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Ekwesianya AC, Ayantunde BO, Ayantunde AA. A cautionary tale of anatomical variations of the extrahepatic biliary system and their implications for surgical procedures: a systematic literature review. Surg Radiol Anat 2025; 47:145. [PMID: 40411573 DOI: 10.1007/s00276-025-03660-6] [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: 04/03/2025] [Accepted: 05/12/2025] [Indexed: 05/26/2025]
Abstract
BACKGROUND The hepatobiliary system has the most associated anatomical variations in the body and they are a direct reflection of the complexity of its embryological development. The anatomical pattern commonly described as 'normal' occurs only in 57-72% of the population. The objective of the study is to review the English Language published literature on the prevalence of the anatomical extra-hepatic biliary system variations and their potential implications for surgical and endoscopic procedures. This will assist both practicing and trainee surgeons in preventing biliary tract injuries while operating in this area. METHODOLOGY A comprehensive literature search was conducted using the PICO framework across SCOPUS, PubMed, MEDLINE, and Cochrane databases. Study characteristics and relevant data were collated. The prevalence of the most clinically important anatomical variations is presented. RESULTS Seventy studies, encompassing 17,207 subjects, were included: 27 studies (9,738 subjects) on cystic duct variations, 17 studies (2,633 subjects) on gallbladder variations, and 26 studies (4,836 subjects) on cystic artery variations. Notable findings include low insertion (11.2%), medial insertion (9.8%), and parallel course (7.4%) of the cystic duct, Hartmann's pouch in 12.2% of gallbladders, and the cystic artery originating from the right hepatic artery in 83.6% or other sources in 16.4%. Moynihan's hump of the right hepatic artery was found in 1.8%. CONCLUSION These variations are frequent and surgically relevant. Understanding them is critical to avoiding complications. Employing the critical view of safety in laparoscopic cholecystectomy ensures proper visualization of anatomical structures, reducing the risk of injury.
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Dai Y, Peng Y, Lu Z, Mao T, Chen K, Lu X, Liu K, Zhou X, Hu W, Wang H. Prenatal prednisone exposure impacts liver development and function in fetal mice and its characteristics. Toxicol Sci 2024; 199:63-80. [PMID: 38439560 DOI: 10.1093/toxsci/kfae027] [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] [Indexed: 03/06/2024] Open
Abstract
Prednisone, a widely used glucocorticoid drug in human and veterinary medicine, has been reported to cause developmental toxicity. However, systematic studies about the effect of prednisone on fetal liver development are still unclear. We investigated the potential effects of maternal exposure to clinically equivalent doses of prednisone during different gestational stages on cell proliferation and apoptosis, cell differentiation, glucose and lipid metabolism, and hematopoiesis in the liver of fetal mice, and explored the potential mechanisms. Results showed that prenatal prednisone exposure (PPE) could suppress cell proliferation, inhibit hepatocyte differentiation, and promote cholangiocyte differentiation in the fetal liver. Meanwhile, PPE could result in the enhancement of glyconeogenesis and bile acid synthesis and the inhibition of fatty acid β-oxidation and hematopoiesis in the fetal liver. Further analysis found that PPE-induced alterations in liver development had obvious stage and sex differences. Overall, the alteration in fetal liver development and function induced by PPE was most pronounced during the whole pregnancy (GD0-18), and the males were relatively more affected than the females. Additionally, fetal hepatic insulin-like growth factor 1 (IGF1) signaling pathway was inhibited by PPE. In conclusion, PPE could impact fetal liver development and multiple functions, and these alterations might be partially related to the inhibition of IGF1 signaling pathway.
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Affiliation(s)
- Yongguo Dai
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
| | - Yu Peng
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
| | - Zhengjie Lu
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province 430071, China
| | - Tongyun Mao
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
| | - Kaiqi Chen
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
| | - Xiaoqian Lu
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
| | - Kexin Liu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
| | - Xinli Zhou
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
| | - Wen Hu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
| | - Hui Wang
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
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3
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Zhang X, Liu K, Lu X, Zheng W, Shi J, Yu S, Feng H, Yu Z. Late-onset Cholestasis with Paucity of Portal Area Secondary to HNF1β Deficiency in Adulthood: A Case Report. J Clin Transl Hepatol 2024; 12:327-331. [PMID: 38426190 PMCID: PMC10899876 DOI: 10.14218/jcth.2023.00464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 12/29/2023] [Accepted: 01/22/2024] [Indexed: 03/02/2024] Open
Abstract
Hepatocyte nuclear factor 1β (HNF1β) is essential for biliary development, while its genetic defect triggers the dysplasia of interlobular bile ducts, leading to life-threatening hepatitis and cholestasis. To date, this disorder has mainly been documented in neonates. Here, we report a case of cholestasis in an adult patient caused by a de novo HNF1β mutation. A liver biopsy revealed remarkable shrinkage of the portal area accompanied by a decrease or absence of interlobular bile ducts, veins, and arteries in the portal area. Our case showed that an HNF1β defect could induce late-onset cholestasis with paucity of the portal area in adulthood.
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Affiliation(s)
- Xuemei Zhang
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Kun Liu
- Department of Pathology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaona Lu
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenlan Zheng
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jia Shi
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shihan Yu
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hai Feng
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhuo Yu
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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4
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Dai Y, Peng Y, Hu W, Liu Y, Wang H. Prenatal amoxicillin exposure induces developmental toxicity in fetal mice and its characteristics. J Environ Sci (China) 2024; 137:287-301. [PMID: 37980015 DOI: 10.1016/j.jes.2023.02.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 11/20/2023]
Abstract
Amoxicillin, a widely used antibiotic in human and veterinary pharmaceuticals, is now considered as an "emerging contaminant" because it exists widespreadly in the environment and brings a series of adverse outcomes. Currently, systematic studies about the developmental toxicity of amoxicillin are still lacking. We explored the potential effects of amoxicillin exposure on pregnancy outcomes, maternal/fetal serum phenotypes, and fetal multiple organ development in mice, at different doses (75, 150, 300 mg/(kg·day)) during late-pregnancy, or at a dose of 300 mg/(kg·day) during different stages (mid-/late-pregnancy) and courses (single-/multi-course). Results showed that prenatal amoxicillin exposure (PAmE) had no significant influence on the body weights of dams, but it could inhibit the physical development and reduce the survival rate of fetuses, especially during the mid-pregnancy. Meanwhile, PAmE altered multiple maternal/fetal serum phenotypes, especially in fetuses. Fetal multi-organ function results showed that PAmE inhibited testicular/adrenal steroid synthesis, long bone/cartilage and hippocampal development, and enhanced ovarian steroid synthesis and hepatic glycogenesis/lipogenesis, and the order of severity might be gonad (testis, ovary) > liver > others. Further analysis found that PAmE-induced multi-organ developmental and functional alterations had differences in stages, courses and fetal gender, and the most obvious changes might be in high-dose, late-pregnancy and multi-course, but there was no typical rule of a dose-response relationship. In conclusion, this study confirmed that PAmE could cause abnormal development and multi-organ function alterations, which deepens our understanding of the risk of PAmE and provides an experimental basis for further exploration of the long-term harm.
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Affiliation(s)
- Yongguo Dai
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Yu Peng
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Wen Hu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China
| | - Yi Liu
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Hui Wang
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
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5
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Righini M, Mancini R, Busutti M, Buscaroli A. Autosomal Dominant Polycystic Kidney Disease: Extrarenal Involvement. Int J Mol Sci 2024; 25:2554. [PMID: 38473800 DOI: 10.3390/ijms25052554] [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: 01/03/2024] [Revised: 02/19/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder, but kidneys are not the only organs involved in this systemic disorder. Individuals with the condition may display additional manifestations beyond the renal system, involving the liver, pancreas, and brain in the context of cystic manifestations, while involving the vascular system, gastrointestinal tract, bones, and cardiac valves in the context of non-cystic manifestations. Despite kidney involvement remaining the main feature of the disease, thanks to longer survival, early diagnosis, and better management of kidney-related problems, a new wave of complications must be faced by clinicians who treated patients with ADPKD. Involvement of the liver represents the most prevalent extrarenal manifestation and has growing importance in the symptom burden and quality of life. Vascular abnormalities are a key factor for patients' life expectancy and there is still debate whether to screen or not to screen all patients. Arterial hypertension is often the earliest onset symptom among ADPKD patients, leading to frequent cardiovascular complications. Although cardiac valvular abnormalities are a frequent complication, they rarely lead to relevant problems in the clinical history of polycystic patients. One of the newest relevant aspects concerns bone disorders that can exert a considerable influence on the clinical course of these patients. This review aims to provide the "state of the art" among the extrarenal manifestation of ADPKD.
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Affiliation(s)
- Matteo Righini
- Nephrology and Dialysis Unit, Santa Maria delle Croci Hospital, AUSL Romagna, 48121 Ravenna, Italy
- Nephrology, Dialysis and Transplantation Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy
| | - Raul Mancini
- Nephrology, Dialysis and Transplantation Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy
| | - Marco Busutti
- Nephrology, Dialysis and Transplantation Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy
| | - Andrea Buscaroli
- Nephrology and Dialysis Unit, Santa Maria delle Croci Hospital, AUSL Romagna, 48121 Ravenna, Italy
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Jiang M, Ren J, Belmonte JCI, Liu GH. Hepatocyte reprogramming in liver regeneration: Biological mechanisms and applications. FEBS J 2023; 290:5674-5688. [PMID: 37556833 DOI: 10.1111/febs.16930] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/17/2023] [Accepted: 08/08/2023] [Indexed: 08/11/2023]
Abstract
The liver is one of the few organs that retain the capability to regenerate in adult mammals. This regeneration process is mainly facilitated by the dynamic behavior of hepatocytes, which are the major functional constituents in the liver. In response to liver injury, hepatocytes undergo remarkable alterations, such as reprogramming, wherein they lose their original identity and acquire properties from other cells. This phenomenon of hepatocyte reprogramming, coupled with hepatocyte expansion, plays a central role in liver regeneration, and its underlying mechanisms are complex and multifaceted. Understanding the fate of reprogrammed hepatocytes and the mechanisms of their conversion has significant implications for the development of innovative therapeutics for liver diseases. Herein, we review the plasticity of hepatocytes in response to various forms of liver injury, with a focus on injury-induced hepatocyte reprogramming. We provide a comprehensive summary of current knowledge on the molecular and cellular mechanisms governing hepatocyte reprogramming, specifically in the context of liver regeneration, providing insight into potential applications of this process in the treatment of liver disorders, including chronic liver diseases and liver cancer.
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Affiliation(s)
- Mengmeng Jiang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Jie Ren
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Key Laboratory of RNA Science and Engineering, CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China
- Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China
- Aging Biomarker Consortium, Beijing, China
- School of Future Technology, University of Chinese Academy of Sciences, Beijing, China
| | | | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
- Aging Biomarker Consortium, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, China
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8
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Yanda MK, Zeidan A, Cebotaru L. Ameliorating liver disease in an autosomal recessive polycystic kidney disease mouse model. Am J Physiol Gastrointest Liver Physiol 2023; 324:G404-G414. [PMID: 36880660 PMCID: PMC10085553 DOI: 10.1152/ajpgi.00255.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 02/27/2023] [Accepted: 02/27/2023] [Indexed: 03/08/2023]
Abstract
Systemic and portal hypertension, liver fibrosis, and hepatomegaly are manifestations associated with autosomal recessive polycystic kidney disease (ARPKD), which is caused by malfunctions of fibrocystin/polyductin (FPC). The goal is to understand how liver pathology occurs and to devise therapeutic strategies to treat it. We injected 5-day-old Pkhd1del3-4/del3-4 mice for 1 mo with the cystic fibrosis transmembrane conductance regulator (CFTR) modulator VX-809 designed to rescue processing and trafficking of CFTR folding mutants. We used immunostaining and immunofluorescence techniques to evaluate liver pathology. We assessed protein expression via Western blotting. We detected abnormal biliary ducts consistent with ductal plate abnormalities, as well as a greatly increased proliferation of cholangiocytes in the Pkhd1del3-4/del3-4 mice. CFTR was present in the apical membrane of cholangiocytes and increased in the Pkhd1del3-4/del3-4 mice, consistent with a role for apically located CFTR in enlarged bile ducts. Interestingly, we also found CFTR in the primary cilium, in association with polycystin (PC2). Localization of CFTR and PC2 and overall length of the cilia were increased in the Pkhd1del3-4/del3-4 mice. In addition, several of the heat shock proteins; 27, 70, and 90 were upregulated, suggesting that global changes in protein processing and trafficking had occurred. We found that a deficit of FPC leads to bile duct abnormalities, enhanced cholangiocyte proliferation, and misregulation of heat shock proteins, which all returned toward wild type (WT) values following VX-809 treatment. These data suggest that CFTR correctors can be useful as therapeutics for ARPKD. Given that these drugs are already approved for use in humans, they can be fast-tracked for clinical use.NEW & NOTEWORTHY ARPKD is a multiorgan genetic disorder resulting in newborn morbidity and mortality. There is a critical need for new therapies to treat this disease. We show that persistent cholangiocytes proliferation occurs in a mouse model of ARPKD along with mislocalized CFTR and misregulated heat shock proteins. We found that VX-809, a CFTR modulator, inhibits proliferation and limits bile duct malformation. The data provide a therapeutic pathway for strategies to treat ADPKD.
