B, Shinohara M, Sugimoto M, Danoy M, Nishikawa M, Sakai Y. Induction of in vitro Metabolic Zonation in Primary Hepatocytes Requires Both Near-Physiological Oxygen Concentration and Flux. Front Bioeng Biotechnol 2020; 8:524. [PMID: 32656187 PMCID: PMC7325921 DOI: 10.3389/fbioe.2020.00524] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 05/01/2020] [Indexed: 12/16/2022] Open
Abstract
Pre-clinical drug screening is an important step in assessing the metabolic effects and hepatic toxicity of new pharmaceutical compounds. However, due to the complexity of the liver microarchitecture, simplified in vitro models do not adequately reflect in vivo situations. Especially spatial heterogeneity, known as metabolic zonation, is often lost due to limitations introduced by typical culture conditions. By culturing primary rat hepatocytes in varied ambient oxygen levels on either gas-permeable or non-permeable culture plates, we highlight the importance of biomimetic oxygen supply for the targeted induction of zonation-like phenotypes. Resulting cellular profiles illustrate the effect of pericellular oxygen concentration and consumption rates on hepatic functionality in terms of zone-specific metabolism and β-catenin signaling. We show that modulation of ambient oxygen tension can partially induce metabolic zonation in vitro when considering high supply rates, leading to in vivo-like drug metabolism. However, when oxygen supply is limited, similar modulation instead triggers an ischemic reprogramming, resembling metabolic profiles of hepatocellular carcinoma and increasing susceptibility toward drug-induced injury. Application of this knowledge will allow for the development of more accurate drug screening models to better identify adverse effects in hepatic drug metabolism.
Collapse
Affiliation(s)
| | - Marie Shinohara
- Department of Mechanical and Biofunctional Systems, Institute of Industrial Science, The University of Tokyo, Tokyo, Japan
| | - Masahiro Sugimoto
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Mathieu Danoy
- CNRS UMI 2820, LIMMS, University of Tokyo, Tokyo, Japan
| | - Masaki Nishikawa
- Department of Chemical System Engineering, University of Tokyo, Tokyo, Japan
| | - Yasuyuki Sakai
- Department of Chemical System Engineering, University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
29
|
El-Derany MO, El-Demerdash E. Pyrvinium pamoate attenuates non-alcoholic steatohepatitis: Insight on hedgehog/Gli and Wnt/β-catenin signaling crosstalk. Biochem Pharmacol 2020; 177:113942. [PMID: 32240652 DOI: 10.1016/j.bcp.2020.113942] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 03/26/2020] [Indexed: 12/13/2022]
|
|
30
|
Jarman EJ, Boulter L. Targeting the Wnt signaling pathway: the challenge of reducing scarring without affecting repair. Expert Opin Investig Drugs 2020; 29:179-190. [DOI: 10.1080/13543784.2020.1718105] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Edward J. Jarman
- MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, Edinburgh, UK
| | - Luke Boulter
- MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, Edinburgh, UK
| |
Collapse
|
|
31
|
Mak KM, Png CYM. The Hepatic Central Vein: Structure, Fibrosis, and Role in Liver Biology. Anat Rec (Hoboken) 2019; 303:1747-1767. [PMID: 31581357 DOI: 10.1002/ar.24273] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 08/11/2019] [Accepted: 08/14/2019] [Indexed: 12/19/2022]
Abstract
The hepatic central vein is a primary source of Wnt2, Wnt9b, and R-spondin3. These angiocrines activate ß-catenin signaling to regulate hepatic metabolic zonation and perivenous gene expression in mice. Little is known about the central vein ultrastructure. Here, we describe the morphological-functional correlates of the central vein and its draining and branching patterns. Central vein fibrosis occurs in liver disease and is often accompanied by perivenous perisinusoidal fibrosis, which may affect perivenous gene expression. We review the biological properties of perivenous hepatocytes and glutamine synthetase that serve as a biomarker of perivenous hepatocytes. Glutamine synthetase and P4502E1 are indicators of ß-catenin activity in centrilobular liver injury and regeneration. The Wnt/ß-catenin pathway is the master regulator of hepatic metabolic zonation and perivenous gene expression and is modulated by the R-spondin-LGR4/5-ZNRF3/RNF43 module. We examined the structures of the molecules of these pathways and their involvements in liver biology. Central vein-derived Wnts and R-spondin3 participate in the cellular-molecular circuitry of the Wnt/ß-catenin and R-spondin-LGR4/5-ZNRF3/RNF43 module. The transport and secretion of lipidated Wnts in Wnt-producing cells require Wntless protein. Secreted Wnts are carried on exosomes in the extracellular matrix to responder cells. The modes of release of Wnts and R-spondin3 from central veins and their transit in the venular wall toward perivenous hepatocytes are unknown. We hypothesize that central vein fibrosis may impact perivenous gene expression. The proposal that the central vein constitutes an anatomical niche of perivenous stem cells that subserve homeostatic hepatic renewal still needs studies using additional mouse models for validation. Anat Rec, 2019. © 2019 American Association for Anatomy Anat Rec, 303:1747-1767, 2020. © 2019 American Association for Anatomy.
