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El-Belkasy RO, El-Kemary M, Hanafy NAN. Evaluating the role of targeted silymarin loaded hyaluronic acid/protein nanoparticles in activating hepatic progenitor stem cells for liver regeneration after CCl 4-induced liver damage. Int J Biol Macromol 2025; 309:142837. [PMID: 40188925 DOI: 10.1016/j.ijbiomac.2025.142837] [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: 08/02/2024] [Revised: 03/26/2025] [Accepted: 04/02/2025] [Indexed: 04/12/2025]
Abstract
BACKGROUND Silymarin is a natural flavonoid component isolated from the Silybum Marianum (Milk Thistle) plant with multiple pharmacological activities. We investigated its anti-fibrotic effect on the liver and demonstrated its role in activating hepatic progenitor stem cells during liver regeneration. METHODS Hybrid polymeric protein nanoparticles were prepared by loading silymarin with an albumin-hyaluronic acid complex to achieve stem cell targeting and increase silymarin's bioavailability. RESULTS TEM, Zeta potential, DLS, UV-visible spectrophotometer, Fluorescence analysis, and FTIR verified the successful formation of nanoparticles and efficient encapsulation. In the present study, The liver fibrotic model was induced by the intraperitoneal injection of carbon tetrachloride, followed by the injection of silymarin NPs into mice twice a week for 4 weeks. We evaluated the expression of hepatic fibrosis markers such as (Collagen I, TGF-β1, SMAD3, and MMP-3) and hepatic progenitor stem cell activation markers such as (HNF1β, FOXl1, CD90, Vimentin, and CD105). The results showed that the targeted silymarin NPs caused significant suppression and downregulation of Collagen I, TGF-β, SMAD-3, and MMP-3 and upregulation of the hepatic progenitor stem cells markers HNF1β, FOXl1, CD90, Vimentin, and CD105. They also didn't induce expression of IL-6, IL-1β, and TNF-α, proving that they cause no signs of inflammation. CONCLUSION The novel point is that these results demonstrated that the targeted Silymarin NPs not only could efficiently alleviate CCl4-induced liver fibrosis more than using only free silymarin; by inhibiting the TGF-β/Smad-3 signaling pathway, but also could activate hepatic progenitor stem cells causing liver regeneration.
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Affiliation(s)
- Rawan O El-Belkasy
- Nanomedicine Department, Institute of Nanoscience and Nanotechnology, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Maged El-Kemary
- Nanomedicine Department, Institute of Nanoscience and Nanotechnology, Kafrelsheikh University, Kafrelsheikh 33516, Egypt; Nile Valley University, Fayoum 63518, Egypt
| | - Nemany A N Hanafy
- Group of Bionanotechnology and Molecular Cell Biology, Nanomedicine Department, Institute of Nanoscience and Nanotechnology, Kafrelsheikh University, 33516 Kafrelsheikh, Egypt; NanoBio4Can program, Koç University Research Center for Translational Medicine (KUTTAM), 34450 Istanbul, Turkey.
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Gupta V, Sehrawat TS, Pinzani M, Strazzabosco M. Portal Fibrosis and the Ductular Reaction: Pathophysiological Role in the Progression of Liver Disease and Translational Opportunities. Gastroenterology 2025; 168:675-690. [PMID: 39251168 PMCID: PMC11885590 DOI: 10.1053/j.gastro.2024.07.044] [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: 03/18/2024] [Revised: 06/27/2024] [Accepted: 07/20/2024] [Indexed: 09/11/2024]
Abstract
A consistent feature of chronic liver diseases and the hallmark of pathologic repair is the so-called "ductular reaction." This is a histologic abnormality characterized by an expansion of dysmorphic cholangiocytes inside and around portal spaces infiltrated by inflammatory, mesenchymal, and vascular cells. The ductular reaction is a highly regulated response based on the reactivation of morphogenetic signaling mechanisms and a complex crosstalk among a multitude of cell types. The nature and mechanism of these exchanges determine the difference between healthy regenerative liver repair and pathologic repair. An orchestrated signaling among cell types directs mesenchymal cells to deposit a specific extracellular matrix with distinct physical and biochemical properties defined as portal fibrosis. Progression of fibrosis leads to vast architectural and vascular changes known as "liver cirrhosis." The signals regulating the ecology of this microenvironment are just beginning to be addressed. Contrary to the tumor microenvironment, immune modulation inside this "benign" microenvironment is scarcely known. One of the reasons for this is that both the ductular reaction and portal fibrosis have been primarily considered a manifestation of cholestatic liver disease, whereas this phenomenon is also present, albeit with distinctive features, in all chronic human liver diseases. Novel human-derived cellular models and progress in "omics" technologies are increasing our knowledge at a fast pace. Most importantly, this knowledge is on the edge of generating new diagnostic and therapeutic advances. Here, we will critically review the latest advances, in terms of mechanisms, pathophysiology, and treatment prospects. In addition, we will delineate future avenues of research, including innovative translational opportunities.
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Affiliation(s)
- Vikas Gupta
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, Connecticut
| | - Tejasav S Sehrawat
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, Connecticut
| | - Massimo Pinzani
- UCL Institute for Liver & Digestive Health, Royal Free Hospital, London, United Kingdom; University of Pittsburgh Medical Center-Mediterranean Institute for Transplantation and Highly Specialized Therapies, Palermo, Italy
| | - Mario Strazzabosco
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, Connecticut.
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3
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Li Z, Sun X. Epigenetic regulation in liver regeneration. Life Sci 2024; 353:122924. [PMID: 39038511 DOI: 10.1016/j.lfs.2024.122924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 07/24/2024]
Abstract
The liver is considered unique in its enormous capacity for regeneration and self-repair. In contrast to other regenerative organs (i.e., skin, skeletal muscle, and intestine), whether the adult liver contains a defined department of stem cells is still controversial. In order to compensate for the massive loss of hepatocytes following liver injury, the liver processes a precisely controlled transcriptional reprogram that can trigger cell proliferation and cell-fate switch. Epigenetic events are thought to regulate the organization of chromatin architecture and gene transcription during the liver regenerative process. In this review, we will summarize how changes to the chromatin by epigenetic modifiers are translated into cell fate transitions to restore liver homeostasis during liver regeneration.
