1
|
Jeropoulos RM, Arroyo J, Davenport M. Predicting and optimising outcome for biliary atresia. Semin Pediatr Surg 2024; 33:151479. [PMID: 39884180 DOI: 10.1016/j.sempedsurg.2025.151479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 01/07/2025] [Indexed: 02/01/2025]
Abstract
Biliary atresia (BA) remains a disease of significant morbidity and mortality world-wide. Early and accurate diagnosis facilitates early intervention and improves outcomes. The gold standard in diagnosing BA is a liver biopsy followed by cholangiography, usually performed intra-operatively. Serum markers, like the aspartate aminotransferase-to-platelet ratio, matrix metalloproteinase-7 and several inflammatory cytokines have been recently investigated as non-invasive alternatives with varying degrees of success. Newer immunohistochemical analysis of liver biopsies, such as the expression of secretin receptors and Ki-67, from infants with BA have improved our understanding of the disease process and has shed a little light in predicting post-operative outcomes. There is little standardisation in the care of BA post operatively, though administration of steroids, prevention and treatment of cholangitis with antibiotics and anti-viral therapy for CMV+ve infants are becoming universally accepted as treatment. Experimental stem cell treatments show promise although remain in the out-of-reach future for now in routine clinical practice. This chapter aims to comprehensively describe recent knowledge on predicting the clinical outcomes of infants with BA, as well as optimising their care post operatively.
Collapse
Affiliation(s)
- Renos M Jeropoulos
- Dept of Paediatric Surgery, Kings College Hospital, London SE59RS, England, United Kingdom
| | - Jorge Arroyo
- Dept of Paediatric Surgery, Kings College Hospital, London SE59RS, England, United Kingdom
| | - Mark Davenport
- Dept of Paediatric Surgery, Kings College Hospital, London SE59RS, England, United Kingdom.
| |
Collapse
|
2
|
Jin C, Jiang P, Zhang Z, Han Y, Wen X, Zheng L, Kuang W, Lian J, Yu G, Qian X, Ren Y, Lu M, Xu L, Chen W, Chen J, Zhou Y, Xin J, Wang B, Jin X, Qian P, Yang Y. Single-cell RNA sequencing reveals the pro-inflammatory roles of liver-resident Th1-like cells in primary biliary cholangitis. Nat Commun 2024; 15:8690. [PMID: 39375367 PMCID: PMC11458754 DOI: 10.1038/s41467-024-53104-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 10/02/2024] [Indexed: 10/09/2024] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by multilineage immune dysregulation, which subsequently causes inflammation, fibrosis, and even cirrhosis of liver. Due to the limitation of traditional assays, the local hepatic immunopathogenesis of PBC has not been fully characterized. Here, we utilize single-cell RNA sequencing technology to depict the immune cell landscape and decipher the molecular mechanisms of PBC patients. We reveal that cholangiocytes and hepatic stellate cells are involved in liver inflammation and fibrosis. Moreover, Kupffer cells show increased levels of inflammatory factors and decreased scavenger function related genes, while T cells exhibit enhanced levels of inflammatory factors and reduced cytotoxicity related genes. Interestingly, we identify a liver-resident Th1-like population with JAK-STAT activation in the livers of both PBC patients and murine PBC model. Finally, blocking the JAK-STAT pathway alleviates the liver inflammation and eliminates the liver-resident Th1-like cells in the murine PBC model. In conclusion, our comprehensive single-cell transcriptome profiling expands the understanding of pathological mechanisms of PBC and provides potential targets for the treatment of PBC in patients.
Collapse
Affiliation(s)
- Ciliang Jin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Penglei Jiang
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - Zhaoru Zhang
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - Yingli Han
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - Xue Wen
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lin Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Kuang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiangshan Lian
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Guodong Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinyue Qian
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - Yue Ren
- Depratment of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Miaomiao Lu
- Depratment of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lingling Xu
- Depratment of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weixin Chen
- Depratment of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiyang Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuwei Zhou
- Depratment of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jinxia Xin
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou, China
| | - Ben Wang
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou, China
| | - Xi Jin
- Depratment of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Pengxu Qian
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China.
| | - Yida Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| |
Collapse
|
3
|
Marakovits C, Francis H. Unraveling the complexities of fibrosis and ductular reaction in liver disease: pathogenesis, mechanisms, and therapeutic insights. Am J Physiol Cell Physiol 2024; 326:C698-C706. [PMID: 38105754 PMCID: PMC11193454 DOI: 10.1152/ajpcell.00486.2023] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/11/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]
Abstract
Ductular reaction and fibrosis are hallmarks of many liver diseases including primary sclerosing cholangitis, primary biliary cholangitis, biliary atresia, alcoholic liver disease, and metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis. Liver fibrosis is the accumulation of extracellular matrix often caused by excess collagen deposition by myofibroblasts. Ductular reaction is the proliferation of bile ducts (which are composed of cholangiocytes) during liver injury. Many other cells including hepatic stellate cells, hepatocytes, hepatic progenitor cells, mesenchymal stem cells, and immune cells contribute to ductular reaction and fibrosis by either directly or indirectly interacting with myofibroblasts and cholangiocytes. This review summarizes the recent findings in cellular links between ductular reaction and fibrosis in numerous liver diseases.