Collapse
Affiliation(s)
- Ki M Mak
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - C Y Maximilian Png
- Division of Vascular Surgery, Massachusetts General Hospital, Boston, Massachusetts
| |
Collapse
|
|
32
|
Wnt ligand and receptor patterning in the liver. Curr Opin Cell Biol 2019; 62:17-25. [PMID: 31509785 DOI: 10.1016/j.ceb.2019.07.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 07/23/2019] [Accepted: 07/24/2019] [Indexed: 12/18/2022]
Abstract
In the liver, the tight spatiotemporal regulation of Wnt/β-catenin signaling is required to establish and maintain a metabolic form of tissue polarity termed zonation. In this review, we discuss the latest technologies applied in the study of liver zonation and provide a summary of the Wnt ligand and receptor expression patterns in the hepatic lobule. We further discuss the mechanisms, by which Wnt instructive cues might be spatially confined and propagated along the central vein-portal triad axis.
Collapse
|
|
33
|
Ribeiro D, Planchon S, Leclercq C, Raundrup K, Alves S, Bessa R, Renaut J, Almeida A. The muscular, hepatic and adipose tissues proteomes in muskox (Ovibos moschatus): Differences between males and females. J Proteomics 2019; 208:103480. [DOI: 10.1016/j.jprot.2019.103480] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 07/28/2019] [Accepted: 08/02/2019] [Indexed: 02/07/2023]
|
|
34
|
Lemaigre FP. Development of the Intrahepatic and Extrahepatic Biliary Tract: A Framework for Understanding Congenital Diseases. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2019; 15:1-22. [PMID: 31299162 DOI: 10.1146/annurev-pathmechdis-012418-013013] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The involvement of the biliary tract in the pathophysiology of liver diseases and the increased attention paid to bile ducts in the bioconstruction of liver tissue for regenerative therapy have fueled intense research into the fundamental mechanisms of biliary development. Here, I review the molecular, cellular and tissular mechanisms driving differentiation and morphogenesis of the intrahepatic and extrahepatic bile ducts. This review focuses on the dynamics of the transcriptional and signaling modules that promote biliary development in human and mouse liver and discusses studies in which the use of zebrafish uncovered unexplored processes in mammalian biliary development. The review concludes by providing a framework for interpreting the mechanisms that may help us understand the origin of congenital biliary diseases.
Collapse
Affiliation(s)
- Frédéric P Lemaigre
- de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium;
| |
Collapse
|
|
35
|
Yang HL, Thiyagarajan V, Shen PC, Mathew DC, Lin KY, Liao JW, Hseu YC. Anti-EMT properties of CoQ0 attributed to PI3K/AKT/NFKB/MMP-9 signaling pathway through ROS-mediated apoptosis. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:186. [PMID: 31068208 PMCID: PMC6505074 DOI: 10.1186/s13046-019-1196-x] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 04/25/2019] [Indexed: 01/08/2023]
Abstract
Background Breast cancer is the most prevalent cancer among women. In triple-negative breast cancer (TNBC) cells, a novel quinone derivative, coenzyme Q0 (CoQ0), promotes apoptosis and cell-cycle arrest. This study explored the anti-epithelial–mesenchymal transition (EMT) and antimetastatic attributes of CoQ0 in TNBC (MDA-MB-231). Methods Invasion, as well as MTT assays were conducted. Lipofectamine RNAiMAX was used to transfect cells with β-catenin siRNA. Through Western blotting and RT-PCR, the major signaling pathways’ protein expressions were examined, and the biopsied tumor tissues underwent immunohistochemical and hematoxylin and eosin staining as well as Western blotting. Results CoQ0 (0.5–2 μM) hindered tumor migration, invasion, and progression. Additionally, it caused MMP-2/− 9, uPA, uPAR, and VEGF downregulation. Furthermore, in highly metastatic MDA-MB-231 cells, TIMP-1/2 expression was subsequently upregulated and MMP-9 expression was downregulated. In addition, CoQ0 inhibited metastasis and EMT in TGF-β/TNF-α-stimulated non-tumorigenic MCF-10A cells. Bioluminescence imaging of MDA-MB-231 luciferase–injected live mice demonstrated that CoQ0 significantly inhibited metastasis of the breast cancer to the lungs and inhibited the development of tumors in MDA-MB-231 xenografted nude mice. Silencing of β-catenin with siRNA stimulated CoQ0-inhibited EMT. Western blotting as well as histological analysis established that CoQ0 reduced xenografted tumor development because apoptosis induction, cell-cycle inhibition, E-cadherin upregulation, β-catenin downregulation, and metastasis and EMT regulatory protein modulation were observed. Conclusions CoQ0 inhibited the progression of metastasis as well as EMT (in vitro and in vivo). The described approach has potential in treating human breast cancer metastasis. Electronic supplementary material The online version of this article (10.1186/s13046-019-1196-x) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Hsin-Ling Yang
- Institute of Nutrition, College of Biopharmaceuticals and Food Sciences, China Medical University, Taichung, 40402, Taiwan
| | - Varadharajan Thiyagarajan
- Department of Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 40402, Taiwan
| | - Pei-Chun Shen
- Institute of Nutrition, College of Biopharmaceuticals and Food Sciences, China Medical University, Taichung, 40402, Taiwan
| | - Dony Chacko Mathew
- Institute of Nutrition, College of Biopharmaceuticals and Food Sciences, China Medical University, Taichung, 40402, Taiwan
| | - Kai-Yuan Lin
- Department of Medical Research, Chi-Mei Medical Center, Tainan, 710, Taiwan
| | - Jiunn-Wang Liao
- Graduate Institute of Veterinary Pathology, National Chung Hsing University, Taichung, 40227, Taiwan
| | - You-Cheng Hseu
- Department of Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 40402, Taiwan. .,Department of Health and Nutrition Biotechnology, Asia University, Taichung, 41354, Taiwan. .,Chinese Medicine Research Center, China Medical University, Taichung, 40402, Taiwan. .,Research Center of Chinese Herbal Medicine, China Medical University, Taichung, 40402, Taiwan.