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Affiliation(s)
- Murali K Yanda
- Departments of Medicine and Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
| | - Adi Zeidan
- Departments of Medicine and Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
| | - Liudmila Cebotaru
- Departments of Medicine and Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
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9
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Gambella A, Kalantari S, Cadamuro M, Quaglia M, Delvecchio M, Fabris L, Pinon M. The Landscape of HNF1B Deficiency: A Syndrome Not Yet Fully Explored. Cells 2023; 12:cells12020307. [PMID: 36672242 PMCID: PMC9856658 DOI: 10.3390/cells12020307] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/05/2023] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
The hepatocyte nuclear factor 1β (HNF1B) gene is involved in the development of specialized epithelia of several organs during the early and late phases of embryogenesis, performing its function mainly by regulating the cell cycle and apoptosis pathways. The first pathogenic variant of HNF1B (namely, R177X) was reported in 1997 and is associated with the maturity-onset diabetes of the young. Since then, more than 230 different HNF1B variants have been reported, revealing a multifaceted syndrome with complex and heterogenous genetic, pathologic, and clinical profiles, mainly affecting the pediatric population. The pancreas and kidneys are the most frequently affected organs, resulting in diabetes, renal cysts, and a decrease in renal function, leading, in 2001, to the definition of HNF1B deficiency syndrome, including renal cysts and diabetes. However, several other organs and systems have since emerged as being affected by HNF1B defect, while diabetes and renal cysts are not always present. Especially, liver involvement has generally been overlooked but recently emerged as particularly relevant (mostly showing chronically elevated liver enzymes) and with a putative relation with tumor development, thus requiring a more granular analysis. Nowadays, HNF1B-associated disease has been recognized as a clinical entity with a broader and more variable multisystem phenotype, but the reasons for the phenotypic heterogeneity are still poorly understood. In this review, we aimed to describe the multifaceted nature of HNF1B deficiency in the pediatric and adult populations: we analyzed the genetic, phenotypic, and clinical features of this complex and misdiagnosed syndrome, covering the most frequent, unusual, and recently identified traits.
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Affiliation(s)
- Alessandro Gambella
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy
- Division of Liver and Transplant Pathology, University of Pittsburgh, Pittsburgh, PA 15232, USA
| | - Silvia Kalantari
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy
| | | | - Marco Quaglia
- Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy
| | - Maurizio Delvecchio
- Metabolic Disease and Genetics Unit, Giovanni XXIII Children’s Hospital, AOU Policlinico di Bari, 70124 Bari, Italy
- Correspondence:
| | - Luca Fabris
- Department of Molecular Medicine, University of Padova, 35121 Padua, Italy
- Liver Center, Digestive Disease Section, Department of Internal Medicine, Yale University, New Haven, CT 06510, USA
| | - Michele Pinon
- Pediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, AOU Città della Salute e della Scienza di Torino, 10126 Turin, Italy
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10
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Mancarella S, Gigante I, Serino G, Pizzuto E, Dituri F, Valentini MF, Wang J, Chen X, Armentano R, Calvisi DF, Giannelli G. Crenigacestat blocking notch pathway reduces liver fibrosis in the surrounding ecosystem of intrahepatic CCA viaTGF-β inhibition. J Exp Clin Cancer Res 2022; 41:331. [PMID: 36443822 PMCID: PMC9703776 DOI: 10.1186/s13046-022-02536-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 11/09/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant tumor characterized by an intensive desmoplastic reaction due to the exaggerated presence of the extracellular (ECM) matrix components. Liver fibroblasts close to the tumor, activated by transforming growth factor (TGF)-β1 and expressing high levels of α-smooth muscle actin (α-SMA), become cancer-associated fibroblasts (CAFs). CAFs are deputed to produce and secrete ECM components and crosstalk with cancer cells favoring tumor progression and resistance to therapy. Overexpression of Notch signaling is implicated in CCA development and growth. The study aimed to determine the effectiveness of the Notch inhibitor, Crenigacestat, on the surrounding microenvironment of iCCA. METHODS We investigated Crenigacestat's effectiveness in a PDX model of iCCA and human primary culture of CAFs isolated from patients with iCCA. RESULTS In silico analysis of transcriptomic profiling from PDX iCCA tissues treated with Crenigacestat highlighted "liver fibrosis" as one of the most modulated pathways. In the iCCA PDX model, Crenigacestat treatment significantly (p < 0.001) reduced peritumoral liver fibrosis. Similar results were obtained in a hydrodynamic model of iCCA. Bioinformatic prediction of the upstream regulators related to liver fibrosis in the iCCA PDX treated with Crenigacestat revealed the involvement of the TGF-β1 pathway as a master regulator gene showing a robust connection between TGF-β1 and Notch pathways. Consistently, drug treatment significantly (p < 0.05) reduced TGF-β1 mRNA and protein levels in tumoral tissue. In PDX tissues, Crenigacestat remarkably inhibited TGF-β signaling and extracellular matrix protein gene expression and reduced α-SMA expression. Furthermore, Crenigacestat synergistically increased Gemcitabine effectiveness in the iCCA PDX model. In 31 iCCA patients, TGF-β1 and α-SMA were upregulated in the tumoral compared with peritumoral tissues. In freshly isolated CAFs from patients with iCCA, Crenigacestat significantly (p < 0.001) inhibited Notch signaling, TGF-β1 secretion, and Smad-2 activation. Consequently, Crenigacestat also inactivated CAFs reducing (p < 0.001) α-SMA expression. Finally, CAFs treated with Crenigacestat produced less (p < 005) ECM components such as fibronectin, collagen 1A1, and collagen 1A2. CONCLUSIONS Notch signaling inhibition reduces the peritumoral desmoplastic reaction in iCCA, blocking the TGF-β1 canonical pathway.
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Affiliation(s)
- Serena Mancarella
- grid.489101.50000 0001 0162 6994National Institute of Gastroenterology “S. De Bellis” Research Hospital, Via Turi 27, 70013 Castellana Grotte, BA Italy
| | - Isabella Gigante
- grid.489101.50000 0001 0162 6994National Institute of Gastroenterology “S. De Bellis” Research Hospital, Via Turi 27, 70013 Castellana Grotte, BA Italy
| | - Grazia Serino
- grid.489101.50000 0001 0162 6994National Institute of Gastroenterology “S. De Bellis” Research Hospital, Via Turi 27, 70013 Castellana Grotte, BA Italy
| | - Elena Pizzuto
- grid.489101.50000 0001 0162 6994National Institute of Gastroenterology “S. De Bellis” Research Hospital, Via Turi 27, 70013 Castellana Grotte, BA Italy
| | - Francesco Dituri
- grid.489101.50000 0001 0162 6994National Institute of Gastroenterology “S. De Bellis” Research Hospital, Via Turi 27, 70013 Castellana Grotte, BA Italy
| | - Maria F. Valentini
- grid.7644.10000 0001 0120 3326Department of Emergency and Organ Transplant, University of Bari Medical School, Bari, Italy
| | - Jingxiao Wang
- grid.266102.10000 0001 2297 6811Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA 94143 USA
| | - Xin Chen
- grid.266102.10000 0001 2297 6811Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA 94143 USA
| | - Raffaele Armentano
- grid.489101.50000 0001 0162 6994National Institute of Gastroenterology “S. De Bellis” Research Hospital, Via Turi 27, 70013 Castellana Grotte, BA Italy
| | - Diego F. Calvisi
- grid.7727.50000 0001 2190 5763Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany
| | - Gianluigi Giannelli
- grid.489101.50000 0001 0162 6994National Institute of Gastroenterology “S. De Bellis” Research Hospital, Via Turi 27, 70013 Castellana Grotte, BA Italy
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11
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Tomita H, Hara A. Development of extrahepatic bile ducts and mechanisms of tumorigenesis: Lessons from mouse models. Pathol Int 2022; 72:589-605. [PMID: 36349994 PMCID: PMC10098476 DOI: 10.1111/pin.13287] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 10/12/2022] [Indexed: 11/11/2022]
Abstract
The biliary system is a highly branched tubular network consisting of intrahepatic bile ducts (IHBDs) and extrahepatic bile ducts (EHBDs). IHBDs are derived from hepatic progenitor cells, while EHBDs originate directly from the endoderm through a separate branching morphogenetic process. Traits that are important for cancer are often found to overlap in developmental and other processes. Therefore, it has been suggested that intrahepatic cholangiocarcinomas (iCCAs) and extrahepatic cholangiocarcinomas (eCCAs) have different developmental mechanisms. While much evidence is being gathered on the mechanism of iCCAs, the evidence for eCCA is still very limited. The main reason for this is that there are very few appropriate animal models for eCCA. We can gain important insights from these animal models, particularly genetically engineered mouse models (GEMMs). GEMMs are immunocompetent and mimic human CCA subtypes with a specific mutational pattern, allowing the development of precancerous lesions, that is, biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB). This review provides a summary of the pathogenesis and mechanisms of eCCA that can be revealed by GEMMs. Furthermore, we discuss several clinical questions, such as whether BilIN and IPNB really become malignant, whether the peribiliary gland is the origin of eCCAs, and others.
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Affiliation(s)
- Hiroyuki Tomita
- Department of Tumor Pathology Gifu University Graduate School of Medicine Gifu Japan
| | - Akira Hara
- Department of Tumor Pathology Gifu University Graduate School of Medicine Gifu Japan
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12
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Norcia LF, Watanabe EM, Hamamoto Filho PT, Hasimoto CN, Pelafsky L, de Oliveira WK, Sassaki LY. Polycystic Liver Disease: Pathophysiology, Diagnosis and Treatment. Hepat Med 2022; 14:135-161. [PMID: 36200122 PMCID: PMC9528914 DOI: 10.2147/hmer.s377530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 09/07/2022] [Indexed: 11/25/2022] Open
Abstract
Polycystic liver disease (PLD) is a clinical condition characterized by the presence of more than 10 cysts in the liver. It is a rare disease Of genetic etiology that presents as an isolated disease or assoc\iated with polycystic kidney disease. Ductal plate malformation, ciliary dysfunction, and changes in cell signaling are the main factors involved in its pathogenesis. Most patients with PLD are asymptomatic, but in 2-5% of cases the disease has disabling symptoms and a significant reduction in quality of life. The diagnosis is based on family history of hepatic and/or renal polycystic disease, clinical manifestations, patient age, and polycystic liver phenotype shown on imaging examinations. PLD treatment has evolved considerably in the last decades. Somatostatin analogues hold promise in controlling disease progression, but liver transplantation remains a unique curative treatment modality.
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Affiliation(s)
- Luiz Fernando Norcia
- Department of Surgery, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Erika Mayumi Watanabe
- Department of Radiology, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Pedro Tadao Hamamoto Filho
- Department of Neurology, Psychology and Psychiatry, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Claudia Nishida Hasimoto
- Department of Surgery, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Leonardo Pelafsky
- Department of Surgery, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Walmar Kerche de Oliveira
- Department of Surgery, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
| | - Ligia Yukie Sassaki
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu, São Paulo, Brazil
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13
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Dynamics of hepatocyte-cholangiocyte cell-fate decisions during liver development and regeneration. iScience 2022; 25:104955. [PMID: 36060070 PMCID: PMC9437857 DOI: 10.1016/j.isci.2022.104955] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 05/17/2022] [Accepted: 08/12/2022] [Indexed: 11/25/2022] Open
Abstract
The immense regenerative potential of the liver is attributed to the ability of its two key cell types – hepatocytes and cholangiocytes – to trans-differentiate to one another either directly or through intermediate progenitor states. However, the dynamic features of decision-making between these cell-fates during liver development and regeneration remains elusive. Here, we identify a core gene regulatory network comprising c/EBPα, TGFBR2, and SOX9 which is multistable in nature, enabling three distinct cell states – hepatocytes, cholangiocytes, and liver progenitor cells (hepatoblasts/oval cells) – and stochastic switching among them. Predicted expression signature for these three states are validated through multiple bulk and single-cell transcriptomic datasets collected across developmental stages and injury-induced liver repair. This network can also explain the experimentally observed spatial organization of phenotypes in liver parenchyma and predict strategies for efficient cellular reprogramming. Our analysis elucidates how the emergent dynamics of underlying regulatory networks drive diverse cell-fate decisions in liver development and regeneration.