Collapse
Affiliation(s)
- Corinn Marakovits
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, United States
| |
Collapse
|
4
|
Lenci I, Carnì P, Milana M, Bicaj A, Signorello A, Baiocchi L. Sequence of events leading to primary biliary cholangitis. World J Gastroenterol 2023; 29:5305-5312. [PMID: 37899786 PMCID: PMC10600805 DOI: 10.3748/wjg.v29.i37.5305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/22/2023] [Accepted: 09/11/2023] [Indexed: 09/25/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that is observed more frequently in middle-aged women. This disorder is considered an autoimmune disease, since liver injury is sustained by the presence of self-directed antimitochondrial antibodies targeting the bile duct cells. The prognosis may vary depending on an early diagnosis and response to therapy. However, nearly a third of patients can progress to liver cirrhosis, thus requiring a liver transplant. Traditional immunosuppressive therapies, commonly employed for other autoimmune diseases, have limited effects on PBC. In fact, dramatic functional changes that occur in the biliary epithelium in the course of inflammation play a major role in perpetuating the injury. In this minireview, after a background on the disease and possible predisposing factors, the sequential cooperation of cellular/molecular events leading to end-stage PBC is discussed in detail. The rise and maintenance of the autoimmune process, as well as the response of the biliary epithelia during inflammatory injury, are key factors in the progression of the disease. The so-called "ductular reaction (DR)", intended as a reactive expansion of cells with biliary phenotype, is a process frequently observed in PBC and partially understood. However, recent findings suggest a strict relationship between this pathological picture and the progression to liver fibrosis, cell senescence, and loss of biliary ducts. All these issues (onset of chronic inflammation, changes in secretive and proliferative biliary functions, DR, and its relationship with other pathological events) are discussed in this manuscript in an attempt to provide a snapshot, for clinicians and researchers, of the most relevant and sequential contributors to the progression of this human cholestatic disease. We believe that interpreting this disorder as a multistep process may help identify possible therapeutic targets to prevent evolution to severe disease.
Collapse
Affiliation(s)
- Ilaria Lenci
- Hepatology Unit, University of Tor Vergata, Rome 00133, Italy
| | - Paola Carnì
- Hepatology Unit, University of Tor Vergata, Rome 00133, Italy
- Postgraduate School in Hepato/Gastroenterology, Catholic University Our Lady of Good Counsel, Tirana 1004, Albania
| | - Martina Milana
- Hepatology Unit, University of Tor Vergata, Rome 00133, Italy
| | - Agreta Bicaj
- Hepatology Unit, University of Tor Vergata, Rome 00133, Italy
- Postgraduate School in Hepato/Gastroenterology, Catholic University Our Lady of Good Counsel, Tirana 1004, Albania
| | | | - Leonardo Baiocchi
- Hepatology Unit, University of Tor Vergata, Rome 00133, Italy
- Postgraduate School in Hepato/Gastroenterology, Catholic University Our Lady of Good Counsel, Tirana 1004, Albania
| |
Collapse
|
5
|
Zhang W, Kyritsi K, Isidan A, Park Y, Li P, Cross-Najafi AA, Lopez K, Kennedy L, Sato K, Glaser S, Francis H, Alpini G, Ekser B. Development of Scaffold-Free Three-Dimensional Cholangiocyte Organoids to Study the Progression of Primary Sclerosing Cholangitis. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1156-1169. [PMID: 37263345 DOI: 10.1016/j.ajpath.2023.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 04/29/2023] [Accepted: 05/15/2023] [Indexed: 06/03/2023]
Abstract
Organoids are novel in vitro models to study intercellular cross talk between the different types of cells in disease pathophysiology. To better understand the underlying mechanisms driving the progression of primary sclerosing cholangitis (PSC), scaffold-free multicellular three-dimensional cholangiocyte organoids (3D-CHOs) were developed using primary liver cells derived from normal subjects and patients with PSC. Human liver samples from healthy donors and patients with PSC were used to isolate primary cholangiocytes [epithelial cell adhesion molecule (EpCam)+/ cytokeratin-19+], liver endothelial cells (CD31+), and hepatic stellate cells (HSCs; CD31-/CD68-/desmin+/vitamin A+). 3D-CHOs were formed using cholangiocytes, HSCs, and liver endothelial cells, and kept viable for up to 1 month. Isolated primary cell lines and 3D-CHOs were further characterized by immunofluorescence, quantitative RT-PCR, and transmission electron microscopy. Transcription profiles for cholangiocytes (SOX9, CFTR, EpCAM, AE, SCT, and SCTR), fibrosis (ACTA2, COL1A1, DESMIN, and TGFβ1), angiogenesis (PECAM, VEGF, CDH5, and vWF), and inflammation (IL-6 and TNF-α) confirmed PSC phenotypes of 3D-CHOs. Because cholangiocytes develop a neuroendocrine phenotype and express neuromodulators, confocal immunofluorescence was used to demonstrate localization of the neurokinin-1 receptor within cytokeratin-19+ cholangiocytes and desmin+ HSCs. Moreover, 3D-CHOs from patients with PSC confirmed PSC phenotypes with up-regulated neurokinin-1 receptor, tachykinin precursor 1, and down-regulated membrane metalloendopeptidase. Scaffold-free multicellular 3D-CHOs showed superiority as an in vitro model in mimicking PSC in vivo phenotypes compared with two-dimensional cell culture, which can be used in PSC disease-related research.