| |
Collapse
|
|
36
|
Zhang R, Kikuchi AT, Nakao T, Russell JO, Preziosi ME, Poddar M, Singh S, Bell AW, England SG, Monga SP. Elimination of Wnt Secretion From Stellate Cells Is Dispensable for Zonation and Development of Liver Fibrosis Following Hepatobiliary Injury. Gene Expr 2019; 19:121-136. [PMID: 30236172 PMCID: PMC6466178 DOI: 10.3727/105221618x15373858350141] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Alterations in the Wnt signaling pathway including those impacting hepatic stellate cells (HSCs) have been implicated in liver fibrosis. In the current study, we first examined the expression of Wnt genes in human HSC (HHSCs) after treatment with a profibrogenic factor TGF-β1. Next, we generated HSC-specific Wntless (Wls) knockout (KO) using the Lrat-cre and Wls-floxed mice. KO and littermate controls (CON) were characterized for any basal phenotype and subjected to two liver fibrosis protocols. In vitro, TGF-β1 induced expression of Wnt2, 5a and 9a while decreasing Wnt2b, 3a, 4, and 11 in HHSC. In vivo, KO and CON mice were born at normal Mendelian ratio and lacked any overt phenotype. Loss of Wnt secretion from HSCs had no effect on liver weight and did not impact β-catenin activation in the pericentral hepatocytes. After 7 days of bile duct ligation (BDL), KO and CON showed comparable levels of serum alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, total and direct bilirubin. Comparable histology, Sirius red staining, and immunohistochemistry for α-SMA, desmin, Ki-67, F4/80, and CD45 indicated similar proliferation, inflammation, and portal fibrosis in both groups. Biweekly administration of carbon tetrachloride for 4 or 8 weeks also led to comparable serum biochemistry, inflammation, and fibrosis in KO and CON. Specific Wnt genes were altered in HHSCs in response to TGF-β1; however, eliminating Wnt secretion from HSC did not impact basal β-catenin activation in normal liver nor did it alter the injury-repair response during development of liver fibrosis.
Collapse
Affiliation(s)
- Rong Zhang
- Department of Pathology, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Alexander T Kikuchi
- Department of Pathology, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Toshimasa Nakao
- Department of Organ Transplantation and General Surgery, Graduate School of Medical Sciences, Kyoto Prefectural University of Medical School, Hirokoji, Kawaramachi, Kamikyo-ku, Kyoto City, Kyoto, Japan
| | - Jacquelyn O Russell
- Department of Pathology, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Morgan E Preziosi
- Department of Pathology, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Minakshi Poddar
- Department of Pathology, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Sucha Singh
- Department of Pathology, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Aaron W Bell
- Department of Pathology, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Steven G England
- Future Therapeutics and Technologies, Abbvie, North Chicago, IL, USA
| | - Satdarshan P Monga
- Department of Pathology, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| |
Collapse
|
|
37
|
Mahmoudvand S, Shokri S, Taherkhani R, Farshadpour F. Hepatitis C virus core protein modulates several signaling pathways involved in hepatocellular carcinoma. World J Gastroenterol 2019; 25:42-58. [PMID: 30643357 PMCID: PMC6328967 DOI: 10.3748/wjg.v25.i1.42] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 12/07/2018] [Accepted: 12/13/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer, and hepatitis C virus (HCV) infection plays a major role in HCC development. The molecular mechanisms by which HCV infection leads to HCC are varied. HCV core protein is an important risk factor in HCV-associated liver pathogenesis and can modulate several signaling pathways involved in cell cycle regulation, cell growth promotion, cell proliferation, apoptosis, oxidative stress and lipid metabolism. The dysregulation of signaling pathways such as transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), Wnt/β-catenin (WNT), cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor α (PPARα) by HCV core protein is implicated in the development of HCC. Therefore, it has been suggested that this protein be considered a favorable target for further studies in the development of HCC. In addition, considering the axial role of these signaling pathways in HCC, they are considered druggable targets for cancer therapy. Therefore, using strategies to limit the dysregulation effects of core protein on these signaling pathways seems necessary to prevent HCV-related HCC.
Collapse
Affiliation(s)
- Shahab Mahmoudvand
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
- Department of Medical Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan 6517838736, Iran
| | - Somayeh Shokri
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
- Department of Medical Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan 6517838736, Iran
| | - Reza Taherkhani
- The Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr 7514633341, Iran
| | - Fatemeh Farshadpour
- The Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr 7514633341, Iran
| |
Collapse
|
|
38
|
Abstract
The essential liver exocrine and endocrine functions require a precise spatial arrangement of the hepatic lobule consisting of the central vein, portal vein, hepatic artery, intrahepatic bile duct system, and hepatocyte zonation. This allows blood to be carried through the liver parenchyma sampled by all hepatocytes and bile produced by the hepatocytes to be carried out of the liver through the intrahepatic bile duct system composed of cholangiocytes. The molecular orchestration of multiple signaling pathways and epigenetic factors is required to set up lineage restriction of the bipotential hepatoblast progenitor into the hepatocyte and cholangiocyte cell lineages, and to further refine cell fate heterogeneity within each cell lineage reflected in the functional heterogeneity of hepatocytes and cholangiocytes. In addition to the complex molecular regulation, there is a complicated morphogenetic choreography observed in building the refined hepatic epithelial architecture. Given the multifaceted molecular and cellular regulation, it is not surprising that impairment of any of these processes can result in acute and chronic hepatobiliary diseases. To enlighten the development of potential molecular and cellular targets for therapeutic options, an understanding of how the intricate hepatic molecular and cellular interactions are regulated is imperative. Here, we review the signaling pathways and epigenetic factors regulating hepatic cell lineages, fates, and epithelial architecture.