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Affiliation(s)
- Zilong Li
- Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117 Jinan, Shandong, China; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021 Jinan, Shandong, China.
| | - Xinyue Sun
- Department of Pharmacology, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China
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Gu Y, Mu Z, Chen Y, Wu C, Shi J, Bai N. Therapeutic potential of ADSCs in diabetic wounds: a proteomics-based approach. Front Cell Dev Biol 2024; 12:1468220. [PMID: 39345337 PMCID: PMC11427884 DOI: 10.3389/fcell.2024.1468220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Accepted: 08/26/2024] [Indexed: 10/01/2024] Open
Abstract
Background Diabetes mellitus (DM), a chronic metabolic disease characterized by elevated blood sugar, leads to delayed or non-healing wounds, increasing amputation risks, and placing a significant burden on patients and society. While extensive research has been conducted on adipose-derived stem cells (ADSCs) for promoting wound healing, there is a scarcity of studies focusing on diabetic wounds, particularly those employing proteomics and bioinformatics approaches. Objective This study aimed to investigate the mechanisms by which ADSCs promote diabetic wound healing using proteomics and bioinformatics techniques. Methods Healthy rat fat tissue was used to isolate ADSCs. A T2DM rat model with back wounds was established. The experimental group received ADSC injections around the wound, while the control group received PBS injections. Wound healing rates were documented and photographed on days 0, 3, 7, 10, and 14. On day 7, wound tissues were excised for HE and Masson's staining. Additionally, on day 7, tissues were analyzed for protein quantification using 4D-DIA, with subsequent GO and KEGG analyses for differentially expressed proteins (DEPs) and protein-protein interaction (PPI) network analysis using STRING database (String v11.5). Finally, Western blot experiments were performed on day 7 wounds to verify target proteins. Results and Conclusions In all measured days postoperatively, the wound healing rate was significantly higher in the ADSC group than in the PBS group (day 7: p < 0.001, day 10: p = 0.001, day 14: p < 0.01), except on day 3 (p > 0.05). Proteomic analysis identified 474 differentially expressed proteins, with 224 key proteins after PPI analysis (78 upregulated and 146 downregulated in the ADSC group). The main cellular locations of these proteins were "cellular anatomical entity" and "protein-containing complex", while the biological processes were "cellular processes" and "biological regulation". The primary molecular functions were "binding" and "catalytic activity", with GO enrichment focused on "Wnt-protein binding", "neural development", and "collagen-containing extracellular matrix". Further analysis of PPI network nodes using LASSO regression identified Thy1 and Wls proteins, significantly upregulated in the ADSC group, as potentially crucial targets for ADSC application in diabetic wound treatment.
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Affiliation(s)
- Yuan Gu
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Zelan Mu
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Yuanzheng Chen
- Department of Burns and Plastic Surgery, Emergency General Hospital, Beijing, China
| | - Can Wu
- Medical Cosmetic Plastic Surgery, Linyi People′s Hospital, Linyi, China
| | - Jie Shi
- Plastic and Cosmetic Surgery, People′s Hospital of Liaoning Province, Shenyang, China
| | - Nan Bai
- Medical Cosmetic Plastic Surgery, Linyi People′s Hospital, Linyi, China
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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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Faccioli LA, Dias ML, Martins-Santos R, Paredes BD, Takiya CM, dos Santos Goldenberg RC. Resident Liver Stem Cells. RESIDENT STEM CELLS AND REGENERATIVE THERAPY 2024:23-51. [DOI: 10.1016/b978-0-443-15289-4.00015-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Martinez Lyons A, Boulter L. NOTCH signalling - a core regulator of bile duct disease? Dis Model Mech 2023; 16:dmm050231. [PMID: 37605966 PMCID: PMC10461466 DOI: 10.1242/dmm.050231] [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: 08/23/2023] Open
Abstract
The Notch signalling pathway is an evolutionarily conserved mechanism of cell-cell communication that mediates cellular proliferation, fate determination and maintenance of stem/progenitor cell populations across tissues. Although it was originally identified as a critical regulator of embryonic liver development, NOTCH signalling activation has been associated with the pathogenesis of a number of paediatric and adult liver diseases. It remains unclear, however, what role NOTCH actually plays in these pathophysiological processes and whether NOTCH activity represents the reactivation of a conserved developmental programme that is essential for adult tissue repair. In this Review, we explore the concepts that NOTCH signalling reactivation in the biliary epithelium is a reiterative and essential response to bile duct damage and that, in disease contexts in which biliary epithelial cells need to be regenerated, NOTCH signalling supports ductular regrowth. Furthermore, we evaluate the recent literature on NOTCH signalling as a critical factor in progenitor-mediated hepatocyte regeneration, which indicates that the mitogenic role for NOTCH signalling in biliary epithelial cell proliferation has also been co-opted to support other forms of epithelial regeneration in the adult liver.
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Affiliation(s)
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Cancer, Edinburgh EH4 2XU, UK
- CRUK Scottish Centre, Institute of Genetics and Cancer, Edinburgh EH4 2XU, UK
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He YH, Pan JX, Xu LM, Gu T, Chen YW. Ductular reaction in non-alcoholic fatty liver disease: When Macbeth is perverted. World J Hepatol 2023; 15:725-740. [PMID: 37397935 PMCID: PMC10308290 DOI: 10.4254/wjh.v15.i6.725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/03/2023] [Accepted: 04/24/2023] [Indexed: 06/25/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) or metabolic (dysfunction)-associated fatty liver disease is the leading cause of chronic liver diseases defined as a disease spectrum comprising hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and hepatic carcinoma. NASH, characterized by hepatocyte injury, steatosis, inflammation, and fibrosis, is associated with NAFLD prognosis. Ductular reaction (DR) is a common compensatory reaction associated with liver injury, which involves the hepatic progenitor cells (HPCs), hepatic stellate cells, myofibroblasts, inflammatory cells (such as macrophages), and their secreted substances. Recently, several studies have shown that the extent of DR parallels the stage of NASH and fibrosis. This review summarizes previous research on the correlation between DR and NASH, the potential interplay mechanism driving HPC differentiation, and NASH progression.