Collapse
Affiliation(s)
- Wenjun Zhang
- Division of Transplant Surgery, Department of Surgery, Indianapolis, Indiana
| | - Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Division of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Abdulkadir Isidan
- Division of Transplant Surgery, Department of Surgery, Indianapolis, Indiana
| | - Yujin Park
- Division of Transplant Surgery, Department of Surgery, Indianapolis, Indiana
| | - Ping Li
- Division of Transplant Surgery, Department of Surgery, Indianapolis, Indiana
| | | | - Kevin Lopez
- Division of Transplant Surgery, Department of Surgery, Indianapolis, Indiana
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Division of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Keisaku Sato
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Division of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, Texas
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Division of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Division of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indianapolis, Indiana.
| |
Collapse
|
6
|
Kyritsi K, Wu N, Zhou T, Carpino G, Baiocchi L, Kennedy L, Chen L, Ceci L, Meyer AA, Barupala N, Franchitto A, Onori P, Ekser B, Gaudio E, Wu C, Marakovits C, Chakraborty S, Francis H, Glaser S, Alpini G. Knockout of secretin ameliorates biliary and liver phenotypes during alcohol-induced hepatotoxicity. Cell Biosci 2023; 13:5. [PMID: 36624475 PMCID: PMC9830859 DOI: 10.1186/s13578-022-00945-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 12/19/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Alcohol-related liver disease (ALD) is characterized by ductular reaction (DR), liver inflammation, steatosis, fibrosis, and cirrhosis. The secretin (Sct)/secretin receptor (SR) axis (expressed only by cholangiocytes) regulates liver phenotypes in cholestasis. We evaluated the role of Sct signaling on ALD phenotypes. METHODS We used male wild-type and Sct-/- mice fed a control diet (CD) or ethanol (EtOH) for 8 wk. Changes in liver phenotypes were measured in mice, female/male healthy controls, and patients with alcoholic cirrhosis. Since Cyp4a10 and Cyp4a11/22 regulate EtOH liver metabolism, we measured their expression in mouse/human liver. We evaluated: (i) the immunoreactivity of the lipogenesis enzyme elongation of very-long-chain fatty acids 1 (Elovl, mainly expressed by hepatocytes) in mouse/human liver sections by immunostaining; (ii) the expression of miR-125b (that is downregulated in cholestasis by Sct) in mouse liver by qPCR; and (iii) total bile acid (BA) levels in mouse liver by enzymatic assay, and the mRNA expression of genes regulating BA synthesis (cholesterol 7a-hydroxylase, Cyp27a1, 12a-hydroxylase, Cyp8b1, and oxysterol 7a-hydroxylase, Cyp7b11) and transport (bile salt export pump, Bsep, Na+-taurocholate cotransporting polypeptide, NTCP, and the organic solute transporter alpha (OSTa) in mouse liver by qPCR. RESULTS In EtOH-fed WT mice there was increased biliary and liver damage compared to control mice, but decreased miR-125b expression, phenotypes that were blunted in EtOH-fed Sct-/- mice. The expression of Cyp4a10 increased in cholangiocytes and hepatocytes from EtOH-fed WT compared to control mice but decreased in EtOH-fed Sct-/- mice. There was increased immunoreactivity of Cyp4a11/22 in patients with alcoholic cirrhosis compared to controls. The expression of miR-125b decreased in EtOH-fed WT mice but returned at normal values in EtOH-fed Sct-/- mice. Elovl1 immunoreactivity increased in patients with alcoholic cirrhosis compared to controls. There was no difference in BA levels between WT mice fed CD or EtOH; BA levels decreased in EtOH-fed Sct-/- compared to EtOH-fed WT mice. There was increased expression of Cyp27a1, Cyp8b1, Cyp7b1, Bsep, NTCP and Osta in total liver from EtOH-fed WT compared to control mice, which decreased in EtOH-fed Sct-/- compared to EtOH-fed WT mice. CONCLUSIONS Targeting Sct/SR signaling may be important for modulating ALD phenotypes.
Collapse
Affiliation(s)
- Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Nan Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Guido Carpino
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza University of Rome, Rome, Italy
| | | | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Division of Research, Indiana Center for Liver Research, Gastroenterology, Medicine, Richard L. Roudebush VA Medical Center and Indiana University, 702 Rotary Circle, Rm. 013C, Indianapolis, IN, 46202-2859, USA
| | - Lixian Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Ludovica Ceci
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza University of Rome, Rome, Italy
| | - Alison Ann Meyer
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Nipuni Barupala
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Antonio Franchitto
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza University of Rome, Rome, Italy
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University, Indianapolis, IN, USA
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza University of Rome, Rome, Italy
| | - Chaodong Wu
- Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Corinn Marakovits
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Sanjukta Chakraborty
- Department of Medical Physiology, Texas A&M University School of Medicine, 8447 Riverside Parkway, MREB II, Room 2342, Bryan, TX, 77807-3260, USA
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
- Division of Research, Indiana Center for Liver Research, Gastroenterology, Medicine, Richard L. Roudebush VA Medical Center and Indiana University, 702 Rotary Circle, Rm. 013C, Indianapolis, IN, 46202-2859, USA.
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University School of Medicine, 8447 Riverside Parkway, MREB II, Room 2342, Bryan, TX, 77807-3260, USA.