Collapse
Affiliation(s)
- Stacey S Huppert
- Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
| | - Makiko Iwafuchi-Doi
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| |
Collapse
|
|
39
|
Mavila N, Tang Y, Berlind J, Ramani K, Wang J, Mato JM, Lu SC. Prohibitin 1 Acts As a Negative Regulator of Wingless/Integrated-Beta-Catenin Signaling in Murine Liver and Human Liver Cancer Cells. Hepatol Commun 2018; 2:1583-1600. [PMID: 30556043 PMCID: PMC6287485 DOI: 10.1002/hep4.1257] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 08/20/2018] [Indexed: 12/12/2022] Open
Abstract
Prohibitin1 (PHB1) is a mitochondrial chaperone with diverse functions that include cell proliferation, apoptosis, and mitochondrial homoeostasis. Liver‐specific Phb1 knockout (KO) mice develop spontaneous injury and hepatocellular carcinoma (HCC). Our previous work demonstrated that PHB1 negatively regulates the H19‐insulin‐like growth factor 2 (IGF2)‐H19‐IGF2 axis signaling pathway and E‐box activity in hepatocytes and HCC cells. Phb1 KO livers exhibited increased expression of multiple wingless/integrated (WNT) target genes compared to control littermates. Therefore, we hypothesized that PHB1 is a negative regulator of WNT‐beta‐catenin signaling in the liver. Analysis of livers from Phb1 KO mice demonstrated an activation of the WNT‐beta‐catenin pathway as determined by phosphorylation of glycogen synthase kinase 3 (GSK3)betaserine [Ser]9 and protein kinase B (AKT)Ser473. Phb1 KO livers showed increased messenger RNA (mRNA) levels of multiple WNT ligands, with Wnt7a (79‐fold), Wnt10a (12‐fold), and Wnt16 (48‐fold) being most highly overexpressed compared to control littermates. Subcellular fractionation of liver cells from Phb1 KO mice indicated that hepatocytes are the main source of WNT ligands. Immunostaining and cellular colocalization analysis of Phb1 KO livers demonstrated expression of WNT7a, WNT10a, and WNT16 in hepatocytes. Chromatin immunoprecipitation revealed increased binding of transcription factor E2F1 (E2F1) to the Wnt10a promoter in Phb1 KO livers and WNT9A in HepG2 cells. PHB1 silencing in HepG2 cells activated WNT signaling, whereas its overexpression caused inactivation of this pathway. PHB1 silencing in HepG2 cells induced the expression of multiple WNT ligands of which WNT9A induction was partly regulated through E2F1. Conclusion: PHB1 acts as a negative regulator of WNT signaling, and its down‐regulation causes the induction of multiple WNT ligands and downstream activation of canonical WNT‐beta‐catenin signaling in murine liver and human HCC cells, in part through E2F1.
Collapse
Affiliation(s)
- Nirmala Mavila
- Division of Digestive and Liver Diseases, Department of Medicine Cedars Sinai Medical Center Los Angeles CA.,Division of Applied Cell Biology and Physiology, Department of Biomedical Sciences Cedars Sinai Medical Center Los Angeles CA
| | - Yuanyuan Tang
- Division of Digestive and Liver Diseases, Department of Medicine Cedars Sinai Medical Center Los Angeles CA.,Department of Oncology The Second Xiangya Hospital, Central South University Changsha China
| | - Joshua Berlind
- Division of Digestive and Liver Diseases, Department of Medicine Cedars Sinai Medical Center Los Angeles CA
| | - Komal Ramani
- Division of Digestive and Liver Diseases, Department of Medicine Cedars Sinai Medical Center Los Angeles CA.,Division of Applied Cell Biology and Physiology, Department of Biomedical Sciences Cedars Sinai Medical Center Los Angeles CA
| | - Jiaohong Wang
- Division of Digestive and Liver Diseases, Department of Medicine Cedars Sinai Medical Center Los Angeles CA
| | - José M Mato
- CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas Technology Park of Bizkaia Derio Spain
| | - Shelly C Lu
- Division of Digestive and Liver Diseases, Department of Medicine Cedars Sinai Medical Center Los Angeles CA
| |
Collapse
|
|
40
|
Yang L, Li LC, Wang X, Wang WH, Wang YC, Xu CR. The contributions of mesoderm-derived cells in liver development. Semin Cell Dev Biol 2018; 92:63-76. [PMID: 30193996 DOI: 10.1016/j.semcdb.2018.09.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 08/31/2018] [Accepted: 09/02/2018] [Indexed: 02/07/2023]
Abstract
The liver is an indispensable organ for metabolism and drug detoxification. The liver consists of endoderm-derived hepatobiliary lineages and various mesoderm-derived cells, and interacts with the surrounding tissues and organs through the ventral mesentery. Liver development, from hepatic specification to liver maturation, requires close interactions with mesoderm-derived cells, such as mesothelial cells, hepatic stellate cells, mesenchymal cells, liver sinusoidal endothelial cells and hematopoietic cells. These cells affect liver development through precise signaling events and even direct physical contact. Through the use of new techniques, emerging studies have recently led to a deeper understanding of liver development and its related mechanisms, especially the roles of mesodermal cells in liver development. Based on these developments, the current protocols for in vitro hepatocyte-like cell induction and liver-like tissue construction have been optimized and are of great importance for the treatment of liver diseases. Here, we review the roles of mesoderm-derived cells in the processes of liver development, hepatocyte-like cell induction and liver-like tissue construction.