Identified minimal regulatory network to model liver development and regeneration Changes in phenotypic landscapes by in-silico perturbations of regulatory networks Ability to explain physiological spatial patterning of liver cell types Decoded strategies for efficient reprogramming among liver cell phenotypes
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14
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Gasperoni JG, Fuller JN, Darido C, Wilanowski T, Dworkin S. Grainyhead-like (Grhl) Target Genes in Development and Cancer. Int J Mol Sci 2022; 23:ijms23052735. [PMID: 35269877 PMCID: PMC8911041 DOI: 10.3390/ijms23052735] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/25/2022] [Accepted: 02/26/2022] [Indexed: 12/12/2022] Open
Abstract
Grainyhead-like (GRHL) factors are essential, highly conserved transcription factors (TFs) that regulate processes common to both natural cellular behaviours during embryogenesis, and de-regulation of growth and survival pathways in cancer. Serving to drive the transcription, and therefore activation of multiple co-ordinating pathways, the three GRHL family members (GRHL1-3) are a critical conduit for modulating the molecular landscape that guides cellular decision-making processes during proliferation, epithelial-mesenchymal transition (EMT) and migration. Animal models and in vitro approaches harbouring GRHL loss or gain-of-function are key research tools to understanding gene function, which gives confidence that resultant phenotypes and cellular behaviours may be translatable to humans. Critically, identifying and characterising the target genes to which these factors bind is also essential, as they allow us to discover and understand novel genetic pathways that could ultimately be used as targets for disease diagnosis, drug discovery and therapeutic strategies. GRHL1-3 and their transcriptional targets have been shown to drive comparable cellular processes in Drosophila, C. elegans, zebrafish and mice, and have recently also been implicated in the aetiology and/or progression of a number of human congenital disorders and cancers of epithelial origin. In this review, we will summarise the state of knowledge pertaining to the role of the GRHL family target genes in both development and cancer, primarily through understanding the genetic pathways transcriptionally regulated by these factors across disparate disease contexts.
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Affiliation(s)
- Jemma G. Gasperoni
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, VIC 3086, Australia; (J.G.G.); (J.N.F.)
| | - Jarrad N. Fuller
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, VIC 3086, Australia; (J.G.G.); (J.N.F.)
| | - Charbel Darido
- The Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia;
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Tomasz Wilanowski
- Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-096 Warsaw, Poland;
| | - Sebastian Dworkin
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, VIC 3086, Australia; (J.G.G.); (J.N.F.)
- Correspondence:
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15
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Zhu S, Rao X, Qian Y, Chen J, Song R, Yan H, Yang X, Hu J, Wang X, Han Z, Zhu Y, Liu R, Jong-Leong Wong J, McCaughan GW, Zheng X. Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt Signaling. Cell Mol Gastroenterol Hepatol 2022; 13:1757-1783. [PMID: 35202885 PMCID: PMC9059100 DOI: 10.1016/j.jcmgh.2022.02.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 02/11/2022] [Accepted: 02/14/2022] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS The liver has complex interconnecting blood vessel and biliary networks; however, how the vascular and biliary network form and regulate each other and liver function are not well-understood. We aimed to examine the role of Heg in mammalian liver development and functional maintenance. METHODS Global (Heg-/-) or liver endothelial cell (EC)-specific deletion of Heg (Lyve1-Cre;Hegfl/fl ) mice were used to study the in vivo function of Heg in the liver. Carbon-ink anterograde and retrograde injection were used to visualize the 3-dimensional patterning of liver portal and biliary networks, respectively. RNA sequencing, histology, and molecular and biochemical assays were used to assess liver gene expression, protein distribution, liver injury response, and function. RESULTS Heg deficiency in liver ECs led to a sparse liver vascular and biliary network. This network paucity does not compromise liver function under baseline conditions but did alter liver zonation. Molecular analysis revealed that endothelial Heg deficiency decreased expression of Wnt ligands/agonists including Wnt2, Wnt9b, and Rspo3 in ECs, which limits Axin2 mediated canonical Wnt signaling and the expression of cytochrome P450 enzymes in hepatocytes. Under chemical-induced stressed conditions, Heg-deficiency in liver ECs protected mice from drug-induced liver injuries. CONCLUSION Our study found that endothelial Heg is essential for the 3-D patterning of the liver vascular and indirectly regulates biliary networks and proper liver zonation via its regulation of Wnt ligand production in liver endothelial cells. The endothelial Heg-initiated changes of the liver metabolic zonation and metabolic enzyme expression in hepatocytes was functionally relevant to xenobiotic metabolism and drug induced liver toxicity.
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Affiliation(s)
- Shichao Zhu
- Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Xiyun Rao
- Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Yude Qian
- Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Jinbiao Chen
- Liver Injury and Cancer Program Centenary Institute and Sydney Medical School, The University of Sydney, A.W Morrow Gastroenterology and Liver Center, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Renhua Song
- Epigenetics and RNA Biology Program Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Huili Yan
- Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Xi Yang
- Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Junhao Hu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
| | - Xiaohong Wang
- Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Zhiming Han
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Yi Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Renjing Liu
- Vascular Epigenetics Laboratory, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia
| | - Justin Jong-Leong Wong
- Epigenetics and RNA Biology Program Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Geoffrey W. McCaughan
- Liver Injury and Cancer Program Centenary Institute and Sydney Medical School, The University of Sydney, A.W Morrow Gastroenterology and Liver Center, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Xiangjian Zheng
- Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China,Correspondence Address correspondence to: Dr Xiangjian Zheng, Pharmacology, Tianjin Medical University, No 22 Qi Xiang Tai Rd, Tianjin 300070, China. tel: 86-22-8333-6835.
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16
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Tanimizu N. The neonatal liver: Normal development and response to injury and disease. Semin Fetal Neonatal Med 2022; 27:101229. [PMID: 33745829 DOI: 10.1016/j.siny.2021.101229] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
The liver emerges from the ventral foregut endoderm around 3 weeks in human and 1 week in mice after fertilization. The fetal liver works as a hematopoietic organ and then develops functions required for performing various metabolic reactions in late fetal and neonatal periods. In parallel with functional differentiation, the liver establishes three dimensional tissue structures. In particular, establishment of the bile excretion system consisting of bile canaliculi of hepatocytes and bile ducts of cholangiocytes is critical to maintain healthy tissue status. This is because hepatocytes produce bile as they functionally mature, and if allowed to remain within the liver tissue can lead to cytotoxicity. In this review, we focus on epithelial tissue morphogenesis in the perinatal period and cholestatic liver diseases caused by abnormal development of the biliary system.
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Affiliation(s)
- Naoki Tanimizu
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo, 060-8556, Japan.
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17
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Sun Q, Shen Z, Liang X, He Y, Kong D, Midgley AC, Wang K. Progress and Current Limitations of Materials for Artificial Bile Duct Engineering. MATERIALS 2021; 14:ma14237468. [PMID: 34885623 PMCID: PMC8658964 DOI: 10.3390/ma14237468] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/19/2021] [Accepted: 10/25/2021] [Indexed: 01/30/2023]
Abstract
Bile duct injury (BDI) and bile tract diseases are regarded as prominent challenges in hepatobiliary surgery due to the risk of severe complications. Hepatobiliary, pancreatic, and gastrointestinal surgery can inadvertently cause iatrogenic BDI. The commonly utilized clinical treatment of BDI is biliary-enteric anastomosis. However, removal of the Oddi sphincter, which serves as a valve control over the unidirectional flow of bile to the intestine, can result in complications such as reflux cholangitis, restenosis of the bile duct, and cholangiocarcinoma. Tissue engineering and biomaterials offer alternative approaches for BDI treatment. Reconstruction of mechanically functional and biomimetic structures to replace bile ducts aims to promote the ingrowth of bile duct cells and realize tissue regeneration of bile ducts. Current research on artificial bile ducts has remained within preclinical animal model experiments. As more research shows artificial bile duct replacements achieving effective mechanical and functional prevention of biliary peritonitis caused by bile leakage or obstructive jaundice after bile duct reconstruction, clinical translation of tissue-engineered bile ducts has become a theoretical possibility. This literature review provides a comprehensive collection of published works in relation to three tissue engineering approaches for biomimetic bile duct construction: mechanical support from scaffold materials, cell seeding methods, and the incorporation of biologically active factors to identify the advancements and current limitations of materials and methods for the development of effective artificial bile ducts that promote tissue regeneration.
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Affiliation(s)
- Qiqi Sun
- Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China; (Q.S.); (D.K.)
| | - Zefeng Shen
- Department of General Surgery, Sir Run-Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; (Z.S.); (X.L.)
| | - Xiao Liang
- Department of General Surgery, Sir Run-Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; (Z.S.); (X.L.)
| | - Yingxu He
- School of Computing, National University of Singapore, Singapore 119077, Singapore;
| | - Deling Kong
- Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China; (Q.S.); (D.K.)
| | - Adam C. Midgley
- Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China; (Q.S.); (D.K.)
- Correspondence: (A.C.M.); (K.W.)
| | - Kai Wang
- Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China; (Q.S.); (D.K.)
- Correspondence: (A.C.M.); (K.W.)
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18
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Lendahl U, Lui VCH, Chung PHY, Tam PKH. Biliary Atresia - emerging diagnostic and therapy opportunities. EBioMedicine 2021; 74:103689. [PMID: 34781099 PMCID: PMC8604670 DOI: 10.1016/j.ebiom.2021.103689] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/15/2021] [Accepted: 10/28/2021] [Indexed: 02/06/2023] Open
Abstract
Biliary Atresia is a devastating pediatric cholangiopathy affecting the bile ducts of the liver. In this review, we describe recent progress in the understanding of liver development with a focus on cholangiocyte differentiation and how use of technical platforms, including rodent, zebrafish and organoid models, advances our understanding of Biliary Atresia. This is followed by a description of potential pathomechanisms, such as autoimmune responses, inflammation, disturbed apical-basal cell polarity, primary cilia dysfunction as well as beta-amyloid accumulation. Finally, we describe current and emerging diagnostic opportunities and recent translation breakthroughs for Biliary Atresia in the area of emerging therapy development, including immunomodulation and organoid-based systems for liver and bile duct repair.
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Affiliation(s)
- Urban Lendahl
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Dr. Li Dak-Sum Research Centre, the University of Hong Kong, Hong Kong.
| | - Vincent C H Lui
- Dr. Li Dak-Sum Research Centre, the University of Hong Kong, Hong Kong; Department of Surgery, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong
| | - Patrick H Y Chung
- Department of Surgery, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong; Department of Surgery, University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Paul K H Tam
- Dr. Li Dak-Sum Research Centre, the University of Hong Kong, Hong Kong; Department of Surgery, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong; Department of Surgery, University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China.
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19
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Jaffey JA. Canine hepatobiliary anatomy, physiology and congenital disorders. J Small Anim Pract 2021; 63:95-103. [PMID: 34409602 DOI: 10.1111/jsap.13410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/21/2021] [Accepted: 07/27/2021] [Indexed: 11/29/2022]
Abstract
The biliary system is an integral component of normal physiologic homeostasis and essential for survival. It acts as a conduit for the removal of detoxified and catabolised compounds as well as aids in fat digestion and absorption. Derangements in this system can have dangerous sequela that are associated with varying degrees of morbidity and mortality. Moreover, abnormalities in development of the biliary system can have varied and unpredictable changes on function and long-term outcome. The aims of this article were to review canine hepatobiliary anatomy, physiology and cholestasis as well as summarise congenital biliary disorders including human corollaries.
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Affiliation(s)
- J A Jaffey
- Department of Specialty Medicine, College of Veterinary Medicine, Midwestern University, Glendale, Arizona, USA
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20
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Pasqua M, Di Gesù R, Chinnici CM, Conaldi PG, Francipane MG. Generation of Hepatobiliary Cell Lineages from Human Induced Pluripotent Stem Cells: Applications in Disease Modeling and Drug Screening. Int J Mol Sci 2021; 22:8227. [PMID: 34360991 PMCID: PMC8348238 DOI: 10.3390/ijms22158227] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/28/2021] [Accepted: 07/28/2021] [Indexed: 12/13/2022] Open
Abstract
The possibility to reproduce key tissue functions in vitro from induced pluripotent stem cells (iPSCs) is offering an incredible opportunity to gain better insight into biological mechanisms underlying development and disease, and a tool for the rapid screening of drug candidates. This review attempts to summarize recent strategies for specification of iPSCs towards hepatobiliary lineages -hepatocytes and cholangiocytes-and their use as platforms for disease modeling and drug testing. The application of different tissue-engineering methods to promote accurate and reliable readouts is discussed. Space is given to open questions, including to what extent these novel systems can be informative. Potential pathways for improvement are finally suggested.
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Affiliation(s)
- Mattia Pasqua
- Fondazione Ri.MED, 90133 Palermo, Italy; (M.P.); (R.D.G.); (C.M.C.)
| | - Roberto Di Gesù
- Fondazione Ri.MED, 90133 Palermo, Italy; (M.P.); (R.D.G.); (C.M.C.)
| | - Cinzia Maria Chinnici
- Fondazione Ri.MED, 90133 Palermo, Italy; (M.P.); (R.D.G.); (C.M.C.)
- Dipartimento della Ricerca, IRCCS ISMETT, 90127 Palermo, Italy;
| | | | - Maria Giovanna Francipane
- Fondazione Ri.MED, 90133 Palermo, Italy; (M.P.); (R.D.G.); (C.M.C.)