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
- Division of Research, Indiana Center for Liver Research, Gastroenterology, Medicine, Richard L. Roudebush VA Medical Center and Indiana University, 702 Rotary Circle, Rm. 013C, Indianapolis, IN, 46202-2859, USA.
| |
Collapse
|
7
|
Ceci L, Chen L, Baiocchi L, Wu N, Kennedy L, Carpino G, Kyritsi K, Zhou T, Owen T, Kundu D, Sybenga A, Isidan A, Ekser B, Franchitto A, Onori P, Gaudio E, Mancinelli R, Francis H, Alpini G, Glaser S. Prolonged Administration of Melatonin Ameliorates Liver Phenotypes in Cholestatic Murine Model. Cell Mol Gastroenterol Hepatol 2022; 14:877-904. [PMID: 35863741 PMCID: PMC9425041 DOI: 10.1016/j.jcmgh.2022.07.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 07/09/2022] [Accepted: 07/11/2022] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is characterized by biliary senescence and hepatic fibrosis. Melatonin exerts its effects by interacting with Melatonin receptor 1 and 2 (MT1/MT2) melatonin receptors. Short-term (1 wk) melatonin treatment reduces a ductular reaction and liver fibrosis in bile duct-ligated rats by down-regulation of MT1 and clock genes, and in multidrug resistance gene 2 knockout (Mdr2-/-) mice by decreased miR200b-dependent angiogenesis. We aimed to evaluate the long-term effects of melatonin on liver phenotype that may be mediated by changes in MT1/clock genes/miR200b/maspin/glutathione-S transferase (GST) signaling. METHODS Male wild-type and Mdr2-/- mice had access to drinking water with/without melatonin for 3 months. Liver damage, biliary proliferation/senescence, liver fibrosis, peribiliary inflammation, and angiogenesis were measured by staining in liver sections, and by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay in liver samples. We confirmed a link between MT1/clock genes/miR200b/maspin/GST/angiogenesis signaling by Ingenuity Pathway Analysis software and measured liver phenotypes and the aforementioned signaling pathway in liver samples from the mouse groups, healthy controls, and PSC patients and immortalized human PSC cholangiocytes. RESULTS Chronic administration of melatonin to Mdr2-/- mice ameliorates liver phenotypes, which were associated with decreased MT1 and clock gene expression. CONCLUSIONS Melatonin improves liver histology and restores the circadian rhythm by interaction with MT1 through decreased angiogenesis and increased maspin/GST activity.
Collapse
Affiliation(s)
- Ludovica Ceci
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Lixian Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | | | - Nan Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico," Rome, Italy
| | - Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Travis Owen
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Debjyoti Kundu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Amelia Sybenga
- Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, Burlington, Vermont
| | - Abdulkadir Isidan
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University, Bryan, Texas.
| |
Collapse
|
8
|
O’Brien A, Zhou T, White T, Medford A, Chen L, Kyritsi K, Wu N, Childs J, Stiles D, Ceci L, Chakraborty S, Ekser B, Baiocchi L, Carpino G, Gaudio E, Wu C, Kennedy L, Francis H, Alpini G, Glaser S. FGF1 Signaling Modulates Biliary Injury and Liver Fibrosis in the Mdr2 -/- Mouse Model of Primary Sclerosing Cholangitis. Hepatol Commun 2022; 6:1574-1588. [PMID: 35271760 PMCID: PMC9234675 DOI: 10.1002/hep4.1909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 12/21/2021] [Accepted: 12/26/2021] [Indexed: 11/16/2022] Open
Abstract
Fibroblast growth factor 1 (FGF1) belongs to a family of growth factors involved in cellular growth and division. MicroRNA 16 (miR-16) is a regulator of gene expression, which is dysregulated during liver injury and insult. However, the role of FGF1 in the progression of biliary proliferation, senescence, fibrosis, inflammation, angiogenesis, and its potential interaction with miR-16, are unknown. In vivo studies were performed in male bile duct-ligated (BDL, 12-week-old) mice, multidrug resistance 2 knockout (Mdr2-/-) mice (10-week-old), and their corresponding controls, treated with recombinant human FGF1 (rhFGF1), fibroblast growth factor receptor (FGFR) antagonist (AZD4547), or anti-FGF1 monoclonal antibody (mAb). In vitro, the human cholangiocyte cell line (H69) and human hepatic stellate cells (HSCs) were used to determine the expression of proliferation, fibrosis, angiogenesis, and inflammatory genes following rhFGF1 treatment. PSC patient and control livers were used to evaluate FGF1 and miR-16 expression. Intrahepatic bile duct mass (IBDM), along with hepatic fibrosis and inflammation, increased in BDL mice treated with rhFGF1, with a corresponding decrease in miR-16, while treatment with AZD4547 or anti-FGF1 mAb decreased hepatic fibrosis, IBDM, and inflammation in BDL and Mdr2-/- mice. In vitro, H69 and HSCs treated with rhFGF1 had increased expression of proliferation, fibrosis, and inflammatory markers. PSC samples also showed increased FGF1 and FGFRs with corresponding decreases in miR-16 compared with healthy controls. Conclusion: Our study demonstrates that suppression of FGF1 and miR-16 signaling decreases the presence of hepatic fibrosis, biliary proliferation, inflammation, senescence, and angiogenesis. Targeting the FGF1 and miR-16 axis may provide therapeutic options in treating cholangiopathies such as PSC.