Collapse
Affiliation(s)
- Li Yang
- Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Lin-Chen Li
- Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Xin Wang
- Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, China
| | - Wei-Hua Wang
- Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Yan-Chun Wang
- Haidian Maternal & Child Health Hospital, Beijing, 100080, China
| | - Cheng-Ran Xu
- Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, China.
| |
Collapse
|
|
41
|
Crosstalk between hepatic tumor cells and macrophages via Wnt/β-catenin signaling promotes M2-like macrophage polarization and reinforces tumor malignant behaviors. Cell Death Dis 2018; 9:793. [PMID: 30022048 PMCID: PMC6052107 DOI: 10.1038/s41419-018-0818-0] [Citation(s) in RCA: 224] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Revised: 06/18/2018] [Accepted: 06/22/2018] [Indexed: 12/12/2022]
Abstract
Tumor-associated macrophages (TAMs) are a major component of tumor microenvironment (TME) and play pivotal roles in the progression of hepatocellular carcinoma (HCC). Wnt signaling is evolutionarily conserved and participates in liver tumorigenesis. Several studies have shown that macrophage-derived Wnt ligands can activate Wnt signaling in tumor cells. However, whether Wnt ligands secreted by tumor cells can trigger Wnt signaling in macrophages is still elusive. In this study, we first verified that canonical Wnt/β-catenin signaling was activated during monocyte-to-macrophage differentiation and in M2-polarized macrophages. Knockdown of β-catenin in M2 macrophages exhibited stronger antitumor characteristics when cocultured with Hepa1-6 HCC cells in a series of experiments. Activation of Wnt signaling promoted M2 macrophage polarization through c-Myc. Moreover, co-culturing naïve macrophages with Hepa1-6 HCC cells in which Wnt ligands secretion was blocked by knockdown of Wntless inhibited M2 polarization in vitro. Consistently, the growth of HCC tumor orthotopically inoculated with Wntless-silenced Hepa1-6 cells was impeded, and the phenotype of M2-like TAMs was abrogated due to attenuated Wnt/β-catenin signaling in TAMs, leading to subverted immunosuppressive TME. Finally, we confirmed the correlation between M2 macrophage polarization and nuclear β-catenin accumulation in CD68+ macrophages in human HCC biopsies. Taken together, our study indicates that tumor cells-derived Wnt ligands stimulate M2-like polarization of TAMs via canonical Wnt/β-catenin signaling, which results in tumor growth, migration, metastasis, and immunosuppression in HCC. To block Wnts secretion from tumor cells and/or Wnt/β-catenin signal activation in TAMs may be potential strategy for HCC therapy in future.
Collapse
|
|
42
|
Wnt4 is significantly upregulated during the early phases of cisplatin-induced acute kidney injury. Sci Rep 2018; 8:10555. [PMID: 30002385 PMCID: PMC6043520 DOI: 10.1038/s41598-018-28595-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 06/25/2018] [Indexed: 02/07/2023] Open
Abstract
Wnt4 is a secreted growth factor associated with renal tubulogenesis. Our previous studies identified that renal and urinary Wnt4 are upregulated following ischemia-reperfusion injury in mice, but the roles of Wnt4 in other forms of acute kidney injury (AKI) remain unclear. Here, we investigated the changes in Wnt4 expression using a cisplatin-induced AKI model. We found that renal and urinary Wnt4 expression increased as early as 12 hours, peaked at day 4 following cisplatin-induced AKI and was closely correlated with histopathological alterations. By contrast, the serum creatinine level was significantly elevated until day 3, indicating that Wnt4 is more sensitive to early tubular injury than serum creatinine. In addition, renal Wnt4 was co-stained with aquaporin-1 and thiazide-sensitive NaCl cotransporter, suggesting that Wnt4 can detect both proximal and distal tubular injuries. These data were further confirmed in a clinical study. Increased urinary Wnt4 expression was detected earlier than serum creatinine and eGFR in patients with contrast-induced AKI after vascular intervention. This study is the first to demonstrate that increased expression of renal and urinary Wnt4 can be detected earlier than serum creatinine after drug-induced AKI. In particular, urinary Wnt4 can potentially serve as a noninvasive biomarker for monitoring patients with tubular injury.