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
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21
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Wu H, Chen C, Ziani S, Nelson LJ, Ávila MA, Nevzorova YA, Cubero FJ. Fibrotic Events in the Progression of Cholestatic Liver Disease. Cells 2021; 10:1107. [PMID: 34062960 PMCID: PMC8147992 DOI: 10.3390/cells10051107] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 02/07/2023] Open
Abstract
Cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with active hepatic fibrogenesis, which can ultimately lead to the development of cirrhosis. However, the exact relationship between the development of liver fibrosis and the progression of cholestatic liver disease remains elusive. Periductular fibroblasts located around the bile ducts seem biologically different from hepatic stellate cells (HSCs). The fibrotic events in these clinical conditions appear to be related to complex crosstalk between immune/inflammatory mechanisms, cytokine signalling, and perturbed homeostasis between cholangiocytes and mesenchymal cells. Several animal models including bile duct ligation (BDL) and the Mdr2-knockout mice have improved our understanding of mechanisms underlying chronic cholestasis. In the present review, we aim to elucidate the mechanisms of fibrosis in order to help to identify potential diagnostic and therapeutic targets.
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Affiliation(s)
- Hanghang Wu
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (C.C.); (S.Z.); (Y.A.N.)
| | - Chaobo Chen
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (C.C.); (S.Z.); (Y.A.N.)
- Health Research Institute Gregorio Marañón (IiSGM), 28007 Madrid, Spain
- Department of General Surgery, Wuxi Xishan People’s Hospital, Wuxi 214000, China
| | - Siham Ziani
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (C.C.); (S.Z.); (Y.A.N.)
| | - Leonard J. Nelson
- Institute for Bioengineering (IBioE), School of Engineering, Faraday Building, The University of Edinburgh, Edinburgh EH9 3 JL, Scotland, UK;
- Institute of Biological Chemistry, Biophysics and Bioengineering (IB3), School of Engineering and Physical Sciences (EPS), Heriot-Watt University, Edinburgh EH14 4AS, Scotland, UK
| | - Matías A. Ávila
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain;
- Centro de Investigacion Biomedica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, 31008 Pamplona, Spain
| | - Yulia A. Nevzorova
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (C.C.); (S.Z.); (Y.A.N.)
- Health Research Institute Gregorio Marañón (IiSGM), 28007 Madrid, Spain
- Centro de Investigacion Biomedica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (C.C.); (S.Z.); (Y.A.N.)
- Health Research Institute Gregorio Marañón (IiSGM), 28007 Madrid, Spain
- Centro de Investigacion Biomedica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
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22
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Wu D, Chen X, Sheng Q, Chen W, Zhang Y, Wu F. Production of Functional Hepatobiliary Organoids from Human Pluripotent Stem Cells. Int J Stem Cells 2021; 14:119-126. [PMID: 33377458 PMCID: PMC7904529 DOI: 10.15283/ijsc20152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/09/2020] [Accepted: 11/18/2020] [Indexed: 12/15/2022] Open
Abstract
The research on human hepatobiliary development and disorders has been constrained by minimal access to human fetal tissue, and low accuracy of animal models. To overcome this problem, we have established a system for the differentiation of human pluripotent stem cells (hPSCs) into functional hepatobiliary organoids (HBOs). We have previously reported that our 45-d approach closely mimics key stages of hepatobiliary development, starting with the differentiation of hiPSC into endoderm and a small part of mesoderm, and subsequently into hepatoblast-like cells, followed by the parallel generation of hepatocyte-like cells and cholangiocyte-like cells, formation of immature HBO expressing early hepatic and biliary markers, and mature HBO displaying hepatobiliary functionality. In this study, we present an updated version of our previous protocol, which only needs 35 days to achieve maturation in vitro. Furthermore, a hepatobiliary culture medium is developed to functionally maintain the HBOs for more than 1.5 months. The capacity of this approach for producing large amounts of functional HBOs and enabling long-term culture in vitro holds promise for applications on developmental research, disease modeling, as well as screening of therapeutic agents.
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Affiliation(s)
- Di Wu
- Department of Central Laboratory, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Xiaoni Chen
- Department of Central Laboratory, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Qingshou Sheng
- Department of Hepatology, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Wenlin Chen
- Department of Hepatology, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Yuncheng Zhang
- Department of Hepatology, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Fenfang Wu
- Department of Central Laboratory, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
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23
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Mariotti V, Fiorotto R, Cadamuro M, Fabris L, Strazzabosco M. New insights on the role of vascular endothelial growth factor in biliary pathophysiology. JHEP Rep 2021; 3:100251. [PMID: 34151244 PMCID: PMC8189933 DOI: 10.1016/j.jhepr.2021.100251] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 01/06/2021] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Abstract
The family of vascular endothelial growth factors (VEGFs) includes 5 members (VEGF-A to -D, and placenta growth factor), which regulate several critical biological processes. VEGF-A exerts a variety of biological effects through high-affinity binding to tyrosine kinase receptors (VEGFR-1, -2 and -3), co-receptors and accessory proteins. In addition to its fundamental function in angiogenesis and endothelial cell biology, VEGF/VEGFR signalling also plays a role in other cell types including epithelial cells. This review provides an overview of VEGF signalling in biliary epithelial cell biology in both normal and pathologic conditions. VEGF/VEGFR-2 signalling stimulates bile duct proliferation in an autocrine and paracrine fashion. VEGF/VEGFR-1/VEGFR-2 and angiopoietins are involved at different stages of biliary development. In certain conditions, cholangiocytes maintain the ability to secrete VEGF-A, and to express a functional VEGFR-2 receptor. For example, in polycystic liver disease, VEGF secreted by cystic cells stimulates cyst growth and vascular remodelling through a PKA/RAS/ERK/HIF1α-dependent mechanism, unveiling a new level of complexity in VEFG/VEGFR-2 regulation in epithelial cells. VEGF/VEGFR-2 signalling is also reactivated during the liver repair process. In this context, pro-angiogenic factors mediate the interactions between epithelial, mesenchymal and inflammatory cells. This process takes place during the wound healing response, however, in chronic biliary diseases, it may lead to pathological neo-angiogenesis, a condition strictly linked with fibrosis progression, the development of cirrhosis and related complications, and cholangiocarcinoma. Novel observations indicate that in cholangiocarcinoma, VEGF is a determinant of lymphangiogenesis and of the immune response to the tumour. Better insights into the role of VEGF signalling in biliary pathophysiology might help in the search for effective therapeutic strategies.
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Key Words
- ADPKD, adult dominant polycystic kidney disease
- Anti-Angiogenic therapy
- BA, biliary atresia
- BDL, bile duct ligation
- CCA, cholangiocarcinoma
- CCl4, carbon tetrachloride
- CLDs, chronic liver diseases
- Cholangiocytes
- Cholangiopathies
- DP, ductal plate
- DPM, ductal plate malformation
- DRCs, ductular reactive cells
- Development
- HIF-1α, hypoxia-inducible factor type 1α
- HSCs, hepatic stellate cells
- IHBD, intrahepatic bile ducts
- IL-, interleukin-
- LECs, lymphatic endothelial cells
- LSECs, liver sinusoidal endothelial cells
- Liver repair
- MMPs, matrix metalloproteinases
- PBP, peribiliary plexus
- PC, polycystin
- PDGF, platelet-derived growth factor
- PIGF, placental growth factor
- PLD, polycystic liver diseases
- Polycystic liver diseases
- SASP, senescence-associated secretory phenotype
- TGF, transforming growth factor
- VEGF, vascular endothelial growth factors
- VEGF-A
- VEGF/VEGFR-2 signalling
- VEGFR-1/2, vascular endothelial growth factor receptor 1/2
- mTOR, mammalian target of rapamycin
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Affiliation(s)
- Valeria Mariotti
- Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA
| | - Romina Fiorotto
- Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA
| | - Massimiliano Cadamuro
- Department of Molecular Medicine, University of Padua, School of Medicine, Padua, Italy
| | - Luca Fabris
- Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA.,Department of Molecular Medicine, University of Padua, School of Medicine, Padua, Italy
| | - Mario Strazzabosco
- Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA
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24
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Hafiz EOA, Bulutoglu B, Mansy SS, Chen Y, Abu-Taleb H, Soliman SAM, El-Hindawi AAF, Yarmush ML, Uygun BE. Development of liver microtissues with functional biliary ductular network. Biotechnol Bioeng 2021; 118:17-29. [PMID: 32856740 PMCID: PMC7775340 DOI: 10.1002/bit.27546] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 07/31/2020] [Accepted: 08/21/2020] [Indexed: 12/15/2022]
Abstract
Liver tissue engineering aims to create transplantable liver grafts that can serve as substitutes for donor's livers. One major challenge in creating a fully functional liver tissue has been to recreate the biliary drainage in an engineered liver construct through integration of bile canaliculi (BC) with the biliary ductular network that would enable the clearance of bile from the hepatocytes to the host duodenum. In this study, we show the formation of such a hepatic microtissue by coculturing rat primary hepatocytes with cholangiocytes and stromal cells. Our results indicate that within the spheroids, hepatocytes maintained viability and function for up to 7 days. Viable hepatocytes became polarized by forming BC with the presence of tight junctions. Morphologically, hepatocytes formed the core of the spheroids, while cholangiocytes resided at the periphery forming a monolayer microcysts and tubular structures extending outward. The spheroids were subsequently cultured in clusters to create a higher order ductular network resembling hepatic lobule. The cholangiocytes formed functional biliary ductular channels in between hepatic spheroids that were able to collect, transport, and secrete bile. Our results constitute the first step to recreate hepatic building blocks with biliary drainage for repopulating the whole liver scaffolds to be used as transplantable liver grafts.
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Affiliation(s)
- Ehab O. A. Hafiz
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Shriners Hospitals for Children in Boston, Boston, Massachusetts, USA
- Electron Microscopy Research Department, Theodor Bilharz Research Institute (TBRI), Giza, Egypt
| | - Beyza Bulutoglu
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Shriners Hospitals for Children in Boston, Boston, Massachusetts, USA
| | - Soheir S. Mansy
- Electron Microscopy Research Department, Theodor Bilharz Research Institute (TBRI), Giza, Egypt
| | - Yibin Chen
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Shriners Hospitals for Children in Boston, Boston, Massachusetts, USA
| | - Hoda Abu-Taleb
- Immunology and Therapeutic Evaluation Department, TBRI, Giza, Egypt
| | - Somia A. M. Soliman
- Pathology Department, Kasr Al Ainy, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Ali A. F. El-Hindawi
- Pathology Department, Kasr Al Ainy, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Martin L. Yarmush
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Shriners Hospitals for Children in Boston, Boston, Massachusetts, USA
| | - Basak E. Uygun
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Shriners Hospitals for Children in Boston, Boston, Massachusetts, USA
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25
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Verstegen MMA, Roos FJM, Burka K, Gehart H, Jager M, de Wolf M, Bijvelds MJC, de Jonge HR, Ardisasmita AI, van Huizen NA, Roest HP, de Jonge J, Koch M, Pampaloni F, Fuchs SA, Schene IF, Luider TM, van der Doef HPJ, Bodewes FAJA, de Kleine RHJ, Spee B, Kremers GJ, Clevers H, IJzermans JNM, Cuppen E, van der Laan LJW. Human extrahepatic and intrahepatic cholangiocyte organoids show region-specific differentiation potential and model cystic fibrosis-related bile duct disease. Sci Rep 2020; 10:21900. [PMID: 33318612 PMCID: PMC7736890 DOI: 10.1038/s41598-020-79082-8] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 12/03/2020] [Indexed: 02/06/2023] Open
Abstract
The development, homeostasis, and repair of intrahepatic and extrahepatic bile ducts are thought to involve distinct mechanisms including proliferation and maturation of cholangiocyte and progenitor cells. This study aimed to characterize human extrahepatic cholangiocyte organoids (ECO) using canonical Wnt-stimulated culture medium previously developed for intrahepatic cholangiocyte organoids (ICO). Paired ECO and ICO were derived from common bile duct and liver tissue, respectively. Characterization showed both organoid types were highly similar, though some differences in size and gene expression were observed. Both ECO and ICO have cholangiocyte fate differentiation capacity. However, unlike ICO, ECO lack the potential for differentiation towards a hepatocyte-like fate. Importantly, ECO derived from a cystic fibrosis patient showed no CFTR channel activity but normal chloride channel and MDR1 transporter activity. In conclusion, this study shows that ECO and ICO have distinct lineage fate and that ECO provide a competent model to study extrahepatic bile duct diseases like cystic fibrosis.