Collapse
Affiliation(s)
- April O’Brien
- Department of Medical PhysiologyTexas A&M University College of MedicineBryanTXUSA
| | - Tianhao Zhou
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisINUSA
| | - Tori White
- Department of Medical PhysiologyTexas A&M University College of MedicineBryanTXUSA
| | - Abigail Medford
- Department of Medical PhysiologyTexas A&M University College of MedicineBryanTXUSA
| | - Lixian Chen
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisINUSA
| | - Konstantina Kyritsi
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisINUSA
| | - Nan Wu
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisINUSA
| | - Jonathan Childs
- Department of Medical PhysiologyTexas A&M University College of MedicineBryanTXUSA
| | - Danaleigh Stiles
- Department of Medical PhysiologyTexas A&M University College of MedicineBryanTXUSA
| | - Ludovica Ceci
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisINUSA
| | - Sanjukta Chakraborty
- Department of Medical PhysiologyTexas A&M University College of MedicineBryanTXUSA
| | - Burcin Ekser
- Division of Transplant SurgeryDepartment of SurgeryIndiana University School of MedicineIndianapolisINUSA
| | - Leonardo Baiocchi
- Hepatology UnitDept of MedicineUniversity of Tor Vergata RomeRomeItaly
| | - Guido Carpino
- Department of MovementHuman and Health Sciences, University of Rome “Foro Italico”RomeItaly
| | - Eugenio Gaudio
- Department of AnatomicalHistologicalForensic Medicine and Orthopedics SciencesSapienza University of RomeRomeItaly
| | - Chaodong Wu
- Department of NutritionTexas A&M UniversityCollege StationTXUSA
| | - Lindsey Kennedy
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisINUSA
- ResearchRichard L. Roudebush VA Medical CenterIndianapolisINUSA
| | - Heather Francis
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisINUSA
- ResearchRichard L. Roudebush VA Medical CenterIndianapolisINUSA
| | - Gianfranco Alpini
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisINUSA
- ResearchRichard L. Roudebush VA Medical CenterIndianapolisINUSA
| | - Shannon Glaser
- Department of Medical PhysiologyTexas A&M University College of MedicineBryanTXUSA
| |
Collapse
|
9
|
Muqaku B, Oeckl P. Peptidomic Approaches and Observations in Neurodegenerative Diseases. Int J Mol Sci 2022; 23:ijms23137332. [PMID: 35806335 PMCID: PMC9266836 DOI: 10.3390/ijms23137332] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/16/2022] [Accepted: 06/28/2022] [Indexed: 02/04/2023] Open
Abstract
Mass spectrometry (MS), with its immense technological developments over the last two decades, has emerged as an unavoidable technique in analyzing biomolecules such as proteins and peptides. Its multiplexing capability and explorative approach make it a valuable tool for analyzing complex clinical samples concerning biomarker research and investigating pathophysiological mechanisms. Peptides regulate various biological processes, and several of them play a critical role in many disease-related pathological conditions. One important example in neurodegenerative diseases is the accumulation of amyloid-beta peptides (Aβ) in the brain of Alzheimer’s disease (AD) patients. When investigating brain function and brain-related pathologies, such as neurodegenerative diseases, cerebrospinal fluid (CSF) represents the most suitable sample because of its direct contact with the brain. In this review, we evaluate publications applying peptidomics analysis to CSF samples, focusing on neurodegenerative diseases. We describe the methodology of peptidomics analysis and give an overview of the achievements of CSF peptidomics over the years. Finally, publications reporting peptides regulated in AD are discussed.
Collapse
Affiliation(s)
- Besnik Muqaku
- German Center for Neurodegenerative Diseases (DZNE e.V.), 89081 Ulm, Germany;
| | - Patrick Oeckl
- German Center for Neurodegenerative Diseases (DZNE e.V.), 89081 Ulm, Germany;
- Department of Neurology, Ulm University Hospital, 89081 Ulm, Germany
- Correspondence: ; Tel.: +49-731-500-63143
| |
Collapse
|
10
|
Huang Y, Zhang S, Weng JF, Huang D, Gu WL. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis. Open Med (Wars) 2022; 17:915-929. [PMID: 35647306 PMCID: PMC9106112 DOI: 10.1515/med-2022-0481] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 03/03/2022] [Accepted: 03/29/2022] [Indexed: 11/17/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is a cholangiopathy caused by genetic and microenvironmental changes, such as bile homeostasis disorders and microbiota dysbiosis. Therapeutic options are limited, and proven surveillance strategies are currently lacking. Clinically, PSC presents as alternating strictures and dilatations of biliary ducts, resulting in the typical “beaded” appearance seen on cholangiography. The pathogenesis of PSC is still unclear, but cholangiocytes play an essential role in disease development, wherein a reactive phenotype is caused by the secretion of neuroendocrine factors. The liver–gut axis is implicated in the pathogenesis of PSC owing to the dysbiosis of microbiota, but the underlying mechanism is still poorly understood. Alterations in cholangiocyte responses and related signalling pathways during PSC progression were elucidated by recent research, providing novel therapeutic targets. In this review, we summarise the currently known underlying mechanisms of PSC pathogenesis caused by the dysbiosis of microbiota and newly reported information regarding cholangiocytes in PSC. We also summarise recently reported in vitro and in vivo models for studying the pathogenesis of PSC.
Collapse
Affiliation(s)
- Yu Huang
- Department of Surgery, Guangzhou First People's Hospital, No. 1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 510180, People's Republic of China
| | - Shuai Zhang
- Department of Surgery, Guangzhou First People's Hospital, Guangdong 510180, People's Republic of China
| | - Jie-Feng Weng
- Department of Surgery, Guangzhou First People's Hospital, Guangdong 510180, People's Republic of China
| | - Di Huang
- Department of Surgery, Guangzhou First People's Hospital, Guangdong 510180, People's Republic of China
| | - Wei-Li Gu
- Department of Surgery, Guangzhou First People's Hospital, No. 1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 510180, People's Republic of China
| |
Collapse
|
11
|
Liver secretin receptor predicts portoenterostomy outcomes and liver injury in biliary atresia. Sci Rep 2022; 12:7233. [PMID: 35508528 PMCID: PMC9068784 DOI: 10.1038/s41598-022-11140-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 04/12/2022] [Indexed: 11/09/2022] Open
Abstract
Biliary atresia (BA) is a chronic neonatal cholangiopathy characterized by fibroinflammatory bile duct damage. Reliable biomarkers for predicting native liver survival (NLS) following portoenterostomy (PE) surgery are lacking. Herein we explore the utility of 22 preidentified profibrotic molecules closely connected to ductular reaction (DR) and prevailing after successful PE (SPE), in predicting PE outcomes and liver injury. We used qPCR and immunohistochemistry in a BA cohort including liver samples obtained at PE (n = 53) and during postoperative follow-up after SPE (n = 25). Of the 13 genes over-expressed in relation to cholestatic age-matched controls at PE, only secretin receptor (SCTR) expression predicted cumulative 5-year NLS and clearance of jaundice. Patients in the highest SCTR expression tertile showed 34-55% lower NLS than other groups at 1-5 years after PE (P = 0.006-0.04 for each year). SCTR expression was also significantly lower [42 (24-63) vs 75 (39-107) fold, P = 0.015] among those who normalized their serum bilirubin after PE. Liver SCTR expression localized in cholangiocytes and correlated positively with liver fibrosis, DR, and transcriptional markers of fibrosis (ACTA2) and cholangiocytes (KRT7, KRT19) both at PE and after SPE. SCTR is a promising prognostic marker for PE outcomes and associates with liver injury in BA.