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Affiliation(s)
- Yang-Huan He
- Department of Gastroenterology and Department of Geriatrics, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Jia-Xing Pan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Lei-Ming Xu
- Department of Gastroenterology, School of Medicine, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200092, China
| | - Ting Gu
- Department of Gastroenterology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Yuan-Wen Chen
- Department of Gastroenterology and Department of Geriatrics, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
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Liu W, Gao L, Hou X, Feng S, Yan H, Pan H, Zhang S, Yang X, Jiang J, Ye F, Zhao Q, Wei L, Han Z. TWEAK Signaling-Induced ID1 Expression Drives Malignant Transformation of Hepatic Progenitor Cells During Hepatocarcinogenesis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300350. [PMID: 37085918 PMCID: PMC10288241 DOI: 10.1002/advs.202300350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/14/2023] [Indexed: 05/03/2023]
Abstract
The malignant transformation of hepatic progenitor cells (HPCs) in the inflammatory microenvironment is the root cause of hepatocarcinogenesis. However, the potential molecular mechanisms are still elusive. The HPCs subgroup is identified by single-cell RNA (scRNA) sequencing and the phenotype of HPCs is investigated in the primary HCC model. Bulk RNA sequencing (RNA-seq) and proteomic analyses are also performed on HPC-derived organoids. It is found that tumors are formed from HPCs in peritumor tissue at the 16th week in a HCC model. Furthermore, it is confirmed that the macrophage-derived TWEAK/Fn14 promoted the expression of inhibitor of differentiation-1 (ID1) in HPCs via NF-κB signaling and a high level of ID1 induced aberrant differentiation of HPCs. Mechanistically, ID1 suppressed differentiation and promoted proliferation in HPCs through the inhibition of HNF4α and Rap1GAP transcriptions. Finally, scRNA sequencing of HCC patients and investigation of clinical specimens also verified that the expression of ID1 is correlated with aberrant differentiation of HPCs into cancer stem cells, patients with high levels of ID1 in HPCs showed a poorer prognosis. This study provides important intervention targets and a theoretical basis for the clinical diagnosis and treatment of HCC.
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Affiliation(s)
- Wenting Liu
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Lu Gao
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Xiaojuan Hou
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Shiyao Feng
- Department of UrologySecond Affiliated HospitalAnhui Medical UniversityHefei230601P. R. China
| | - Haixin Yan
- Department of UrologySecond Affiliated HospitalAnhui Medical UniversityHefei230601P. R. China
| | - Hongyu Pan
- Department of Hepatic SurgeryThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
| | - Shichao Zhang
- Department of Hepatic SurgeryThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
| | - Xue Yang
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Jinghua Jiang
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Fei Ye
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Qiudong Zhao
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Lixin Wei
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Zhipeng Han
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
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Rizvi F, Lee YR, Diaz-Aragon R, So J, Florentino RM, Smith AR, Everton E, Ostrowska A, Jung K, Tam Y, Muramatsu H, Pardi N, Weissman D, Soto-Gutierrez A, Shin D, Gouon-Evans V. VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.17.537186. [PMID: 37131823 PMCID: PMC10153196 DOI: 10.1101/2023.04.17.537186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. Yet, during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, we propose vascular-endothelial-growth-factor A (VEGFA) as a therapeutic means to accelerate biliary epithelial cell (BEC)-to-hepatocyte conversion. Investigation in zebrafish establishes that blocking VEGF receptors abrogates BEC-driven liver repair, while VEGFA overexpression promotes it. Delivery of VEGFA via non-integrative and safe nucleoside-modified mRNA encapsulated into lipid-nanoparticles (mRNA-LNP) in acutely or chronically injured mouse livers induces robust BEC-to-hepatocyte conversion and reversion of steatosis and fibrosis. In human and murine diseased livers, we further identified VEGFA-receptor KDR-expressing BECs associated with KDR-expressing cell-derived hepatocytes. This defines KDR-expressing cells, most likely being BECs, as facultative progenitors. This study reveals novel therapeutic benefits of VEGFA delivered via nucleoside-modified mRNA-LNP, whose safety is widely validated with COVID-19 vaccines, for harnessing BEC-driven repair to potentially treat liver diseases. Highlights Complementary mouse and zebrafish models of liver injury demonstrate the therapeutic impact of VEGFA-KDR axis activation to harness BEC-driven liver regeneration.VEGFA mRNA LNPs restore two key features of the chronic liver disease in humans such as steatosis and fibrosis.Identification in human cirrhotic ESLD livers of KDR-expressing BECs adjacent to clusters of KDR+ hepatocytes suggesting their BEC origin.KDR-expressing BECs may represent facultative adult progenitor cells, a unique BEC population that has yet been uncovered.
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Shafritz DA, Ebrahimkhani MR, Oertel M. Therapeutic Cell Repopulation of the Liver: From Fetal Rat Cells to Synthetic Human Tissues. Cells 2023; 12:529. [PMID: 36831196 PMCID: PMC9954009 DOI: 10.3390/cells12040529] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/20/2023] [Accepted: 01/26/2023] [Indexed: 02/10/2023] Open
Abstract
Progenitor cells isolated from the fetal liver can provide a unique cell source to generate new healthy tissue mass. Almost 20 years ago, it was demonstrated that rat fetal liver cells repopulate the normal host liver environment via a mechanism akin to cell competition. Activin A, which is produced by hepatocytes, was identified as an important player during cell competition. Because of reduced activin receptor expression, highly proliferative fetal liver stem/progenitor cells are resistant to activin A and therefore exhibit a growth advantage compared to hepatocytes. As a result, transplanted fetal liver cells are capable of repopulating normal livers. Important for cell-based therapies, hepatic stem/progenitor cells containing repopulation potential can be separated from fetal hematopoietic cells using the cell surface marker δ-like 1 (Dlk-1). In livers with advanced fibrosis, fetal epithelial stem/progenitor cells differentiate into functional hepatic cells and out-compete injured endogenous hepatocytes, which cause anti-fibrotic effects. Although fetal liver cells efficiently repopulate the liver, they will likely not be used for human cell transplantation. Thus, utilizing the underlying mechanism of repopulation and developed methods to produce similar growth-advantaged cells in vitro, e.g., human induced pluripotent stem cells (iPSCs), this approach has great potential for developing novel cell-based therapies in patients with liver disease. The present review gives a brief overview of the classic cell transplantation models and various cell sources studied as donor cell candidates. The advantages of fetal liver-derived stem/progenitor cells are discussed, as well as the mechanism of liver repopulation. Moreover, this article reviews the potential of in vitro developed synthetic human fetal livers from iPSCs and their therapeutic benefits.