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Affiliation(s)
- Monique M A Verstegen
- Department of Surgery, Erasmus MC-University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
| | - Floris J M Roos
- Department of Surgery, Erasmus MC-University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
| | - Ksenia Burka
- Department of Surgery, Erasmus MC-University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
| | - Helmuth Gehart
- Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Utrecht, The Netherlands
| | - Myrthe Jager
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Maaike de Wolf
- Department of Surgery, Erasmus MC-University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
| | - Marcel J C Bijvelds
- Department of Gastroenterology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Hugo R de Jonge
- Department of Gastroenterology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Arif I Ardisasmita
- Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Nick A van Huizen
- Department of Surgery, Erasmus MC-University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.,Department of Neurology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Henk P Roest
- Department of Surgery, Erasmus MC-University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
| | - Jeroen de Jonge
- Department of Surgery, Erasmus MC-University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
| | - Michael Koch
- Goethe-University Frankfurt, Buchmann Institute for Molecular Life Sciences, Frankfurt, Germany
| | - Francesco Pampaloni
- Goethe-University Frankfurt, Buchmann Institute for Molecular Life Sciences, Frankfurt, Germany
| | - Sabine A Fuchs
- Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Imre F Schene
- Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Theo M Luider
- Department of Neurology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Hubert P J van der Doef
- Department of Pediatric Gastroenterology Hepatology and Nutrition, University Medical Center Groningen, University of Groningen, Utrecht, The Netherlands
| | - Frank A J A Bodewes
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Ruben H J de Kleine
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Bart Spee
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University Utrecht, Utrecht, The Netherlands
| | - Gert-Jan Kremers
- Erasmus Optical Imaging Centre, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Hans Clevers
- Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jan N M IJzermans
- Department of Surgery, Erasmus MC-University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
| | - Edwin Cuppen
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC-University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
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26
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Feng S, Wu J, Qiu WL, Yang L, Deng X, Zhou Y, Chen Y, Li X, Yu L, Li H, Xu ZR, Xiao Y, Ren X, Zhang L, Wang C, Sun Z, Wang J, Ding X, Chen Y, Gadue P, Pan G, Ogawa M, Ogawa S, Na J, Zhang P, Hui L, Yin H, Chen L, Xu CR, Cheng X. Large-scale Generation of Functional and Transplantable Hepatocytes and Cholangiocytes from Human Endoderm Stem Cells. Cell Rep 2020; 33:108455. [PMID: 33296648 DOI: 10.1016/j.celrep.2020.108455] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 08/27/2020] [Accepted: 11/07/2020] [Indexed: 12/15/2022] Open
Abstract
The ever-increasing therapeutic and pharmaceutical demand for liver cells calls for systems that enable mass production of hepatic cells. Here we describe a large-scale suspension system that uses human endoderm stem cells (hEnSCs) as precursors to generate functional and transplantable hepatocytes (E-heps) or cholangiocytes (E-chos). hEnSC-derived hepatic populations are characterized by single-cell transcriptomic analyses and compared with hESC-derived counterparts, in-vitro-maintained or -expanded primary hepatocytes and adult cells, which reveals that hepatic differentiation of hEnSCs recapitulates in vivo development and that the heterogeneities of the resultant populations can be manipulated by regulating the EGF and MAPK signaling pathways. Functional assessments demonstrate that E-heps and E-chos possess properties comparable with adult counterparts and that, when transplanted intraperitoneally, encapsulated E-heps were able to rescue rats with acute liver failure. Our study lays the foundation for cell-based therapeutic agents and in vitro applications for liver diseases.
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Affiliation(s)
- Sisi Feng
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China
| | - Jiaying Wu
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China
| | - Wei-Lin Qiu
- Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 10087, China; PKU-Tsinghua-NIBS Graduate Program, Peking University, Beijing 100871, China
| | - Li Yang
- Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 10087, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Xiaogang Deng
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China
| | - Ying Zhou
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China
| | - Yabin Chen
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
| | - Xiao Li
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China
| | - Lei Yu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education, Shanghai 200032, China
| | - Hongsheng Li
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China
| | - Zi-Ran Xu
- Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 10087, China; PKU-Tsinghua-NIBS Graduate Program, Peking University, Beijing 100871, China
| | - Yini Xiao
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China
| | - Xiongzhao Ren
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China
| | - Ludi Zhang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China
| | - Chenhua Wang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China
| | - Zhen Sun
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
| | - Jinglin Wang
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 21008, China
| | - Xiaoyan Ding
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China
| | - Yuelei Chen
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China
| | - Paul Gadue
- Department of Pathology, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Guoyu Pan
- Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Mina Ogawa
- McEwen Centre for Regenerative Medicine, University Health Network, Toronto, ON, Canada; Toronto General Research Institute, University Health Network, Toronto, ON, Canada
| | - Shinichiro Ogawa
- McEwen Centre for Regenerative Medicine, University Health Network, Toronto, ON, Canada; Toronto General Research Institute, University Health Network, Toronto, ON, Canada
| | - Jie Na
- Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Peilin Zhang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai 200438, China
| | - Lijian Hui
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China
| | - Hao Yin
- Organ Transplant Center, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
| | - Luonan Chen
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China; Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China.
| | - Cheng-Ran Xu
- Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 10087, China.
| | - Xin Cheng
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China.
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27
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Rauff B, Malik A, Bhatti YA, Chudhary SA, Qadri I, Rafiq S. Notch signalling pathway in development of cholangiocarcinoma. World J Gastrointest Oncol 2020; 12:957-974. [PMID: 33005291 PMCID: PMC7509998 DOI: 10.4251/wjgo.v12.i9.957] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/03/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) comprises of extra-hepatic cholangiocarcinoma and intrahepatic cholangiocarcinoma cancers as a result of inflammation of epithelium cell lining of the bile duct. The incidence rate is increasing dramatically worldwide with highest rates in Eastern and South Asian regions. Major risk factors involve chronic damage and inflammation of bile duct epithelium from primary sclerosing cholangitis, chronic hepatitis virus infection, gallstones and liver fluke infection. Various genetic variants have also been identified and as CCA develops on the background of biliary inflammation, diverse range of molecular mechanisms are involved in its progression. Among these, the Notch signalling pathway acts as a major driver of cholangiocarcinogenesis and its components (receptors, ligands and downstream signalling molecules) represent a promising therapeutic targets. Gamma-Secretase Inhibitors have been recognized in inhibiting the Notch pathway efficiently. A comprehensive knowledge of the molecular pathways activated by the Notch signalling cascade as well as its functional crosstalk with other signalling pathways provide better approach in developing innovative therapies against CCA.
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Affiliation(s)
- Bisma Rauff
- Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore 54000, Pakistan
| | - Arif Malik
- Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore 54000, Pakistan
| | - Yasir Ali Bhatti
- Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore 54000, Pakistan
| | - Shafiq Ahmad Chudhary
- Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore 54000, Pakistan
| | - Ishtiaq Qadri
- Department of Biology, Faculty of Science, King Abdulaziz University Jeddah Kingdom of Saudi Arabia
| | - Shafquat Rafiq
- Department of Gastrointestinal medicine, Croydon University Hospital, Croydon CR7 7YE, United Kingdom
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28
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Gilloteaux J. Primary cilia in the Syrian hamster biliary tract: Bile flow antennae and outlooks about signaling on the hepato-biliary-pancreatic stem cells. TRANSLATIONAL RESEARCH IN ANATOMY 2020. [DOI: 10.1016/j.tria.2020.100063] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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29
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Zhang L, Gan L, Liu Q, Li Y, Lin J, Ou S. Obstructive jaundice in a patient with polycystic liver disease complicated with polycystic kidney and polycystic lung: A case report. Medicine (Baltimore) 2020; 99:e19511. [PMID: 32243367 PMCID: PMC7220720 DOI: 10.1097/md.0000000000019511] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
RATIONALE Polycystic liver disease (PLD) is an autosomal-dominant disorder that is commonly associated with autosomal-dominant polycystic kidney disease (PKD) but rarely complicated with polycystic lung. Here, we report the first case of severe obstructive jaundice caused by multiple liver cysts in a patient with PLD complicated by PKD and polycystic lung. PATIENT CONCERNS A 72-year-old man with a history of PLD complicated with polycystic kidney presented with progressive jaundice, hematuria, poor appetite, nausea, and weight loss since 3 months. DIAGNOSIS PLD complicated with PKD and polycystic lung was identified using computed tomography, and obstructive jaundice was identified using magnetic resonance imaging and magnetic resonance cholangiopancreatography. INTERVENTIONS The patient could not undergo surgery, and was therefore treated with combined bilirubin adsorption and continuous veno-venous hemofiltration. OUTCOMES The patient's symptoms and laboratory findings improved after bilirubin adsorption and continuous veno-venous hemofiltration. Unfortunately, the patient was unable to continue the treatment due to financial reasons, and died of shock most likely due to cyst rupture. LESSONS Imaging examination of the lungs is necessary for patients with PLD. Although infrequent, jaundice can occur in these patients and cause severe hyperbilirubinemia. When surgery is contraindicated, blood purification may serve as an alternative treatment for patients with PLD-related obstructive jaundice.
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30
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Rizki-Safitri A, Shinohara M, Tanaka M, Sakai Y. Tubular bile duct structure mimicking bile duct morphogenesis for prospective in vitro liver metabolite recovery. J Biol Eng 2020; 14:11. [PMID: 32206088 PMCID: PMC7081557 DOI: 10.1186/s13036-020-0230-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 02/13/2020] [Indexed: 12/13/2022] Open
Abstract
Background Liver metabolites are used to diagnose disease and examine drugs in clinical pharmacokinetics. Therefore, development of an in vitro assay system that reproduces liver metabolite recovery would provide important benefits to pharmaceutical research. However, liver models have proven challenging to develop because of the lack of an appropriate bile duct structure for the accumulation and transport of metabolites from the liver parenchyma. Currently available bile duct models, such as the bile duct cyst-embedded extracellular matrix (ECM), lack any morphological resemblance to the tubular morphology of the living bile duct. Moreover, these systems cannot overcome metabolite recovery issues because they are established in isolated culture systems. Here, we successfully established a non-continuous tubular bile duct structure model in an open-culture system, which closely resembled an in vivo structure. This system was utilized to effectively collect liver metabolites separately from liver parenchymal cells. Results Triple-cell co-culture of primary rat hepatoblasts, rat biliary epithelial cells, and mouse embryonic fibroblasts was grown to mimic the morphogenesis of the bile duct during liver development. Overlaying the cells with ECM containing a Matrigel and collagen type I gel mixture promoted the development of a tubular bile duct structure. In this culture system, the expression of specific markers and signaling molecules related to biliary epithelial cell differentiation was highly upregulated during the ductal formation process. This bile duct structure also enabled the separate accumulation of metabolite analogs from liver parenchymal cells. Conclusions A morphogenesis-based culture system effectively establishes an advanced bile duct structure and improves the plasticity of liver models feasible for autologous in vitro metabolite-bile collection, which may enhance the performance of high-throughput liver models in cell-based assays.
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Affiliation(s)
- Astia Rizki-Safitri
- 1Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.,2Center for International Research on Integrative Biomedical Systems (CIBiS), Institute of Industrial Science (IIS), The University of Tokyo, Tokyo, Japan
| | - Marie Shinohara
- 2Center for International Research on Integrative Biomedical Systems (CIBiS), Institute of Industrial Science (IIS), The University of Tokyo, Tokyo, Japan.,3Department of Chemical System Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Minoru Tanaka
- 4Laboratory of Stem Cell Regulation, Institute for Quantitative Biosciences (IQB), The University of Tokyo, Tokyo, Japan.,5Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine (NCGM), Tokyo, Japan
| | - Yasuyuki Sakai
- 1Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.,2Center for International Research on Integrative Biomedical Systems (CIBiS), Institute of Industrial Science (IIS), The University of Tokyo, Tokyo, Japan.,3Department of Chemical System Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.,6Max Planck-The University of Tokyo, Center for Integrative Inflammology, The University of Tokyo, Tokyo, Japan
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31
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Chen F, Wang H, Xiao J. Regulated differentiation of stem cells into an artificial 3D liver as a transplantable source. Clin Mol Hepatol 2020; 26:163-179. [PMID: 32098013 PMCID: PMC7160355 DOI: 10.3350/cmh.2019.0022n] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 02/02/2020] [Indexed: 02/07/2023] Open
Abstract
End-stage liver disease is one of the leading causes of death around the world. Since insufficient sources of transplantable liver and possible immune rejection severely hinder the wide application of conventional liver transplantation therapy, artificial three-dimensional (3D) liver culture and assembly from stem cells have become a new hope for patients with end-stage liver diseases, such as cirrhosis and liver cancer. However, the induced differentiation of single-layer or 3D-structured hepatocytes from stem cells cannot physiologically support essential liver functions due to the lack of formation of blood vessels, immune regulation, storage of vitamins, and other vital hepatic activities. Thus, there is emerging evidence showing that 3D organogenesis of artificial vascularized liver tissue from combined hepatic cell types derived from differentiated stem cells is practical for the treatment of end-stage liver diseases. The optimization of novel biomaterials, such as decellularized matrices and natural macromolecules, also strongly supports the organogenesis of 3D tissue with the desired complex structure. This review summarizes new research updates on novel differentiation protocols of stem cell-derived major hepatic cell types and the application of new supportive biomaterials. Future biological and clinical challenges of this concept are also discussed.