Collapse
|
12
|
Abstract
Yes-associated protein 1 (YAP1) is a transcriptional coactivator that activates transcriptional enhanced associate domain transcription factors upon inactivation of the Hippo signaling pathway, to regulate biological processes like proliferation, survival, and differentiation. YAP1 is most prominently expressed in biliary epithelial cells (BECs) in normal adult livers and during development. In the current review, we will discuss the multiple roles of YAP1 in the development and morphogenesis of bile ducts inside and outside the liver, as well as in orchestrating the cholangiocyte repair response to biliary injury. We will review how biliary repair can occur through the process of hepatocyte-to-BEC transdifferentiation and how YAP1 is pertinent to this process. We will also discuss the liver's capacity for metabolic reprogramming as an adaptive mechanism in extreme cholestasis, such as when intrahepatic bile ducts are absent due to YAP1 loss from hepatic progenitors. Finally, we will discuss the roles of YAP1 in the context of pediatric pathologies afflicting bile ducts, such as Alagille syndrome and biliary atresia. In conclusion, we will comprehensively discuss the spatiotemporal roles of YAP1 in biliary development and repair after biliary injury while describing key interactions with other well-known developmental pathways.
Collapse
Affiliation(s)
- Laura Molina
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine
| | - Kari Nejak-Bowen
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine,Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Satdarshan P. Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine,Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania,Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh and UPMC, Pittsburgh, Pennsylvania
| |
Collapse
|
13
|
Meadows V, Baiocchi L, Kundu D, Sato K, Fuentes Y, Wu C, Chakraborty S, Glaser S, Alpini G, Kennedy L, Francis H. Biliary Epithelial Senescence in Liver Disease: There Will Be SASP. Front Mol Biosci 2021; 8:803098. [PMID: 34993234 PMCID: PMC8724525 DOI: 10.3389/fmolb.2021.803098] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Cellular senescence is a pathophysiological phenomenon in which proliferative cells enter cell cycle arrest following DNA damage and other stress signals. Natural, permanent DNA damage can occur after repetitive cell division; however, acute stress or other injuries can push cells into premature senescence and eventually a senescence-associated secretory phenotype (SASP). In recent years, there has been increased evidence for the role of premature senescence in disease progression including diabetes, cardiac diseases, and end-stage liver diseases including cholestasis. Liver size and function change with aging, and presumably with increasing cellular senescence, so it is important to understand the mechanisms by which cellular senescence affects the functional nature of the liver in health and disease. As well, cells in a SASP state secrete a multitude of inflammatory and pro-fibrogenic factors that modulate the microenvironment. Cellular SASP and the associated, secreted factors have been implicated in the progression of liver diseases, such as cholestatic injury that target the biliary epithelial cells (i.e., cholangiocytes) lining the bile ducts. Indeed, cholangiocyte senescence/SASP is proposed to be a driver of disease phenotypes in a variety of liver injuries. Within this review, we will discuss the impact of cholangiocyte senescence and SASP in the pathogenesis of cholestatic disorders.
Collapse
Affiliation(s)
- Vik Meadows
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States
| | | | - Debjyoti Kundu
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States
| | - Keisaku Sato
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States
| | - Yessenia Fuentes
- Clinical and Translational Sciences Institute, STEM GEHCS Program, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Chaodong Wu
- Department of Nutrition, Texas A&M University, College Station, TX, United States
| | - Sanjukta Chakraborty
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, United States
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, United States
| | - Gianfranco Alpini
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States
| | - Lindsey Kennedy
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States
| | - Heather Francis
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States
| |
Collapse
|
14
|
Baiocchi L, Lenci I, Milana M, Kennedy L, Sato K, Zhang W, Ekser B, Ceci L, Meadows V, Glaser S, Alpini G, Francis H. Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment? Cells 2021; 10:1692. [PMID: 34359861 PMCID: PMC8303798 DOI: 10.3390/cells10071692] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/30/2021] [Accepted: 06/30/2021] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinoma is a lethal disease with scarce response to current systemic therapy. The rare occurrence and large heterogeneity of this cancer, together with poor knowledge of its molecular mechanisms, are elements contributing to the difficulties in finding an appropriate cure. Cholangiocytes (and their cellular precursors) are considered the liver component giving rise to cholangiocarcinoma. These cells respond to several hormones, neuropeptides and molecular stimuli employing the cAMP/PKA system for the translation of messages in the intracellular space. For instance, in physiological conditions, stimulation of the secretin receptor determines an increase of intracellular levels of cAMP, thus activating a series of molecular events, finally determining in bicarbonate-enriched choleresis. However, activation of the same receptor during cholangiocytes' injury promotes cellular growth again, using cAMP as the second messenger. Since several scientific pieces of evidence link cAMP signaling system to cholangiocytes' proliferation, the possible changes of this pathway during cancer growth also seem relevant. In this review, we summarize the current findings regarding the cAMP pathway and its role in biliary normal and neoplastic cell proliferation. Perspectives for targeting the cAMP machinery in cholangiocarcinoma therapy are also discussed.