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Affiliation(s)
- David A. Shafritz
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Mo R. Ebrahimkhani
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15213, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Michael Oertel
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15213, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
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Kim M, Rizvi F, Shin D, Gouon-Evans V. Update on Hepatobiliary Plasticity. Semin Liver Dis 2023; 43:13-23. [PMID: 36764306 PMCID: PMC10005859 DOI: 10.1055/s-0042-1760306] [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] [Indexed: 02/12/2023]
Abstract
The liver field has been debating for decades the contribution of the plasticity of the two epithelial compartments in the liver, hepatocytes and biliary epithelial cells (BECs), to derive each other as a repair mechanism. The hepatobiliary plasticity has been first observed in diseased human livers by the presence of biphenotypic cells expressing hepatocyte and BEC markers within bile ducts and regenerative nodules or budding from strings of proliferative BECs in septa. These observations are not surprising as hepatocytes and BECs derive from a common fetal progenitor, the hepatoblast, and, as such, they are expected to compensate for each other's loss in adults. To investigate the cell origin of regenerated cell compartments and associated molecular mechanisms, numerous murine and zebrafish models with ability to trace cell fates have been extensively developed. This short review summarizes the clinical and preclinical studies illustrating the hepatobiliary plasticity and its potential therapeutic application.
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Affiliation(s)
- Minwook Kim
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Fatima Rizvi
- Department of Medicine, Gastroenterology Section, Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, Massachusetts
| | - Donghun Shin
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Valerie Gouon-Evans
- Department of Medicine, Gastroenterology Section, Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, Massachusetts
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Calamita G, Delporte C. Aquaporins in Glandular Secretion. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1398:225-249. [PMID: 36717498 DOI: 10.1007/978-981-19-7415-1_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Exocrine and endocrine glands deliver their secretory product, respectively, at the surface of the target organs or within the bloodstream. The release of their products has been shown to rely on secretory mechanisms often involving aquaporins (AQPs). This chapter will provide insight into the role of AQPs in secretory glands located within the gastrointestinal tract, including salivary glands, gastric glands, duodenal Brunner's glands, liver, gallbladder, intestinal goblets cells, and pancreas, as well and in other parts of the body, including airway submucosal glands, lacrimal glands, mammary glands, and eccrine sweat glands. The involvement of AQPs in both physiological and pathophysiological conditions will also be highlighted.
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Affiliation(s)
- Giuseppe Calamita
- Department of Biosciences, Biotechnologies and Environment, University of Bari "Aldo Moro", Bari, Italy
| | - Christine Delporte
- Laboratory of Pathophysiological and Nutritional Biochemistry, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
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Nambiar SM, Lee J, Yanum JA, Garcia V, Jiang H, Dai G. Maternal hepatocytes heterogeneously and dynamically exhibit developmental phenotypes partially via yes-associated protein 1 during pregnancy. Am J Physiol Gastrointest Liver Physiol 2023; 324:G38-G50. [PMID: 36283963 PMCID: PMC9799147 DOI: 10.1152/ajpgi.00197.2022] [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: 08/08/2022] [Revised: 10/11/2022] [Accepted: 10/21/2022] [Indexed: 02/08/2023]
Abstract
Pregnancy induces reprogramming of maternal physiology to support fetal development and growth. Maternal hepatocytes undergo hypertrophy and hyperplasia to drive maternal liver growth and alter their gene expression profiles simultaneously. This study aimed to further understand maternal hepatocyte adaptation to pregnancy. Timed pregnancies were generated in mice. In a nonpregnant state, most hepatocytes expressed Cd133, α-fetal protein (Afp) and epithelial cell adhesion molecule (Epcam) mRNAs, whereas overall, at the protein level, they exhibited a CD133-/AFP- phenotype; however, pericentral hepatocytes were EpCAM+. As pregnancy advanced, although most maternal hepatocytes retained Cd133, Afp, and Epcam mRNA expression, they generally displayed a phenotype of CD133+/AFP+, and EpCAM protein expression was switched from pericentral to periportal maternal hepatocytes. In addition, we found that the Hippo/yes-associated protein (YAP) pathway does not respond to pregnancy. Yap1 gene deletion specifically in maternal hepatocytes did not affect maternal liver growth or metabolic zonation. However, the absence of Yap1 gene eliminated CD133 protein expression without interfering with Cd133 transcript expression in maternal livers. We demonstrated that maternal hepatocytes acquire heterogeneous and dynamic developmental phenotypes, resembling fetal hepatocytes, partially via YAP1 through a posttranscriptional mechanism. Moreover, maternal liver is a new source of AFP. In addition, maternal liver grows and maintains its metabolic zonation independent of the Hippo/YAP1 pathway. Our findings revealed a novel and gestation-dependent phenotypic plasticity in adult hepatocytes.NEW & NOTEWORTHY We found that maternal hepatocytes exhibit developmental phenotypes in a temporal and spatial manner, similarly to fetal hepatocytes. They acquire this new property partially via yes-associated protein 1.