Collapse
|
|
43
|
Preziosi M, Okabe H, Poddar M, Singh S, Monga SP. Endothelial Wnts regulate β-catenin signaling in murine liver zonation and regeneration: A sequel to the Wnt-Wnt situation. Hepatol Commun 2018; 2:845-860. [PMID: 30027142 PMCID: PMC6049069 DOI: 10.1002/hep4.1196] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Revised: 03/18/2018] [Accepted: 03/26/2018] [Indexed: 12/29/2022] Open
Abstract
β-Catenin in hepatocytes, under the control of Wnts, regulates pericentral gene expression. It also contributes to liver regeneration (LR) after partial hepatectomy (PH) by regulating cyclin-D1 gene expression as shown in the β-catenin and Wnt coreceptors low-density lipoprotein receptor-related protein 5/6 conditional knockouts (KO). However, conditional deletion of Wntless (Wls), required for Wnt secretion, in hepatocytes, cholangiocytes, or macrophages lacked any impact on zonation, while Wls deletion in macrophages only marginally affected LR. Here, we address the contribution of hepatic endothelial cells (ECs) in zonation and LR by characterizing EC-Wls-KO generated by interbreeding Wls-floxed and lymphatic vessel endothelial hyaluronan receptor (Lyve1)-cre mice. These mice were also used to study LR after PH. While Lyve1 expression in adult liver is limited to sinusoidal ECs only, Lyve1-cre mice bred to ROSA26-Stopflox/flox-enhanced yellow fluorescent protein (EYFP) mice showed EYFP labeling in sinusoidal and central vein ECs. EC-Wls-KO mice showed decreased liver weights; lacked glutamine synthetase, cytochrome P450 2e1, and cytochrome P450 1a2; and were resistant to acetaminophen-induced liver injury. After PH, EC-Wls-KO showed quantitative and qualitative differences in cyclin-D1 expression at 24-72 hours, which led to a lower hepatocyte proliferation at 40 hours but a rebound increase by 72 hours. ECs and macrophages isolated from regenerating livers at 12 hours showed significant up-regulation of Wnt2 and Wnt9b messenger RNA; these are the same two Wnts involved in baseline β-catenin activity in pericentral hepatocytes. Conclusion: At baseline, ECs secrete Wnt proteins essential for β-catenin activation in pericentral hepatocytes. During LR, sinusoidal and central vein ECs and secondarily macrophages secrete Wnt2, while predominantly central vein ECs and secondarily macrophages are the likely source of Wnt9b. This process spatiotemporally regulates β-catenin activation in hepatocytes to induce cell proliferation. (Hepatology Communications 2018;2:845-860).
Collapse
Affiliation(s)
- Morgan Preziosi
- Department of PathologyUniversity of Pittsburgh Medical CenterPittsburghPA
- Pittsburgh Liver Research CenterUniversity of Pittsburgh and University of Pittsburgh Medical CenterPittsburghPA
| | - Hirohisa Okabe
- Department of Gastroenterological SurgeryKumamoto UniversityKumamotoJapan
| | - Minakshi Poddar
- Department of PathologyUniversity of Pittsburgh Medical CenterPittsburghPA
- Pittsburgh Liver Research CenterUniversity of Pittsburgh and University of Pittsburgh Medical CenterPittsburghPA
| | - Sucha Singh
- Department of PathologyUniversity of Pittsburgh Medical CenterPittsburghPA
- Pittsburgh Liver Research CenterUniversity of Pittsburgh and University of Pittsburgh Medical CenterPittsburghPA
| | - Satdarshan P. Monga
- Department of PathologyUniversity of Pittsburgh Medical CenterPittsburghPA
- Pittsburgh Liver Research CenterUniversity of Pittsburgh and University of Pittsburgh Medical CenterPittsburghPA
- Department of MedicineUniversity of PittsburghPittsburghPA
| |
Collapse
|
|
44
|
Emerging role and therapeutic implication of Wnt signaling pathways in liver fibrosis. Gene 2018; 674:57-69. [PMID: 29944952 DOI: 10.1016/j.gene.2018.06.053] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 06/14/2018] [Accepted: 06/16/2018] [Indexed: 02/08/2023]
Abstract
Activation of hepatic stellate cells (HSCs) is a pivotal cellular event in liver fibrosis. Therefore, improving our understanding of the molecular pathways that are involved in these processes is essential to generate new therapies for liver fibrosis. Greater knowledge of the role of the Wnt signaling pathway in liver fibrosis could improve understanding of the liver fibrosis pathogenesis. The aim of this review is to describe the present knowledge about the Wnt signaling pathway, which significantly participates in liver fibrosis and HSC activation, and look ahead on new perspectives of Wnt signaling pathway research. Moreover, we will discuss the different interactions with Wnt signaling pathway-regulated liver fibrosis. The Wnt signaling pathway modulates several important aspects of function, including cell proliferation, activation and differentiation. Targeting the Wnt signaling pathway can be a promising direction in liver fibrosis treatment. We discuss new perspectives of Wnt signaling pathway activation in liver fibrosis. For example, antagonist to Wnt and Wnt ligands could inhibit liver fibrosis by regulating Wnt/β-catenin signaling pathway. These findings identify the Wnt signaling pathway as a potentially important for therapeutic targets in liver fibrosis. Future studies are needed in order to find safer and more effective Wnt-based drugs.