Collapse
Affiliation(s)
- Leonardo Baiocchi
- Hepatology Unit, University of Tor Vergata, 00133 Rome, Italy; (L.B.); (I.L.); (M.M.)
| | - Ilaria Lenci
- Hepatology Unit, University of Tor Vergata, 00133 Rome, Italy; (L.B.); (I.L.); (M.M.)
| | - Martina Milana
- Hepatology Unit, University of Tor Vergata, 00133 Rome, Italy; (L.B.); (I.L.); (M.M.)
| | - Lindsey Kennedy
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN 46202, USA; (L.K.); (K.S.); (L.C.); (V.M.)
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Keisaku Sato
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN 46202, USA; (L.K.); (K.S.); (L.C.); (V.M.)
| | - Wenjun Zhang
- Division of Transplant Surgery, Department of Surgery, Indiana University, Indianapolis, IN 46202, USA; (W.Z.); (B.E.)
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University, Indianapolis, IN 46202, USA; (W.Z.); (B.E.)
| | - Ludovica Ceci
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN 46202, USA; (L.K.); (K.S.); (L.C.); (V.M.)
| | - Vik Meadows
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN 46202, USA; (L.K.); (K.S.); (L.C.); (V.M.)
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX 77807, USA;
| | - Gianfranco Alpini
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN 46202, USA; (L.K.); (K.S.); (L.C.); (V.M.)
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Heather Francis
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN 46202, USA; (L.K.); (K.S.); (L.C.); (V.M.)
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| |
Collapse
|
15
|
Baiocchi L, Glaser S, Francis H, Kennedy L, Felli E, Alpini G, Gracia‐Sancho J. Impact of Aging on Liver Cells and Liver Disease: Focus on the Biliary and Vascular Compartments. Hepatol Commun 2021; 5:1125-1137. [PMID: 34278165 PMCID: PMC8279468 DOI: 10.1002/hep4.1725] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/26/2021] [Accepted: 03/16/2021] [Indexed: 12/11/2022] Open
Abstract
The aging process is represented by the time-dependent decay in physiologic functions of living beings. Major interest has been focused in recent years on the determinants of this progressive condition due to its correlative relationship with the onset of diseases. Several hallmark features have been observed in aging, such as genetic alterations, mitochondrial impairment, and telomere shortening. At the cellular level, a senescent phenotype has been identified in response to aging that is characterized by a flat appearance, proliferative arrest, and production of specific molecules. The net effect of these cells in the course of diseases is an argument of debate. In fact, while the onset of a senescent phenotype may prevent tumor spreading, these cells appear to support pathological processes in some conditions. Several studies are now focused on clarifying the specific molecular pathways of aging/senescence in different cells, tissues, or organs. Biliary and vascular components, within the liver, have emerged as important determinants of some form of liver disease. In this review we summarize the most recent achievements on aging/senescence, focusing on the biliary and vascular liver system. Conclusion: Several findings, in both preclinical animal models and on human liver specimens, converge in supporting the presence of specific aging hallmarks in the diseases involving these hepatic compartments.
Collapse
Affiliation(s)
- Leonardo Baiocchi
- Hepatology UnitDepartment of MedicineUniversity of Tor VergataRomeItaly
| | - Shannon Glaser
- Medical PhysiologyTexas A&M College of MedicineBryanTXUSA
| | - Heather Francis
- Hepatology and MedicineIndiana UniversityIndianapolisINUSA
- Richard L. Roudebush VA Medical CenterIndianapolisINUSA
| | - Lindsey Kennedy
- Hepatology and MedicineIndiana UniversityIndianapolisINUSA
- Richard L. Roudebush VA Medical CenterIndianapolisINUSA
| | - Eric Felli
- HepatologyDepartment of Biomedical ResearchInselspitalBernSwitzerland
| | - Gianfranco Alpini
- Hepatology and MedicineIndiana UniversityIndianapolisINUSA
- Richard L. Roudebush VA Medical CenterIndianapolisINUSA
| | - Jordi Gracia‐Sancho
- Liver Vascular BiologyIDIBAPS Biomedical Research Institute and CIBEREHDBarcelonaSpain
- HepatologyDepartment of Biomedical ResearchInselspitalBernSwitzerland
| |
Collapse
|
16
|
Tian X, Wang Y, Lu Y, Wang W, Du J, Chen S, Zhou H, Cai W, Xiao Y. Conditional depletion of macrophages ameliorates cholestatic liver injury and fibrosis via lncRNA-H19. Cell Death Dis 2021; 12:646. [PMID: 34168124 PMCID: PMC8225916 DOI: 10.1038/s41419-021-03931-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 12/13/2022]
Abstract
Although macrophages are recognized as important players in the pathogenesis of chronic liver diseases, their roles in cholestatic liver fibrosis remain incompletely understood. We previously reported that long noncoding RNA-H19 (lncRNA-H19) contributes to cholangiocyte proliferation and cholestatic liver fibrosis of biliary atresia (BA). We here show that monocyte/macrophage CD11B mRNA levels are increased significantly in livers of BA patients and positively correlated with the progression of liver inflammation and fibrosis. The macrophages increasingly infiltrate and accumulate in the fibrotic niche and peribiliary areas in livers of BA patients. Selective depletion of macrophages using the transgenic CD11b-diphtheria toxin receptor (CD11b-DTR) mice halts bile duct ligation (BDL)-induced progression of liver damage and fibrosis. Meanwhile, macrophage depletion significantly reduces the BDL-induced hepatic lncRNA-H19. Overexpression of H19 in livers using adeno-associated virus serotype 9 (AAV9) counteracts the effects of macrophage depletion on liver fibrosis and cholangiocyte proliferation. Additionally, both H19 knockout (H19-/-) and conditional deletion of H19 in macrophage (H19ΔCD11B) significantly depress the macrophage polarization and recruitment. lncRNA-H19 overexpressed in THP-1 macrophages enhance expression of Rho-GTPase CDC42 and RhoA. In conclusions, selectively depletion of macrophages suppresses cholestatic liver injuries and fibrosis via the lncRNA-H19 and represents a potential therapeutic strategy for rapid liver fibrosis in BA patients.