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Affiliation(s)
- Shashank Manohar Nambiar
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Joonyong Lee
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Jennifer Abla Yanum
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Veronica Garcia
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Huaizhou Jiang
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Guoli Dai
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
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15
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Peng J, Li F, Wang J, Wang C, Jiang Y, Liu B, He J, Yuan K, Pan C, Lin M, Zhou B, Chen L, Gao D, Zhao Y. Identification of a rare Gli1 + progenitor cell population contributing to liver regeneration during chronic injury. Cell Discov 2022; 8:118. [PMID: 36316325 PMCID: PMC9622734 DOI: 10.1038/s41421-022-00474-3] [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: 01/28/2022] [Accepted: 09/21/2022] [Indexed: 11/06/2022] Open
Abstract
In adults, hepatocytes are mainly replenished from the existing progenitor pools of hepatocytes and cholangiocytes during chronic liver injury. However, it is unclear whether other cell types in addition to classical hepatocytes and cholangiocytes contribute to hepatocyte regeneration after chronic liver injuries. Here, we identified a new biphenotypic cell population that contributes to hepatocyte regeneration during chronic liver injuries. We found that a cell population expressed Gli1 and EpCAM (EpCAM+Gli1+), which was further characterized with both epithelial and mesenchymal identities by single-cell RNA sequencing. Genetic lineage tracing using dual recombinases revealed that Gli1+ nonhepatocyte cell population could generate hepatocytes after chronic liver injury. EpCAM+Gli1+ cells exhibited a greater capacity for organoid formation with functional hepatocytes in vitro and liver regeneration upon transplantation in vivo. Collectively, these findings demonstrate that EpCAM+Gli1+ cells can serve as a new source of liver progenitor cells and contribute to liver repair and regeneration.
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Affiliation(s)
- Jiayin Peng
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Fei Li
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Jia Wang
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, China
| | - Chaoxiong Wang
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, China
| | - Yiao Jiang
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, China
| | - Biao Liu
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, China
| | - Juan He
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, China
| | - Kai Yuan
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Chenyu Pan
- grid.24516.340000000123704535Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Moubin Lin
- grid.24516.340000000123704535Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Bin Zhou
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Luonan Chen
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Dong Gao
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China ,grid.9227.e0000000119573309Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Yun Zhao
- grid.9227.e0000000119573309State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China ,grid.440637.20000 0004 4657 8879School of Life Science and Technology, ShanghaiTech University, Shanghai, China ,grid.410726.60000 0004 1797 8419Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang China
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16
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Koren E, Feldman A, Yusupova M, Kadosh A, Sedov E, Ankawa R, Yosefzon Y, Nasser W, Gerstberger S, Kimel LB, Priselac N, Brown S, Sharma S, Gorenc T, Shalom-Feuerstein R, Steller H, Shemesh T, Fuchs Y. Thy1 marks a distinct population of slow-cycling stem cells in the mouse epidermis. Nat Commun 2022; 13:4628. [PMID: 35941116 PMCID: PMC9360001 DOI: 10.1038/s41467-022-31629-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 06/27/2022] [Indexed: 12/17/2022] Open
Abstract
The presence of distinct stem cells that maintain the interfollicular epidermis is highly debated. Here, we report a population of keratinocytes, marked by Thy1, in the basal layer of the interfollicular epidermis. We find that epidermal cells expressing differential levels of Thy1 display distinct transcriptional signatures. Thy1+ keratinocytes do not express T cell markers, express a unique transcriptional profile, cycle significantly slower than basal epidermal progenitors and display significant expansion potential in vitro. Multicolor lineage tracing analyses and mathematical modeling reveal that Thy1+ basal keratinocytes do not compete neutrally alike interfollicular progenitors and contribute long-term to both epidermal replenishment and wound repair. Importantly, ablation of Thy1+ cells strongly impairs these processes, thus indicating the non-redundant function of Thy1+ stem cells in the epidermis. Collectively, these results reveal a distinct stem cell population that plays a critical role in epidermal homeostasis and repair.
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Affiliation(s)
- Elle Koren
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion Israel Institute of Technology, Haifa, Israel
- Lorry Lokey Interdisciplinary Center for Life Sciences & Engineering, Technion Israel Institute of Technology, Haifa, Israel
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Alona Feldman
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion Israel Institute of Technology, Haifa, Israel
- Lorry Lokey Interdisciplinary Center for Life Sciences & Engineering, Technion Israel Institute of Technology, Haifa, Israel
| | - Marianna Yusupova
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion Israel Institute of Technology, Haifa, Israel
- Lorry Lokey Interdisciplinary Center for Life Sciences & Engineering, Technion Israel Institute of Technology, Haifa, Israel
| | - Avihay Kadosh
- Laboratory of Biophysics, Department of Biology, Technion Israel Institute of Technology, Haifa, Israel
| | - Egor Sedov
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion Israel Institute of Technology, Haifa, Israel
- Lorry Lokey Interdisciplinary Center for Life Sciences & Engineering, Technion Israel Institute of Technology, Haifa, Israel
| | - Roi Ankawa
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion Israel Institute of Technology, Haifa, Israel
- Lorry Lokey Interdisciplinary Center for Life Sciences & Engineering, Technion Israel Institute of Technology, Haifa, Israel
| | - Yahav Yosefzon
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion Israel Institute of Technology, Haifa, Israel
- Lorry Lokey Interdisciplinary Center for Life Sciences & Engineering, Technion Israel Institute of Technology, Haifa, Israel
| | - Waseem Nasser
- Department of Genetics and Developmental Biology, The Rappaport Faculty of Medicine and Research Institute, Technion Israel Institute of Technology, Haifa, Israel
| | | | - Liam B Kimel
- Laboratory of Biophysics, Department of Biology, Technion Israel Institute of Technology, Haifa, Israel
| | - Noa Priselac
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion Israel Institute of Technology, Haifa, Israel
- Lorry Lokey Interdisciplinary Center for Life Sciences & Engineering, Technion Israel Institute of Technology, Haifa, Israel
| | - Samara Brown
- Strang Laboratory of Apoptosis and Cancer Biology, The Rockefeller University, New York, New York, 10065, USA
| | - Sam Sharma
- Strang Laboratory of Apoptosis and Cancer Biology, The Rockefeller University, New York, New York, 10065, USA
| | - Travis Gorenc
- Strang Laboratory of Apoptosis and Cancer Biology, The Rockefeller University, New York, New York, 10065, USA
| | - Ruby Shalom-Feuerstein
- Department of Genetics and Developmental Biology, The Rappaport Faculty of Medicine and Research Institute, Technion Israel Institute of Technology, Haifa, Israel
| | - Hermann Steller
- Strang Laboratory of Apoptosis and Cancer Biology, The Rockefeller University, New York, New York, 10065, USA
| | - Tom Shemesh
- Laboratory of Biophysics, Department of Biology, Technion Israel Institute of Technology, Haifa, Israel.
| | - Yaron Fuchs
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion Israel Institute of Technology, Haifa, Israel.