Collapse
|
|
45
|
Kling JC, Jordan MA, Pitt LA, Meiners J, Thanh-Tran T, Tran LS, Nguyen TTK, Mittal D, Villani R, Steptoe RJ, Khosrotehrani K, Berzins SP, Baxter AG, Godfrey DI, Blumenthal A. Temporal Regulation of Natural Killer T Cell Interferon Gamma Responses by β-Catenin-Dependent and -Independent Wnt Signaling. Front Immunol 2018; 9:483. [PMID: 29616022 PMCID: PMC5864864 DOI: 10.3389/fimmu.2018.00483] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 02/23/2018] [Indexed: 12/13/2022] Open
Abstract
Natural killer T (NKT) cells are prominent innate-like lymphocytes in the liver with critical roles in immune responses during infection, cancer, and autoimmunity. Interferon gamma (IFN-γ) and IL-4 are key cytokines rapidly produced by NKT cells upon recognition of glycolipid antigens presented by antigen-presenting cells (APCs). It has previously been reported that the transcriptional coactivator β-catenin regulates NKT cell differentiation and functionally biases NKT cell responses toward IL-4, at the expense of IFN-γ production. β-Catenin is not only a central effector of Wnt signaling but also contributes to other signaling networks. It is currently unknown whether Wnt ligands regulate NKT cell functions. We thus investigated how Wnt ligands and β-catenin activity shape liver NKT cell functions in vivo in response to the glycolipid antigen, α-galactosylceramide (α-GalCer) using a mouse model. Pharmacologic targeting of β-catenin activity with ICG001, as well as myeloid-specific genetic ablation of Wntless (Wls), to specifically target Wnt protein release by APCs, enhanced early IFN-γ responses. By contrast, within several hours of α-GalCer challenge, myeloid-specific Wls deficiency, as well as pharmacologic targeting of Wnt release using the small molecule inhibitor IWP-2 impaired α-GalCer-induced IFN-γ responses, independent of β-catenin activity. These data suggest that myeloid cell-derived Wnt ligands drive early Wnt/β-catenin signaling that curbs IFN-γ responses, but that, subsequently, Wnt ligands sustain IFN-γ expression independent of β-catenin activity. Our analyses in ICG001-treated mice confirmed a role for β-catenin activity in driving early IL-4 responses by liver NKT cells. However, neither pharmacologic nor genetic perturbation of Wnt production affected the IL-4 response, suggesting that IL-4 production by NKT cells in response to α-GalCer is not driven by released Wnt ligands. Collectively, these data reveal complex temporal roles of Wnt ligands and β-catenin signaling in the regulation of liver NKT cell activation, and highlight Wnt-dependent and -independent contributions of β-catenin to NKT cell functions.
Collapse
Affiliation(s)
- Jessica C Kling
- The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
| | - Margaret A Jordan
- Comparative Genomics Centre, James Cook University, Townsville, QLD, Australia
| | - Lauren A Pitt
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - Jana Meiners
- The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
| | - Thao Thanh-Tran
- The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
| | - Le Son Tran
- The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
| | - Tam T K Nguyen
- The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
| | - Deepak Mittal
- The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
| | - Rehan Villani
- The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
| | - Raymond J Steptoe
- The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
| | - Kiarash Khosrotehrani
- The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
| | - Stuart P Berzins
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia.,Fiona Elsey Cancer Research Institute; and Federation University, Ballarat, VIC, Australia
| | - Alan G Baxter
- Comparative Genomics Centre, James Cook University, Townsville, QLD, Australia
| | - Dale I Godfrey
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia.,ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC, Australia
| | - Antje Blumenthal
- The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
| |
Collapse
|
|
46
|
Deregulation of Frizzled Receptors in Hepatocellular Carcinoma. Int J Mol Sci 2018; 19:ijms19010313. [PMID: 29361730 PMCID: PMC5796257 DOI: 10.3390/ijms19010313] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 01/14/2018] [Accepted: 01/19/2018] [Indexed: 12/14/2022] Open
Abstract
G protein-coupled receptors (GPCRs) have a substantial role in tumorigenesis and are described as a “cancer driver”. Aberrant expression or activation of GPCRs leads to the deregulation of downstream signaling pathways, thereby promoting cancer progression. In hepatocellular carcinoma (HCC), the Wnt signaling pathway is frequently activated and it is associated with an aggressive HCC phenotype. Frizzled (FZD) receptors, a family member of GPCRs, are known to mediate Wnt signaling. Accumulating findings have revealed the deregulation of FZD receptors in HCC and their functional roles have been implicated in HCC progression. Given the important role of FZD receptors in HCC, we summarize here the expression pattern of FZD receptors in HCC and their corresponding functional roles during HCC progression. We also further review and highlight the potential targeting of FZD receptors as an alternative therapeutic strategy in HCC.
Collapse
|
|
47
|
In vitro and in vivo anti-tumor activity of CoQ0 against melanoma cells: inhibition of metastasis and induction of cell-cycle arrest and apoptosis through modulation of Wnt/β-catenin signaling pathways. Oncotarget 2017; 7:22409-26. [PMID: 26968952 PMCID: PMC5008369 DOI: 10.18632/oncotarget.7983] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 02/23/2016] [Indexed: 12/13/2022] Open
Abstract
Coenzyme Q0 (CoQ0, 2,3-dimethoxy-5-methyl-1,4-benzoquinone), a novel quinone derivative, has been shown to modulate cellular redox balance. However, effect of this compound on melanoma remains unclear. This study examined the in vitro or in vivo anti-tumor, apoptosis, and anti-metastasis activities of CoQ0 (0-20 μM) through inhibition of Wnt/β-catenin signaling pathway. CoQ0 exhibits a significant cytotoxic effect on melanoma cell lines (B16F10, B16F1, and A2058), while causing little toxicity toward normal (HaCaT) cells. The suppression of β-catenin was seen with CoQ0 administration accompanied by a decrease in the expression of Wnt/β-catenin transcriptional target c-myc, cyclin D1, and survivin through GSK3β-independent pathway. We found that CoQ0 treatment caused G1 cell-cycle arrest by reducing the levels of cyclin E and CDK4. Furthermore, CoQ0 treatment induced apoptosis through caspase-9/-3 activation, PARP degradation, Bcl-2/Bax dysregulation, and p53 expression. Notably, non- or sub-cytotoxic concentrations of CoQ0 markedly inhibited migration and invasion, accompanied by the down-regulation of MMP-2 and -9, and up-regulation of TIMP-1 and -2 expressions in highly metastatic B16F10 cells. Furthermore, the in vivo study results revealed that CoQ0 treatment inhibited the tumor growth in B16F10 xenografted nude mice. Histological analysis and western blotting confirmed that CoQ0 significantly decreased the xenografted tumor progression as demonstrated by induction of apoptosis, suppression of β-catenin, and inhibition of cell cycle-, apoptotic-, and metastatic-regulatory proteins. The data suggest that CoQ0 unveils a novel mechanism by down-regulating Wnt/β-catenin pathways and could be used as a potential lead compound for melanoma chemotherapy.