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Affiliation(s)
- Feng Chen
- National Key Disciplines for Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital, Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Jia Xiao
- Clinical Medicine Research Institute, The First Affiliated Hospital of Jinan University, Guangzhou, China
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Khandekar G, Llewellyn J, Kriegermeier A, Waisbourd-Zinman O, Johnson N, Du Y, Giwa R, Liu X, Kisseleva T, Russo PA, Theise ND, Wells RG. Coordinated development of the mouse extrahepatic bile duct: Implications for neonatal susceptibility to biliary injury. J Hepatol 2020; 72:135-145. [PMID: 31562906 PMCID: PMC7079197 DOI: 10.1016/j.jhep.2019.08.036] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 08/09/2019] [Accepted: 08/30/2019] [Indexed: 01/19/2023]
Abstract
BACKGROUND & AIMS The extrahepatic bile duct is the primary tissue initially affected by biliary atresia. Biliary atresia is a cholangiopathy which exclusively affects neonates. Current animal models suggest that the developing bile duct is uniquely susceptible to damage. In this study, we aimed to define the anatomical and functional differences between the neonatal and adult mouse extrahepatic bile ducts. METHODS We studied mouse passaged cholangiocytes, mouse BALB/c neonatal and adult primary cholangiocytes, as well as isolated extrahepatic bile ducts, and a collagen reporter mouse. The methods used included transmission electron microscopy, lectin staining, immunostaining, rhodamine uptake assays, bile acid toxicity assays, and in vitro modeling of the matrix. RESULTS The cholangiocyte monolayer of the neonatal extrahepatic bile duct was immature, lacking the uniform apical glycocalyx and mature cell-cell junctions typical of adult cholangiocytes. Functional studies showed that the glycocalyx protected against bile acid injury and that neonatal cholangiocyte monolayers were more permeable than adult monolayers. In adult ducts, the submucosal space was filled with collagen I, elastin, hyaluronic acid, and proteoglycans. In contrast, the neonatal submucosa had little collagen I and elastin, although both increased rapidly after birth. In vitro modeling of the matrix suggested that the composition of the neonatal submucosa relative to the adult submucosa led to increased diffusion of bile. A Col-GFP reporter mouse showed that cells in the neonatal but not adult submucosa were actively producing collagen. CONCLUSION We identified 4 key differences between the neonatal and adult extrahepatic bile duct. We showed that these features may have functional implications, suggesting the neonatal extrahepatic bile ducts are particularly susceptible to injury and fibrosis. LAY SUMMARY Biliary atresia is a disease that affects newborns and is characterized by extrahepatic bile duct injury and obstruction, resulting in liver injury. We identify 4 key differences between the epithelial and submucosal layers of the neonatal and adult extrahepatic bile duct and show that these may render the neonatal duct particularly susceptible to injury.
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MESH Headings
- Animals
- Animals, Newborn
- Bile Ducts, Extrahepatic/cytology
- Bile Ducts, Extrahepatic/diagnostic imaging
- Bile Ducts, Extrahepatic/embryology
- Bile Ducts, Extrahepatic/growth & development
- Biliary Atresia
- Cell Survival
- Cells, Cultured
- Collagen Type I/metabolism
- Collagen Type I, alpha 1 Chain
- Disease Models, Animal
- Elastin/metabolism
- Epithelial Cells/metabolism
- Female
- Green Fluorescent Proteins/metabolism
- Humans
- Hyaluronic Acid/metabolism
- Immunohistochemistry
- Intercellular Junctions/metabolism
- Male
- Mice
- Mice, Inbred BALB C
- Microscopy, Electron, Transmission
- Mucous Membrane/metabolism
- Proteoglycans/metabolism
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Affiliation(s)
- Gauri Khandekar
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
| | - Jessica Llewellyn
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
| | - Alyssa Kriegermeier
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Orith Waisbourd-Zinman
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States; Schneider Children's Hospital, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Nicolette Johnson
- Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
| | - Yu Du
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
| | - Roquibat Giwa
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
| | - Xiao Liu
- Department of Surgery University of California, San Diego, La Jolla, CA, United States
| | - Tatiana Kisseleva
- Department of Surgery University of California, San Diego, La Jolla, CA, United States
| | - Pierre A Russo
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Neil D Theise
- Department of Pathology, New York University School of Medicine, New York, NY, United States
| | - Rebecca G Wells
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States; Department of Bioengineering, School of Engineering and Applied Sciences, The University of Pennsylvania, Philadelphia, PA, United States; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States; Center for Engineering MechanoBiology, The University of Pennsylvania, Philadelphia, PA, United States.
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Sato A, Kakinuma S, Miyoshi M, Kamiya A, Tsunoda T, Kaneko S, Tsuchiya J, Shimizu T, Takeichi E, Nitta S, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Koshikawa N, Seiki M, Nakauchi H, Asahina Y, Watanabe M. Vasoactive Intestinal Peptide Derived From Liver Mesenchymal Cells Mediates Tight Junction Assembly in Mouse Intrahepatic Bile Ducts. Hepatol Commun 2019; 4:235-254. [PMID: 32025608 PMCID: PMC6996346 DOI: 10.1002/hep4.1459] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 11/23/2019] [Indexed: 01/20/2023] Open
Abstract
Formation of intrahepatic bile ducts (IHBDs) proceeds in accordance with their microenvironment. Particularly, mesenchymal cells around portal veins regulate the differentiation and ductular morphogenesis of cholangiocytes in the developing liver; however, further studies are needed to fully understand the arrangement of IHBDs into a continuous hierarchical network. This study aims to clarify the interaction between biliary and liver mesenchymal cells during IHBD formation. To identify candidate factors contributing to this cell–cell interaction, mesenchymal cells were isolated from embryonic day 16.5 matrix metalloproteinase 14 (MMP14)‐deficient (knockout [KO]) mice livers, in which IHBD formation is retarded, and compared with those of the wild type (WT). WT mesenchymal cells significantly facilitated the formation of luminal structures comprised of hepatoblast‐derived cholangiocytes (cholangiocytic cysts), whereas MMP14‐KO mesenchymal cells failed to promote cyst formation. Comprehensive analysis revealed that expression of vasoactive intestinal peptide (VIP) was significantly suppressed in MMP14‐KO mesenchymal cells. VIP and VIP receptor 1 (VIPR1) were mainly expressed in periportal mesenchymal cells and cholangiocytic progenitors during IHBD development, respectively, in vivo. VIP/VIPR1 signaling significantly encouraged cholangiocytic cyst formation and up‐regulated tight junction protein 1, cystic fibrosis transmembrane conductance regulator, and aquaporin 1, in vitro. VIP antagonist significantly suppressed the tight junction assembly and the up‐regulation of ion/water transporters during IHBD development in vivo. In a cholestatic injury model of adult mice, exogenous VIP administration promoted the restoration of damaged tight junctions in bile ducts and improved hyperbilirubinemia. Conclusion: VIP is produced by periportal mesenchymal cells during the perinatal stage. It supports bile duct development by establishing tight junctions and up‐regulating ion/water transporters in cholangiocytes. VIP contributes to prompt recovery from cholestatic damage through the establishment of tight junctions in the bile ducts.
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Affiliation(s)
- Ayako Sato
- Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan
| | - Sei Kakinuma
- Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan.,Department of Liver Disease Control Tokyo Medical and Dental University (TMDU) Tokyo Japan
| | - Masato Miyoshi
- Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan
| | - Akihide Kamiya
- Department of Molecular Life Sciences School of Medicine Tokai University Isehara Japan
| | - Tomoyuki Tsunoda
- Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan
| | - Jun Tsuchiya
- Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan
| | - Taro Shimizu
- Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan
| | - Eiko Takeichi
- Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan
| | - Sayuri Nitta
- Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan
| | - Fukiko Kawai-Kitahata
- Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan
| | - Miyako Murakawa
- Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan
| | - Yasuhiro Itsui
- Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan
| | - Mina Nakagawa
- Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan
| | - Seishin Azuma
- Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan
| | - Naohiko Koshikawa
- Division of Cancer Cell Research Institute of Medical Science University of Tokyo Tokyo Japan
| | - Motoharu Seiki
- Division of Cancer Cell Research Institute of Medical Science University of Tokyo Tokyo Japan
| | - Hiromitsu Nakauchi
- Institute for Stem Cell Biology and Regenerative Medicine Stanford University School of Medicine Stanford CA.,Division of Stem Cell Therapy Institute of Medical Science University of Tokyo Tokyo Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan.,Department of Liver Disease Control Tokyo Medical and Dental University (TMDU) Tokyo Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan.,Advanced Research Institute Tokyo Medical and Dental University (TMDU) Tokyo Japan
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Funfak A, Bouzhir L, Gontran E, Minier N, Dupuis-Williams P, Gobaa S. Biophysical Control of Bile Duct Epithelial Morphogenesis in Natural and Synthetic Scaffolds. Front Bioeng Biotechnol 2019; 7:417. [PMID: 31921820 PMCID: PMC6923240 DOI: 10.3389/fbioe.2019.00417] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 11/29/2019] [Indexed: 12/11/2022] Open
Abstract
The integration of bile duct epithelial cells (cholangiocytes) in artificial liver culture systems is important in order to generate more physiologically relevant liver models. Understanding the role of the cellular microenvironment on differentiation, physiology, and organogenesis of cholangiocytes into functional biliary tubes is essential for the development of new liver therapies, notably in the field of cholangiophaties. In this study, we investigated the role of natural or synthetic scaffolds on cholangiocytes cyst growth, lumen formation and polarization. We demonstrated that cholangiocyte cyst formation efficiency can be similar between natural and synthetic matrices provided that the mechanical properties of the hydrogels are matched. When using synthetic matrices, we also tried to understand the impact of elasticity, matrix metalloprotease-mediated degradation and integrin ligand density on cyst morphogenesis. We demonstrated that hydrogel stiffness regulates cyst formation. We found that controlling integrin ligand density was key in the establishment of large polarized cysts of cholangiocytes. The mechanism of lumen formation was found to rely on cell self-organization and proliferation. The formed cholangiocyte organoids showed a good MDR1 (multi drug resistance protein) transport activity. Our study highlights the advantages of fully synthetic scaffold as a tool to develop bile duct models.
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Affiliation(s)
- Anette Funfak
- Institut Pasteur, Biomaterials and Microfluidics Core Facility, Paris, France
| | - Latifa Bouzhir
- Université Paris-Saclay, UMR-S1174 INSERM, Orsay, France
| | - Emilie Gontran
- Université Paris-Saclay, UMR-S1174 INSERM, Orsay, France
| | - Nicolas Minier
- Institut Pasteur, Biomaterials and Microfluidics Core Facility, Paris, France.,Université de Technologie de Compiègne, Alliance Sorbonne Université, Compiègne, France
| | - Pascale Dupuis-Williams
- Université Paris-Saclay, UMR-S1174 INSERM, Orsay, France.,ESPCI, PSL University, Paris, France
| | - Samy Gobaa
- Institut Pasteur, Biomaterials and Microfluidics Core Facility, Paris, France
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Autosomal Dominant Polycystic Kidney Disease with Hepatic Cysts Complications in a Hemodialysis Patient: A Case Report. ARS MEDICA TOMITANA 2019. [DOI: 10.2478/arsm-2019-0014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease in humans. It is a multisystemic disorder characterized by progressive cystic dilatation of both kidneys, with variable extrarenal manifestations in the gastrointestinal tract (hepatic cysts), cardiovascular system, reproductive organs and brain. An important issue of patients with hepatorenal cystic disease is the fact that complications can arise due to the growing of the cysts: local kidney complications (intracystic infection, intracystic hemorrhage) and local liver complications (portal hypertension as a result of portal vein compression by cysts, bile duct compression, ruptures and bleedings of the cysts, obstruction of the liver veins).
Objective: The main purpose of our case presentation is to emphasize the fact that ADPKD can be an aggressive disease with multiple complications, which requires an early diagnosis in order to properly avoid possible complications.
Material and Method: We present the case of a 61 years old male, known with polycystic hepatorenal disease, chronic kidney disease (CKD) in chronic hemodialysis since 2010, renal hypertension, hypertensive cardiomyopathy, renal anemia and stage 1 chronic lymphatic leukemia. The patient was diagnosed with hepatorenal polycystic disease 20 years ago and 9 years ago he started undergoing renal replacement therapy by hemodialysis. Three months ago, the patient presented a suddenly installed ascitic syndrome for which an MRI was performed. The imagistic investigation revealed multiple kidney and liver cysts, with secondary compression of the portal vein and a tumoral mass that may suggest an adenocarcinoma.
Results: The investigations performed confirm the diagnosis of portal hypertension secondary to compression due to cystic formations.
Conclusions: Hepatorenal polycystic disease has numerous clinical variations, so it needs to be followed in a multidisciplinary way with rapid therapeutic measures to prevent complications. Further investigations are needed when dealing with suspicious cystic formations with an uncertain substrate.
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Fattahi P, Haque A, Son KJ, Guild J, Revzin A. Microfluidic devices, accumulation of endogenous signals and stem cell fate selection. Differentiation 2019; 112:39-46. [PMID: 31884176 DOI: 10.1016/j.diff.2019.10.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 09/06/2019] [Accepted: 10/16/2019] [Indexed: 12/20/2022]
Affiliation(s)
- Pouria Fattahi
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Amranul Haque
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Kyung Jin Son
- Department of Biomedical Engineering, University of California, Davis, CA, USA
| | - Joshua Guild
- Department of Cell & Tissue Biology, University of California, San Francisco, CA, USA
| | - Alexander Revzin
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
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37
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Buisson EM, Jeong J, Kim HJ, Choi D. Regenerative Medicine of the Bile Duct: Beyond the Myth. Int J Stem Cells 2019; 12:183-194. [PMID: 31022996 PMCID: PMC6657949 DOI: 10.15283/ijsc18055] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 08/31/2018] [Accepted: 09/03/2018] [Indexed: 12/12/2022] Open
Abstract
Cholangiopathies are rare diseases of the bile duct with high mortality rates. The current treatment for cholangiopathies is liver transplantation, but there are significant obstacles including a shortage of donors and a high risk of complications. Currently, there is only one available medicine on the market targeting cholangiopathies, and the results have been inadequate in clinical therapy. To overcome these obstacles, many researchers have used human induced pluripotent stem cells (hPSC) as a source for cholangiocyte-like cell generation and have incorporated advances in bioprinting to create artificial bile ducts for implantation and transplantation. This has allowed the field to move dramatically forward in studies of biliary regenerative medicine. In this review, the authors provide an overview of cholangiocytes, the organogenesis of the bile duct, cholangiopathies, and the current treatment and advances that have been made that are opening new doors to the study of cholangiopathies.