- Lorry Lokey Interdisciplinary Center for Life Sciences & Engineering, Technion Israel Institute of Technology, Haifa, Israel.
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17
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Elrazik NAA, El-Mesery M, El-Shishtawy MM. Sesamol protects against liver fibrosis induced in rats by modulating lysophosphatidic acid receptor expression and TGF-β/Smad3 signaling pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2022; 395:1003-1016. [PMID: 35648193 PMCID: PMC9276582 DOI: 10.1007/s00210-022-02259-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 05/20/2022] [Indexed: 11/18/2022]
Abstract
The present study aimed to investigate the hepatoprotective effect of sesamol (SML), a nutritional phenolic compound obtained from sesame seeds, in liver fibrosis induced by thioacetamide (TAA) in rats and to explore the underlying mechanisms. Thirty-two male Sprague-Dawley rats were equally divided into four groups: control, TAA, TAA + SML 50 mg/kg, and TAA + SML 100 mg/kg groups. Liver functions and hepatic contents of glutathione (GSH) and malondialdehyde (MDA) were measured colorimetrically. Gene expressions of lysophosphatidic acid receptor (LPAR)-1 and -3, connective tissue growth factor (CTGF), transforming growth factor (TGF)-β1, small mothers against decapentaplegic (Smad)-3 and -7, α-smooth muscle actin (α-SMA), and cytokeratin 19 (CK19) were analyzed by qRT-PCR. Moreover, phosphorylated Smad3 (pSmad3) was quantified by ELISA. Additionally, TGF-β1, α-SMA, CK19, and vascular endothelial growth factor (VEGF) protein concentrations were semi-quantitatively analyzed by immunostaining of liver sections. SML treatment markedly improved liver index and liver functions. Moreover, SML protected against liver fibrosis in a dose-dependent manner as indicated by down-regulation of LPAR1, LPAR3, CTGF, TGF-β1/Smad3, and α-SMA expressions and a decrease in pSmad3 level, as well as an up-regulation of Smad7 expression. In addition, SML suppressed ductular reaction hinted by the decrease in CK19 expression. These results reveal the anti-fibrotic effect of SML against liver fibrosis that might be attributed to down-regulation of LPAR1/3 expressions, inhibition of TGF-β1/Smad3 pathway, and ductular reaction.
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Affiliation(s)
- Nesma A Abd Elrazik
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, P.O. Box, Mansoura, 35516, Egypt
| | - Mohamed El-Mesery
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, P.O. Box, Mansoura, 35516, Egypt
| | - Mamdouh M El-Shishtawy
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, P.O. Box, Mansoura, 35516, Egypt.
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18
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Wang GY, Garcia V, Lee J, Yanum J, Lin J, Jiang H, Dai G. Nrf2 deficiency causes hepatocyte dedifferentiation and reduced albumin production in an experimental extrahepatic cholestasis model. PLoS One 2022; 17:e0269383. [PMID: 35696363 PMCID: PMC9191739 DOI: 10.1371/journal.pone.0269383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 05/19/2022] [Indexed: 11/18/2022] Open
Abstract
The transcription factor Nrf2 modulates the initiation and progression of a number of diseases including liver disorders. We evaluated whether Nrf2 mediates hepatic adaptive responses to cholestasis. Wild-type and Nrf2-null mice were subjected to bile duct ligation (BDL) or a sham operation. As cholestasis progressed to day 15 post-BDL, hepatocytes in the wild-type mice exhibited a tendency to dedifferentiate, indicated by the very weak expression of hepatic progenitor markers: CD133 and tumor necrosis factor-like weak induced apoptosis receptor (Fn14). During the same period, Nrf2 deficiency augmented this tendency, manifested by higher CD133 expression, earlier, stronger, and continuous induction of Fn14 expression, and markedly reduced albumin production. Remarkably, as cholestasis advanced to the late stage (40 days after BDL), hepatocytes in the wild-type mice exhibited a Fn14+ phenotype and strikingly upregulated the expression of deleted in malignant brain tumor 1 (DMBT1), a protein essential for epithelial differentiation during development. In contrast, at this stage, hepatocytes in the Nrf2-null mice entirely inhibited the upregulation of DMBT1 expression, displayed a strong CD133+/Fn14+ phenotype indicative of severe dedifferentiation, and persistently reduced albumin production. We revealed that Nrf2 maintains hepatocytes in the differentiated state potentially via the increased activity of the Nrf2/DMBT1 pathway during cholestasis.
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Affiliation(s)
- Guo-Ying Wang
- Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States of America
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital, Sun Yet-Sen University, Guangdong, China
| | - Veronica Garcia
- Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States of America
| | - Joonyong Lee
- Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States of America
| | - Jennifer Yanum
- Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States of America
| | - Jingmei Lin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Huaizhou Jiang
- Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States of America
- School of Traditional Chinese Medicine, Anhui University of Chinese Medicine, Anhui, China
| | - Guoli Dai
- Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States of America
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19
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Bellanti F, di Bello G, Tamborra R, Amatruda M, Lo Buglio A, Dobrakowski M, Kasperczyk A, Kasperczyk S, Serviddio G, Vendemiale G. Impact of senescence on the transdifferentiation process of human hepatic progenitor-like cells. World J Stem Cells 2021; 13:1595-1609. [PMID: 34786160 PMCID: PMC8567448 DOI: 10.4252/wjsc.v13.i10.1595] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/14/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Senescence is characterized by a decline in hepatocyte function, with impairment of metabolism and regenerative capacity. Several models that duplicate liver functions in vitro are essential tools for studying drug metabolism, liver diseases, and organ regeneration. The human HepaRG cell line represents an effective model for the study of liver metabolism and hepatic progenitors. However, the impact of senescence on HepaRG cells is not yet known.
AIM To characterize the effects of senescence on the transdifferentiation capacity and mitochondrial metabolism of human HepaRG cells.