Collapse
|
|
48
|
Pope C, Piekos SC, Chen L, Mishra S, Zhong XB. The role of H19, a long non-coding RNA, in mouse liver postnatal maturation. PLoS One 2017; 12:e0187557. [PMID: 29099871 PMCID: PMC5669494 DOI: 10.1371/journal.pone.0187557] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 10/21/2017] [Indexed: 12/16/2022] Open
Abstract
H19 RNA is highly expressed at early postnatal ages and precipitously decreases at a specific time corresponding with increases in expression of genes important for mature liver function, such as drug metabolizing enzymes. H19’s role in the regulation of liver maturation is currently unknown. Using an H19 knockout mouse model to determine the role of H19 in liver development, we quantified gene expression for insulin growth factor signaling, Wnt signaling, key cytochrome P450 (P450) enzymes known to change as the liver develops, and fetal and adult plasma protein produced in liver. In mice lacking H19 expression, liver weights were significantly increased immediately after birth and significant increases were found in the number of actively proliferating cells. Increases in cell proliferation may be due to increases in β-catenin protein affecting Wnt signaling, increases in insulin-like growth factor 2 (IGF2) expression, and/or increases in insulin-like growth factor 1 receptor (IGF1R) expression at the protein level. Loss of targeted inhibition of IGF1R by microRNA 675 (miR-675) may be the cause of IGF1R increases, as miR-675 expression is also abrogated with loss of H19 expression in our model. P450 expression patterns were largely unchanged. No change in the production of plasma proteins was found, indicating H19 may not be important for liver maturation despite its role in controlling cell proliferation during liver growth. H19 may be important for normal liver development, and understanding how the liver matures will assist in predicting drug efficacy and toxicity in pediatric populations.
Collapse
Affiliation(s)
- Chad Pope
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America
- * E-mail: ,
| | - Stephanie C. Piekos
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America
| | - Liming Chen
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America
| | - Shashank Mishra
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, United States of America
| | - Xiao-bo Zhong
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America
| |
Collapse
|
|
49
|
Michalopoulos GK. Hepatostat: Liver regeneration and normal liver tissue maintenance. Hepatology 2017; 65:1384-1392. [PMID: 27997988 DOI: 10.1002/hep.28988] [Citation(s) in RCA: 311] [Impact Index Per Article: 38.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 11/30/2016] [Accepted: 11/30/2016] [Indexed: 12/13/2022]
Abstract
In contrast to all other organs, liver-to-body-weight ratio needs to be maintained always at 100% of what is required for body homeostasis. Adjustment of liver size to 100% of what is required for homeostasis has been called "hepatostat." Removal of a portion of any other organ is followed with local regeneration of a limited degree, but it never attempts to reach 100% of the original size. The complex mechanisms involved in this uniquely hepatic process encompass a variety of regenerative pathways that are specific to different types of injury. The most studied form of liver regeneration (LR) is that occurring after loss of hepatocytes in a single acute injury, such as rodent LR after two-thirds partial hepatectomy or administration of damaging chemicals (CCl4 , acetaminophen, etc.). Alternative regenerative pathways become activated when normal regeneration is thwarted and trigger the appearance of "progenitor" cells. Chronic loss of hepatocytes is associated with regenerative efforts characterized by continual hepatocyte proliferation and often has adverse consequences (development of cirrhosis or liver cancer). Even though a very few hepatocytes proliferate at any given time in normal liver, the mechanisms involved in the maintenance of liver weight by this slow process in the absence of liver injury are not as well understood. (Hepatology 2017;65:1384-1392).
Collapse
|
|
50
|
Enhanced Wnt Signalling in Hepatocytes is Associated with Schistosoma japonicum Infection and Contributes to Liver Fibrosis. Sci Rep 2017; 7:230. [PMID: 28331224 PMCID: PMC5428310 DOI: 10.1038/s41598-017-00377-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 02/23/2017] [Indexed: 12/16/2022] Open
Abstract
Liver fibrosis is the most serious pathology caused by Schistosoma japonicum infection, which arises when schistosome eggs are deposited in the liver. Eosinophils, macrophages and hepatic stellate cells (HSCs) have been identified as major cellular contributors to the development of granulomas and fibrosis, but little is known about the effects of hepatocytes on granuloma formation. Here, we found that the levels of Wnt signalling-related molecules, transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF) in hepatocytes were markedly elevated after S. japonicum infection. Liver fibrosis was exacerbated when exogenous Wnt3a was introduced, but was alleviated when Wnt signalling was suppressed by DKK1, accompanied by the reduced expression of TGF-β and CTGF in hepatocytes. These results indicate that the hepatocytic expression of TGF-β and CTGF is mediated by Wnt signalling. Additionally, the hepatocytes isolated from infected mice promoted the activation of primary HSCs in vitro, however, this effect was not observed when hepatocytes from DKK1 treated S. japonicum-infected mice was employed in the co-culture system. Our findings identify a novel pro-fibrogenic role of hepatocytes in schistosomiasis-induced liver fibrosis that is dependent on Wnt signalling, which may serve as a potential target for ameliorating hepatic fibrosis caused by helminths.
Collapse
|