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Affiliation(s)
- Elina Maria Buisson
- Department of Translational Medicine, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea.,Department of Surgery, Hanyang University College of Medicine, Hanyang University, Seoul, Korea.,HY Indang Center of Regenerative Medicine and Stem Cell Research, Hanyang University, Hanyang University, Seoul, Korea
| | - Jaemin Jeong
- Department of Surgery, Hanyang University College of Medicine, Hanyang University, Seoul, Korea.,HY Indang Center of Regenerative Medicine and Stem Cell Research, Hanyang University, Hanyang University, Seoul, Korea
| | - Han Joon Kim
- Department of Surgery, Hanyang University College of Medicine, Hanyang University, Seoul, Korea
| | - Dongho Choi
- Department of Translational Medicine, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea.,Department of Surgery, Hanyang University College of Medicine, Hanyang University, Seoul, Korea.,HY Indang Center of Regenerative Medicine and Stem Cell Research, Hanyang University, Hanyang University, Seoul, Korea
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Abstract
Navigating the complexities of interpreting a liver biopsy performed on a neonate with conjugated/direct hyperbilirubinemia can be an arduous task given these biopsies are infrequently encountered. The list of entities is long and yet there are only a few histologic patterns of liver injury. The first step for the pathologist is to determine the histologic pattern, which will guide further inquiry into the useful clinical information to have while evaluating the biopsy. Ultimately, the goal is to identify those conditions that will benefit from early intervention. We begin with a review of biliary development to help understand what findings may be physiologic versus pathologic, particularly in premature infants. Then we review eight cases that cover the three most common histologic patterns of injury in patients with neonatal cholestasis: biliary obstructive, neonatal hepatitis, and paucity of intrahepatic bile ducts. The entities that serve as prototypes for these histologic patterns are covered, including biliary atresia, idiopathic neonatal hepatitis, and Alagille syndrome, along with rarer entities that have histologic overlap. The cases with accompanying tables and algorithms are intended to help place the histologic findings in the context of the overall clinical work-up, including genetic testing.
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Affiliation(s)
- Soo-Jin Cho
- Department of Pathology, University of California San Francisco, San Francisco, CA United States
| | - Grace E Kim
- Department of Pathology, University of California San Francisco, San Francisco, CA United States.
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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.
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Affiliation(s)
- Frédéric P Lemaigre
- de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium;
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40
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Abstract
Cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts, are highly specialized cells residing in a complex anatomic niche where they participate in bile production and homeostasis. Cholangiocytes are damaged in a variety of human diseases termed cholangiopathies, often causing advanced liver failure. The regulation of cholangiocyte transport properties is increasingly understood, as is their anatomical and functional heterogeneity along the biliary tract. Furthermore, cholangiocytes are pivotal in liver regeneration, especially when hepatocyte regeneration is compromised. The role of cholangiocytes in innate and adaptive immune responses, a critical subject relevant to immune-mediated cholangiopathies, is also emerging. Finally, reactive ductular cells are present in many cholestatic and other liver diseases. In chronic disease states, this repair response contributes to liver inflammation, fibrosis and carcinogenesis and is a subject of intense investigation. This Review highlights advances in cholangiocyte research, especially their role in development and liver regeneration, their functional and biochemical heterogeneity, their activation and involvement in inflammation and fibrosis and their engagement with the immune system. We aim to focus further attention on cholangiocyte pathobiology and the search for new disease-modifying therapies targeting the cholangiopathies.
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Pinon M, Carboni M, Colavito D, Cisarò F, Peruzzi L, Pizzol A, Calosso G, David E, Calvo PL. Not only Alagille syndrome. Syndromic paucity of interlobular bile ducts secondary to HNF1β deficiency: a case report and literature review. Ital J Pediatr 2019; 45:27. [PMID: 30791938 PMCID: PMC6385394 DOI: 10.1186/s13052-019-0617-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 02/11/2019] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND paucity of interlobular bile ducts is an important observation at liver biopsy in the diagnostic work-up of neonatal cholestasis. To date, other than in the Alagille syndrome, syndromic paucity of interlobular bile ducts has been documented in four cholestatic neonates with HFN1β mutations. A syndromic phenotype, known as renal cysts and diabetes syndrome (RCAD), has been identified. This is usually characterized by a wide clinical spectrum, including renal cysts, maturity-onset diabetes of the young, exocrine pancreatic insufficiency, urogenital abnormalities and a not well established liver involvement. Herein we report a novel case of paucity of interlobular bile ducts due to an HFN1β defect. CASE PRESENTATION A 5-week-old boy was admitted to our department for cholestatic jaundice with increased gamma-glutamyl transpeptidase and an unremarkable clinical examination. He had been delivered by Caesarian section at 38 weeks' gestation from unrelated parents, with a birth weight of 2600 g (3rd percentile). Screening for cholestatic diseases, including Alagille syndrome, was negative except for a minor pulmonary artery stenosis at echocardiography and a doubt of a thoracic butterfly hemivertebra. The finding of hyperechogenic kidneys with multiple bilateral cortical cysts at ultrasound examination, associated with moderately impaired renal function with proteinuria, polyuria and metabolic acidosis, was suggestive of ciliopathy. A liver biopsy was performed revealing paucity of interlobular bile ducts, thus the diagnosis of Alagille syndrome was reconsidered. Although genetic tests for liver cholestatic diseases were performed with negative results for Alagille syndrome (JAG1 and NOTCH2), a de-novo missense mutation of HNF1β gene was detected. At 18 months of age our patient has persistent cholestasis and his itching is not under satisfactory control. CONCLUSIONS Alagille syndrome may not be the only syndrome determining paucity of interlobular bile ducts in neonates presenting with cholestasis and renal impairment, especially in small for gestational age newborns. We suggest that HNF1β deficiency should also be ruled out, taking into consideration HNF1β mutations, together with Alagille syndrome, in next generation sequencing strategies in neonates with cholestasis, renal impairment and/or paucity of interlobular bile ducts at liver biopsy.
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Affiliation(s)
- Michele Pinon
- Pediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
| | - Michele Carboni
- Pediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
- Postgraduation School of Pediatrics, Regina Margherita Children’s Hospital, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, University of Turin, Turin, Italy
| | | | - Fabio Cisarò
- Pediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
| | - Licia Peruzzi
- Pediatric Nephrology Unit, Regina Margherita Children’s Hospital, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, University of Turin, Turin, Italy
| | - Antonio Pizzol
- Pediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
- Postgraduation School of Pediatrics, Regina Margherita Children’s Hospital, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, University of Turin, Turin, Italy
| | - Giulia Calosso
- Pediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
- Postgraduation School of Pediatrics, Regina Margherita Children’s Hospital, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, University of Turin, Turin, Italy
| | - Ezio David
- Department of Pathology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, University of Turin, Turin, Italy
| | - Pier Luigi Calvo
- Pediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
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Directing the growth and alignment of biliary epithelium within extracellular matrix hydrogels. Acta Biomater 2019; 85:84-93. [PMID: 30590182 DOI: 10.1016/j.actbio.2018.12.039] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 12/04/2018] [Accepted: 12/21/2018] [Indexed: 12/13/2022]
Abstract
Three-dimensional (3D) printing of decellularized extracellular matrix (dECM) hydrogels is a promising technique for regenerative engineering. 3D-printing enables the reproducible and precise patterning of multiple cells and biomaterials in 3D, while dECM has high organ-specific bioactivity. However, dECM hydrogels often display poor printability on their own and necessitate additives or support materials to enable true 3D structures. In this study, we used a sacrificial material, 3D-printed Pluronic F-127, to serve as a platform into which dECM hydrogel can be incorporated to create specifically designed structures made entirely up of dECM. The effects of 3D dECM are studied in the context of engineering the intrahepatic biliary tree, an often-understudied topic in liver tissue engineering. Encapsulating biliary epithelial cells (cholangiocytes) within liver dECM has been shown to lead to the formation of complex biliary trees in vitro. By varying several aspects of the dECM structures' geometry, such as width and angle, we show that we can guide the directional formation of biliary trees. This is confirmed by computational 3D image analysis of duct alignment. This system also enables fabrication of a true multi-layer dECM structure and the formation of 3D biliary trees into which other cell types can be seeded. For example, we show that hepatocyte spheroids can be easily incorporated within this system, and that the seeding sequence influences the resulting structures after seven days in culture. STATEMENT OF SIGNIFICANCE: The field of liver tissue engineering has progressed significantly within the past several years, however engineering the intrahepatic biliary tree has remained a significant challenge. In this study, we utilize the inherent bioactivity of decellularized extracellular matrix (dECM) hydrogels and 3D-printing of a sacrificial biomaterial to create spatially defined, 3D biliary trees. The creation of patterned, 3D dECM hydrogels in the past has only been possible with additives to the gel that may stifle its bioactivity, or with rigid and permanent support structures that may present issues upon implantation. Additionally, the biological effect of 3D spatially patterned liver dECM has not been demonstrated independent of the effects of dECM bioactivity alone. This study demonstrates that sacrificial materials can be used to create pure, multi-layer dECM structures, and that strut width and angle can be changed to influence the formation and alignment of biliary trees encapsulated within. Furthermore, this strategy allows co-culture of other cells such as hepatocytes. We demonstrate that not only does this system show promise for tissue engineering the intrahepatic biliary tree, but it also aids in the study of duct formation and cell-cell interactions.
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Cholangiocyte death in ductopenic cholestatic cholangiopathies: Mechanistic basis and emerging therapeutic strategies. Life Sci 2019; 218:324-339. [DOI: 10.1016/j.lfs.2018.12.044] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 12/26/2018] [Indexed: 02/07/2023]
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MET Activation by a Macrocyclic Peptide Agonist that Couples to Biological Responses Differently from HGF in a Context-Dependent Manner. Int J Mol Sci 2018; 19:ijms19103141. [PMID: 30322054 PMCID: PMC6213957 DOI: 10.3390/ijms19103141] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 10/10/2018] [Accepted: 10/10/2018] [Indexed: 12/11/2022] Open
Abstract
Non-native ligands for growth factor receptors with distinct chemical properties and different biological activities have the potential to become therapeutic applications. We previously generated MET/hepatocyte growth factor (HGF) receptor agonists using bivalent macrocyclic peptides. The highest MET-activating agonists exhibited biological activity that was indistinguishable from the effects of HGF. In this study, we investigated MET activation, signal characteristics, and biological responses induced by a macrocyclic peptide partial agonist known as aML5-PEG11. aML5-PEG11 induced weak tyrosine phosphorylation of MET while enhancing cell migration with potency comparable to HGF. aML5-PEG11 induced marked AKT (protein kinase B) and ERK (extracellular signal-regulated kinase) activation at a comparable potency and time-dependency to HGF, which suggests that enhancement of cell motility is attributable to activation of these molecules. In a 3-D culture of bile duct cancer cells in collagen gel, HGF induced robust activation of MET, ERK, and AKT, which was associated with enhanced expression of genes involved in bile duct development and subsequent branching of tubulogenesis. In contrast, aML5-PEG11 induced marginal activation of MET, ERK, and AKT (levels near the detection limits), which was associated with failure to enhance the expression of genes involved in bile duct development and a lack of tubulogenic response. Thus, MET activation by aML5-PEG11 couples to biological responses differently from HGF in an extracellular context-dependent manner.
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Kamiya A, Chikada H, Ida K, Ando E, Tsuruya K, Kagawa T, Inagaki Y. An in vitro model of polycystic liver disease using genome-edited human inducible pluripotent stem cells. Stem Cell Res 2018; 32:17-24. [PMID: 30172093 DOI: 10.1016/j.scr.2018.08.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 08/14/2018] [Accepted: 08/22/2018] [Indexed: 01/23/2023] Open
Abstract
In the developing liver, bile duct structure is formed through differentiation of hepatic progenitor cells (HPC) into cholangiocytes. A subtype of polycystic liver diseases characterized by uncontrolled expansion of bile ductal cells is caused by genetic abnormalities such as in that of protein kinase C substrate 80 K-H (PRKCSH). In this study, we aimed to mimic the disease process in vitro by genome editing of the PRKCSH locus in human inducible pluripotent stem (iPS) cells. A proportion of cultured human iPS cell-derived CD13+CD133+ HPC differentiated into CD13- cells. During the subsequent gel embedding culture, CD13- cells formed bile ductal marker-positive cystic structures with the polarity of epithelial cells. A deletion of PRKCSH gene increased expression of cholangiocytic transcription factors in CD13- cells and the number of cholangiocytic cyst structure. These results suggest that PRKCSH deficiency promotes the differentiation of HPC-derived cholangiocytes, providing a good in vitro model to analyze the molecular mechanisms underlying polycystic diseases.