METHODS We compared the transdifferentiation capacity of cells over 10 (passage 10 [P10]) vs P20. Aging was evaluated by senescence-associated (SA) beta-galactosidase activity and the comet assay. HepaRG transdifferentiation was analyzed by confocal microscopy and flow cytometry (expression of cluster of differentiation 49a [CD49a], CD49f, CD184, epithelial cell adhesion molecule [EpCAM], and cytokeratin 19 [CK19]), quantitative PCR analysis (expression of albumin, cytochrome P450 3A4 [CYP3A4], γ-glutamyl transpeptidase [γ-GT], and carcinoembryonic antigen [CEA]), and functional analyses (albumin secretion, CYP3A4, and γ-GT). Mitochondrial respiration and the ATP and nicotinamide adenine dinucleotide (NAD+)/NAD with hydrogen (NADH) content were also measured.
RESULTS SA β-galactosidase staining was higher in P20 than P10 HepaRG cells; in parallel, the comet assay showed consistent DNA damage in P20 HepaRG cells. With respect to P10, P20 HepaRG cells exhibited a reduction of CD49a, CD49f, CD184, EpCAM, and CK19 after the induction of transdifferentiation. Furthermore, lower gene expression of albumin, CYP3A4, and γ-GT, as well as reduced albumin secretion capacity, CYP3A4, and γ-GT activity were reported in transdifferentiated P20 compared to P10 cells. By contrast, the gene expression level of CEA was not reduced by transdifferentiation in P20 cells. Of note, both cellular and mitochondrial oxygen consumption was lower in P20 than in P10 transdifferentiated cells. Finally, both ATP and NAD+/NADH were depleted in P20 cells with respect to P10 cells.
CONCLUSION SA mitochondrial dysfunction may limit the transdifferentiation potential of HepaRG cells, with consequent impairment of metabolic and regenerative properties, which may alter applications in basic studies.
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Affiliation(s)
- Francesco Bellanti
- Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Giorgia di Bello
- Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Rosanna Tamborra
- Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Marco Amatruda
- Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Aurelio Lo Buglio
- Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Michał Dobrakowski
- Department of Biochemistry, Medical University of Silesia, Zabrze 41-808, Poland
| | | | - Sławomir Kasperczyk
- Department of Biochemistry, Medical University of Silesia, Zabrze 41-808, Poland
| | - Gaetano Serviddio
- Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Gianluigi Vendemiale
- Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
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20
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Ultrastructural Profile Combined with Immunohistochemistry of a Hepatic Progenitor Cell Line in Pediatric Autoimmune Hepatitis: New Insights into the Morphological Pattern of the Disease. Cells 2021; 10:cells10081899. [PMID: 34440668 PMCID: PMC8392671 DOI: 10.3390/cells10081899] [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: 06/01/2021] [Revised: 07/13/2021] [Accepted: 07/20/2021] [Indexed: 12/12/2022] Open
Abstract
Considering that the heterogenic population of a hepatic progenitor cell line (HPCL) can play a vital role in autoimmune hepatitis (AIH), we decided to conduct pioneering retrospective evaluation of these cells in pediatric AIH by means of transmission electron microscopy (TEM). The aim of the study was to assess the ultrastructure of the HPCL in children with untreated AIH. Ultrastructural analysis of the HPCL population, preceded by immunohistochemical staining for cytokeratin 7 (CK7), was performed using pretreatment liver biopsies from 23 children with clinicopathologically diagnosed AIH. Immunohistochemical assessment for CK7 allowed detection of proliferating immature epithelial cells differentiating towards periportal and intralobular intermediate hepatocytes without marked formation of ductular reactions in AIH children. Using TEM, we distinguished three morphological types of HPCs: I—the most undifferentiated progenitor cells; III—intermediate hepatocyte-like cells; II—intermediate bile duct cells. Most frequent were the cells differentiating towards hepatocytes, most rare—those differentiating towards cholangiocytes. The results indicate that an HPCL may be an important source of hepatocyte regeneration. Ultrastructural analyses of the HPCL population, combined with immunohistochemistry for CK7, might be a useful tool to evaluate liver cell regeneration, including fibrogenesis, and may help better understand the morphological pattern of the disease, in pediatric AIH. Frequent appearance of an HPCL in the vicinity of fibrotic foci, often accompanied by hyperactive Kupffer cells and transitional hepatic stellate cells, may indicate their significant involvement in liver fibrogenesis.
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21
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Kim S, Han G, Hwang D, Won D, Shin Y, Kim C, Kang JM, Park J, Jung H, Park W, Yun J. Design and Usability Evaluations of a 3D-Printed Implantable Drug Delivery Device for Acute Liver Failure in Preclinical Settings. Adv Healthc Mater 2021; 10:e2100497. [PMID: 34160141 DOI: 10.1002/adhm.202100497] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 05/18/2021] [Indexed: 12/11/2022]
Abstract
Acute liver failure (ALF) requiring liver transplantation is a disease that occurs due to rapid hepatocellular dysfunction. As liver transplantation has various limitations, including donor scarcity, high cost, and immuno-incompatibility, continuous local delivery of biopharmaceuticals to the liver tissue can be a promising ALF treatment option. Here, the in vivo safety and usability of a 3D-printed implantable drug delivery device for effective ALF treatment is evaluated. The implantable reservoir consists of a 3D-printed container and a semipermeable membrane for repeated administrations of drugs, specifically to the liver tissue. The physical stability and function of the 3D-printed reservoir are confirmed by the mechanical properties and in vitro drug release test, respectively. In mice implanted with the reservoir system, mortality, weight changes, clinical signs, hematological and serum biochemical changes, and organ weight changes are not observed, suggesting no foreign body reaction. The usability of the reservoir system is further evaluated using an ALF model of 70% hepatectomized mice treated with N-acetylcysteine through the system, showing cell-specific regeneration and significant liver injury alleviation. Overall, the 3D-printed reservoir system is safe for studying the therapeutic potential of ALF treatment, and it can be used for the delivery of various active pharmaceutical ingredients.