Collapse
MESH Headings
- Animals
- CD11b Antigen/genetics
- CD11b Antigen/metabolism
- Case-Control Studies
- Cell Proliferation
- Cholestasis/complications
- Heparin-binding EGF-like Growth Factor/genetics
- Heparin-binding EGF-like Growth Factor/metabolism
- Humans
- Liver/metabolism
- Liver/pathology
- Liver Cirrhosis, Biliary/genetics
- Liver Cirrhosis, Biliary/metabolism
- Liver Cirrhosis, Biliary/pathology
- Liver Cirrhosis, Biliary/prevention & control
- Liver Cirrhosis, Experimental/genetics
- Liver Cirrhosis, Experimental/metabolism
- Liver Cirrhosis, Experimental/pathology
- Liver Cirrhosis, Experimental/prevention & control
- Macrophage Activation
- Macrophages/metabolism
- Macrophages/pathology
- Mice, Inbred C57BL
- Mice, Knockout
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- THP-1 Cells
- cdc42 GTP-Binding Protein/genetics
- cdc42 GTP-Binding Protein/metabolism
- rhoA GTP-Binding Protein/genetics
- rhoA GTP-Binding Protein/metabolism
- Mice
Collapse
Affiliation(s)
- Xinbei Tian
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Wang
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Ying Lu
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
- Shanghai Institute of Pediatric Research, Shanghai, China
| | - Weipeng Wang
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Du
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
- Shanghai Institute of Pediatric Research, Shanghai, China
| | - Shanshan Chen
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Huiping Zhou
- Department of Microbiology and Immunology and McGuire Veterans AfSfairs Medical Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Wei Cai
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
- Shanghai Institute of Pediatric Research, Shanghai, China.
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Yongtao Xiao
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
- Shanghai Institute of Pediatric Research, Shanghai, China.
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| |
Collapse
|
17
|
Baiocchi L, Sato K, Ekser B, Kennedy L, Francis H, Ceci L, Lenci I, Alvaro D, Franchitto A, Onori P, Gaudio E, Wu C, Chakraborty S, Glaser S, Alpini G. Cholangiocarcinoma: bridging the translational gap from preclinical to clinical development and implications for future therapy. Expert Opin Investig Drugs 2021; 30:365-375. [PMID: 33226854 PMCID: PMC8441992 DOI: 10.1080/13543784.2021.1854725] [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: 09/18/2020] [Accepted: 11/19/2020] [Indexed: 12/17/2022]
Abstract
Introduction: Cholangiocarcinoma (CCA) is a devastating liver tumor with a poor prognosis. While less than 50% of the patients with CCA may benefit from surgical resection, the rest undergoes chemotherapy with disappointing results (mean survival <2 years). Alternative pharmacological treatments are needed to improve the outcomes in patients with CCA.Areas covered: In this review, we discuss CCA-related (1) experimental systems used in preclinical studies; (2) pharmacological targets identified by genetic analysis; (3) results obtained in preliminary trials in human with their pros and cons; and (4) possible targeting of endocrinal modulation. A PubMed bibliographic search matching the term 'cholangiocarcinoma' with 'experimental model', 'preclinical model', 'genetic target', 'targeted therapy', 'clinical trial', or 'translational research' was conducted and manuscripts published between 2010 and 2020 were retrieved for reading and reviewing.Expert opinion: Several factors contribute to the translational gap between bench research and clinical practice in CCA. The tumor heterogeneity, lack of a preclinical model recapitulating the different features of CCA, and difficult patient enrollment in clinical trials are elements to consider for basic and clinical research in CCA. Establishment of international networks formed by experts in the field of CCA may improve future research and its translational findings on patients.
Collapse
Affiliation(s)
- Leonardo Baiocchi
- Liver Unit, Department of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Keisaku Sato
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Lindsey Kennedy
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
- Richard L. Roudebush VA Medical Center, Indianapolis, IN
| | - Heather Francis
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
- Richard L. Roudebush VA Medical Center, Indianapolis, IN
| | - Ludovica Ceci
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | - Ilaria Lenci
- Liver Unit, Department of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Domenico Alvaro
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Antonio Franchitto
- Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Chaodong Wu
- Department of Nutrition, Texas A&M University, College Station, TX
| | | | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University, Bryan, TX
| | - Gianfranco Alpini
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
- Richard L. Roudebush VA Medical Center, Indianapolis, IN
| |
Collapse
|