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Affiliation(s)
- Akihide Kamiya
- Department of Molecular Life Sciences, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, Japan; Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
| | - Hiromi Chikada
- Department of Molecular Life Sciences, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, Japan; Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan
| | - Kinuyo Ida
- Department of Molecular Life Sciences, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, Japan
| | - Emi Ando
- Department of Molecular Life Sciences, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, Japan
| | - Kota Tsuruya
- Department of Molecular Life Sciences, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, Japan; Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan
| | - Tatehiro Kagawa
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan
| | - Yutaka Inagaki
- Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan; Department of Regenerative Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan
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Bezerra JA, Wells RG, Mack CL, Karpen SJ, Hoofnagle J, Doo E, Sokol RJ. Biliary Atresia: Clinical and Research Challenges for the Twenty-First Century. Hepatology 2018; 68:1163-1173. [PMID: 29604222 PMCID: PMC6167205 DOI: 10.1002/hep.29905] [Citation(s) in RCA: 228] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 03/08/2018] [Accepted: 03/27/2018] [Indexed: 12/12/2022]
Abstract
Biliary atresia (BA) is a fibroinflammatory disease of the intrahepatic and extrahepatic biliary tree. Surgical hepatic portoenterostomy (HPE) may restore bile drainage, but progression of the intrahepatic disease results in complications of portal hypertension and advanced cirrhosis in most children. Recognizing that further progress in the field is unlikely without a better understanding of the underlying cause(s) and pathogenesis of the disease, the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a research workshop focused on innovative and promising approaches and on identifying future areas of research. Investigators discussed recent advances using gestational ultrasound and results of newborn BA screening with serum direct (conjugated) bilirubin that support a prenatal onset of biliary injury. Experimental and human studies implicate the toxic properties of environmental toxins (e.g., biliatresone) and of viruses (e.g., cytomegalovirus) to the biliary system. Among host factors, sequence variants in genes related to biliary development and ciliopathies, a notable lack of a cholangiocyte glycocalyx and of submucosal collagen bundles in the neonatal extrahepatic bile ducts, and an innate proinflammatory bias of the neonatal immune system contribute to an increased susceptibility to damage and obstruction following epithelial injury. These advances form the foundation for a future research agenda focused on identifying the environmental and host factor(s) that cause BA, the potential use of population screening, studies of the mechanisms of prominent fibrosis in young infants, determinations of clinical surrogates of disease progression, and the design of clinical trials that target subgroups of patients with initial drainage following HPE. (Hepatology 2018; 00:000-000).
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Affiliation(s)
- Jorge A. Bezerra
- Liver Care Center of Cincinnati Children’s Hospital Medical Center and the Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Rebecca G. Wells
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Cara L. Mack
- Pediatric Liver Center, Children’s Hospital Colorado and Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Saul J. Karpen
- Emory University School of Medicine and Children’s Healthcare of Atlanta, GA, USA
| | - Jay Hoofnagle
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Edward Doo
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Ronald J. Sokol
- Pediatric Liver Center, Children’s Hospital Colorado and Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
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Lewis PL, Su J, Yan M, Meng F, Glaser SS, Alpini GD, Green RM, Sosa-Pineda B, Shah RN. Complex bile duct network formation within liver decellularized extracellular matrix hydrogels. Sci Rep 2018; 8:12220. [PMID: 30111800 PMCID: PMC6093899 DOI: 10.1038/s41598-018-30433-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 07/30/2018] [Indexed: 02/07/2023] Open
Abstract
The biliary tree is an essential component of transplantable human liver tissue. Despite recent advances in liver tissue engineering, attempts at re-creating the intrahepatic biliary tree have not progressed significantly. The finer branches of the biliary tree are structurally and functionally complex and heterogeneous and require harnessing innate developmental processes for their regrowth. Here we demonstrate the ability of decellularized liver extracellular matrix (dECM) hydrogels to induce the in vitro formation of complex biliary networks using encapsulated immortalized mouse small biliary epithelial cells (cholangiocytes). This phenomenon is not observed using immortalized mouse large cholangiocytes, or with purified collagen 1 gels or Matrigel. We also show phenotypic stability via immunostaining for specific cholangiocyte markers. Moreover, tight junction formation and maturation was observed to occur between cholangiocytes, exhibiting polarization and transporter activity. To better define the mechanism of duct formation, we utilized three fluorescently labeled, but otherwise identical populations of cholangiocytes. The cells, in a proximity dependent manner, either branch out clonally, radiating from a single nucleation point, or assemble into multi-colored structures arising from separate populations. These findings present liver dECM as a promising biomaterial for intrahepatic bile duct tissue engineering and as a tool to study duct remodeling in vitro.
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Affiliation(s)
- Phillip L. Lewis
- 0000 0001 2299 3507grid.16753.36Biomedical Engineering, Northwestern University, Evanston, IL, USA ,0000 0001 2299 3507grid.16753.36Simpson Querrey Institute, Northwestern University, Chicago, IL, USA
| | - Jimmy Su
- 0000 0001 2299 3507grid.16753.36Biomedical Engineering, Northwestern University, Evanston, IL, USA ,0000 0001 2299 3507grid.16753.36Simpson Querrey Institute, Northwestern University, Chicago, IL, USA
| | - Ming Yan
- 0000 0001 2299 3507grid.16753.36Biomedical Engineering, Northwestern University, Evanston, IL, USA ,0000 0001 2299 3507grid.16753.36Simpson Querrey Institute, Northwestern University, Chicago, IL, USA
| | - Fanyin Meng
- 0000 0004 0420 5847grid.413775.3Research Central Texas Veterans Health Care System, Temple, TX, USA ,grid.486749.0Baylor Scott & White Health Digestive Disease Research Center, Temple, TX, USA
| | - Shannon S. Glaser
- 0000 0004 0420 5847grid.413775.3Research Central Texas Veterans Health Care System, Temple, TX, USA ,grid.486749.0Baylor Scott & White Health Digestive Disease Research Center, Temple, TX, USA ,0000 0004 4687 2082grid.264756.4Medical Physiology, Texas A&M University College of Medicine, Temple, TX, USA
| | - Gianfranco D. Alpini
- 0000 0004 0420 5847grid.413775.3Research Central Texas Veterans Health Care System, Temple, TX, USA ,grid.486749.0Baylor Scott & White Health Digestive Disease Research Center, Temple, TX, USA ,0000 0004 4687 2082grid.264756.4Medical Physiology, Texas A&M University College of Medicine, Temple, TX, USA
| | - Richard M. Green
- 0000 0001 2299 3507grid.16753.36Division of Gastroenterology and Hepatology, Northwestern University, Chicago, IL, USA
| | - Beatriz Sosa-Pineda
- 0000 0001 2299 3507grid.16753.36Nephrology, Northwestern University, Chicago, IL, USA
| | - Ramille N. Shah
- 0000 0001 2299 3507grid.16753.36Simpson Querrey Institute, Northwestern University, Chicago, IL, USA ,0000 0001 2299 3507grid.16753.36Materials Science and Engineering, Northwestern University, Evanston, IL, USA ,0000 0001 2299 3507grid.16753.36Surgery (Transplant Division), Northwestern University, Chicago, IL, USA
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Graffmann N, Ncube A, Wruck W, Adjaye J. Cell fate decisions of human iPSC-derived bipotential hepatoblasts depend on cell density. PLoS One 2018; 13:e0200416. [PMID: 29990377 PMCID: PMC6039024 DOI: 10.1371/journal.pone.0200416] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 06/26/2018] [Indexed: 12/28/2022] Open
Abstract
During embryonic development bipotential hepatoblasts differentiate into hepatocytes and cholangiocytes- the two main cell types within the liver. Cell fate decision depends on elaborate interactions between distinct signalling pathways, namely Notch, WNT, TGFβ, and Hedgehog. Several in vitro protocols have been established to differentiate human pluripotent stem cells into either hepatocyte or cholangiocyte like cells (HLC/CLC) to enable disease modelling or drug screening. During HLC differentiation we observed the occurrence of epithelial cells with a phenotype divergent from the typical hepatic polygonal shape- we refer to these as endoderm derived epithelial cells (EDECs). These cells do not express the mature hepatocyte marker ALB or the progenitor marker AFP. However they express the cholangiocyte markers SOX9, OPN, CFTR as well as HNF4α, CK18 and CK19. Interestingly, they express both E Cadherin and Vimentin, two markers that are mutually exclusive, except for cancer cells. EDECs grow spontaneously under low density cell culture conditions and their occurrence was unaffected by interfering with the above mentioned signalling pathways.
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Affiliation(s)
- Nina Graffmann
- Institute for Stem Cell Research and Regenerative Medicine, Medical faculty, Heinrich-Heine University, Düsseldorf, Germany
| | - Audrey Ncube
- Institute for Stem Cell Research and Regenerative Medicine, Medical faculty, Heinrich-Heine University, Düsseldorf, Germany
| | - Wasco Wruck
- Institute for Stem Cell Research and Regenerative Medicine, Medical faculty, Heinrich-Heine University, Düsseldorf, Germany
| | - James Adjaye
- Institute for Stem Cell Research and Regenerative Medicine, Medical faculty, Heinrich-Heine University, Düsseldorf, Germany
- * E-mail:
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So J, Khaliq M, Evason K, Ninov N, Martin BL, Stainier DY, Shin D. Wnt/β-catenin signaling controls intrahepatic biliary network formation in zebrafish by regulating notch activity. Hepatology 2018; 67:2352-2366. [PMID: 29266316 PMCID: PMC5991997 DOI: 10.1002/hep.29752] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 11/10/2017] [Accepted: 12/17/2017] [Indexed: 12/27/2022]
Abstract
UNLABELLED Malformations of the intrahepatic biliary structure cause cholestasis, a liver pathology that corresponds to poor bile flow, which leads to inflammation, fibrosis, and cirrhosis. Although the specification of biliary epithelial cells (BECs) that line the bile ducts is fairly well understood, the molecular mechanisms underlying intrahepatic biliary morphogenesis remain largely unknown. Wnt/β-catenin signaling plays multiple roles in liver biology; however, its role in intrahepatic biliary morphogenesis remains unclear. Using pharmacological and genetic tools that allow one to manipulate Wnt/β-catenin signaling, we show that in zebrafish both suppression and overactivation of Wnt/β-catenin signaling impaired intrahepatic biliary morphogenesis. Hepatocytes, but not BECs, exhibited Wnt/β-catenin activity; and the global suppression of Wnt/β-catenin signaling reduced Notch activity in BECs. Hepatocyte-specific suppression of Wnt/β-catenin signaling also reduced Notch activity in BECs, indicating a cell nonautonomous role for Wnt/β-catenin signaling in regulating hepatic Notch activity. Reducing Notch activity to the same level as that observed in Wnt-suppressed livers also impaired biliary morphogenesis. Intriguingly, expression of the Notch ligand genes jag1b and jag2b in hepatocytes was reduced in Wnt-suppressed livers and enhanced in Wnt-overactivated livers, revealing their regulation by Wnt/β-catenin signaling. Importantly, restoring Notch activity rescued the biliary defects observed in Wnt-suppressed livers. CONCLUSION Wnt/β-catenin signaling cell nonautonomously controls Notch activity in BECs by regulating the expression of Notch ligand genes in hepatocytes, thereby regulating biliary morphogenesis. (Hepatology 2018;67:2352-2366).
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Affiliation(s)
- Juhoon So
- Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Mehwish Khaliq
- Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Kimberley Evason
- Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, Diabetes Center, and Liver Center, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Nikolay Ninov
- Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, Diabetes Center, and Liver Center, University of California, San Francisco, San Francisco, CA 94158, USA,Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
| | - Benjamin L. Martin
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Didier Y.R. Stainier
- Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, Diabetes Center, and Liver Center, University of California, San Francisco, San Francisco, CA 94158, USA,Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
| | - Donghun Shin
- Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA,Correspondence: Donghun Shin, 3501 5 Ave. #5063 Pittsburgh, PA 15260, 1-412-624-2144 (phone), 1-412-383-2211 (fax),
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50
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Ober EA, Lemaigre FP. Development of the liver: Insights into organ and tissue morphogenesis. J Hepatol 2018; 68:1049-1062. [PMID: 29339113 DOI: 10.1016/j.jhep.2018.01.005] [Citation(s) in RCA: 148] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 12/29/2017] [Accepted: 01/06/2018] [Indexed: 02/08/2023]
Abstract
Recent development of improved tools and methods to analyse tissues at the three-dimensional level has expanded our capacity to investigate morphogenesis of foetal liver. Here, we review the key morphogenetic steps during liver development, from the prehepatic endoderm stage to the postnatal period, and consider several model organisms while focussing on the mammalian liver. We first discuss how the liver buds out of the endoderm and gives rise to an asymmetric liver. We next outline the mechanisms driving liver and lobe growth, and review morphogenesis of the intra- and extrahepatic bile ducts; morphogenetic responses of the biliary tract to liver injury are discussed. Finally, we describe the mechanisms driving formation of the vasculature, namely venous and arterial vessels, as well as sinusoids.
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Affiliation(s)
- Elke A Ober
- Novo Nordisk Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, Denmark
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