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Affiliation(s)
- Shin‐Young Kim
- Department of Biotechnology The Catholic University of Korea 43 Jibong‐ro Bucheon‐Si Gyeonggi‐do 14662 Republic of Korea
| | - Ginam Han
- Department of Biotechnology The Catholic University of Korea 43 Jibong‐ro Bucheon‐Si Gyeonggi‐do 14662 Republic of Korea
- Department of Biomedical‐Chemical Engineering The Catholic University of Korea 43 Jibong‐ro Bucheon‐Si Gyeonggi‐do 14662 Republic of Korea
| | - Da‐Bin Hwang
- Department of Biotechnology The Catholic University of Korea 43 Jibong‐ro Bucheon‐Si Gyeonggi‐do 14662 Republic of Korea
| | - Dong‐Hoon Won
- Department of Biotechnology The Catholic University of Korea 43 Jibong‐ro Bucheon‐Si Gyeonggi‐do 14662 Republic of Korea
| | - Yoo‐Sub Shin
- Department of Biotechnology The Catholic University of Korea 43 Jibong‐ro Bucheon‐Si Gyeonggi‐do 14662 Republic of Korea
| | - Changuk Kim
- Department of Biotechnology The Catholic University of Korea 43 Jibong‐ro Bucheon‐Si Gyeonggi‐do 14662 Republic of Korea
| | - Jeon Min Kang
- Biomedical Engineering Research Center Asan Institute for Life Sciences Asan Medical Center 88 Olympic‐ro 43‐gil Songpa‐gu Seoul 05505 Republic of Korea
| | - Jung‐Hoon Park
- Biomedical Engineering Research Center Asan Institute for Life Sciences Asan Medical Center 88 Olympic‐ro 43‐gil Songpa‐gu Seoul 05505 Republic of Korea
| | - Hyun‐Do Jung
- Department of Biotechnology The Catholic University of Korea 43 Jibong‐ro Bucheon‐Si Gyeonggi‐do 14662 Republic of Korea
- Department of Biomedical‐Chemical Engineering The Catholic University of Korea 43 Jibong‐ro Bucheon‐Si Gyeonggi‐do 14662 Republic of Korea
| | - Wooram Park
- Department of Biotechnology The Catholic University of Korea 43 Jibong‐ro Bucheon‐Si Gyeonggi‐do 14662 Republic of Korea
- Department of Biomedical‐Chemical Engineering The Catholic University of Korea 43 Jibong‐ro Bucheon‐Si Gyeonggi‐do 14662 Republic of Korea
| | - Jun‐Won Yun
- Department of Biotechnology The Catholic University of Korea 43 Jibong‐ro Bucheon‐Si Gyeonggi‐do 14662 Republic of Korea
- Department of Medical and Biological Sciences The Catholic University of Korea 43 Jibong‐ro Bucheon‐Si Gyeonggi‐do 14662 Republic of Korea
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22
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Aquaporins implicated in the cell proliferation and the signaling pathways of cell stemness. Biochimie 2021; 188:52-60. [PMID: 33894294 DOI: 10.1016/j.biochi.2021.04.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 04/11/2021] [Accepted: 04/16/2021] [Indexed: 12/20/2022]
Abstract
Aquaporins (AQPs) are water channel proteins facilitating passive transport of water and other small molecules across biomembranes. Regulation of osmotic homeostasis via AQPs is accompanied by dynamic participation of various cellular signaling pathways. Recently emerging evidence reveals that functional roles of AQPs are further extended from the osmotic regulation via water permeation into the cell proliferation and differentiation. In particular, anomalous expression of AQPs has been demonstrated in various types of cancer cells and cancer stem-like cells and it has been proposed as markers for proliferation and progression of cancer cells. Thus, a more comprehensive view on AQPs could bring a great interest in the cell stemness accompanied by the expression of AQPs. AQPs are broadly expressed across tissues and cells in a cell type- and lineage-specific manner during development via spatiotemporal transcriptional regulation. Moreover, AQPs are expressed in various adult stem cells and cells associated with a stem cell niche as well as cancer stem-like cells. However, the expression and regulatory mechanisms of AQP expression in stem cells have not been well understood. This review highlighted the AQPs expression in stem cell niches/stem cells and the involvement of AQPs in the cell proliferation and signaling pathways associated with cell stemness.
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23
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Yamashita T, Kaneko S. Liver cancer stem cells: Recent progress in basic and clinical research. Regen Ther 2021; 17:34-37. [PMID: 33816720 PMCID: PMC7988346 DOI: 10.1016/j.reth.2021.03.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 03/02/2021] [Indexed: 12/15/2022] Open
Abstract
The cancer stem cell (CSC) hypothesis was proposed over 4 decades ago and states that tumor growth is maintained by a small subset of cancer cells analogous to normal tissue stem cells in terms of self-renewal and differentiation capacity. Advances in CSC isolation were initially achieved in hematological malignancies and later in solid tumors, including hepatocellular carcinoma (HCC), the major histological type of liver cancer. Increasing evidence suggests the importance of liver CSCs for tumor growth, metastasis, and chemo/radiation resistance in HCC, but the application of the liver CSC concept for the clinical diagnosis and treatment of HCC has not yet been achieved to the extent initially expected. Furthermore, the heterogeneity and plasticity of liver CSCs has recently been noted and might be related to drug resistance and the rapid growth and/or metastasis of the tumor after treatment. Here, we introduce our recent advancement in liver CSC research and discuss the clinical implications, which may lead to the development of improved diagnostics and treatment in HCC.
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Affiliation(s)
- Taro Yamashita
- Department of General Medicine, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
- Corresponding author. Department of General Medicine, Kanazawa University Hospital, 13-1 Takara-Machi, Kanazawa, Ishikawa 920-8641, Japan.
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
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24
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Zhang W, Chen J, Ni R, Yang Q, Luo L, He J. Contributions of biliary epithelial cells to hepatocyte homeostasis and regeneration in zebrafish. iScience 2021; 24:102142. [PMID: 33665561 PMCID: PMC7900353 DOI: 10.1016/j.isci.2021.102142] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 12/03/2020] [Accepted: 01/29/2021] [Indexed: 12/27/2022] Open
Abstract
Whether transdifferentiation of the biliary epithelial cells (BECs) to hepatocytes occurs under physiological conditions and contributes to liver homeostasis remains under long-term debate. Similar questions have been raised under pathological circumstances if a fibrotic liver is suffered from severe injuries. To address these questions in zebrafish, we established a sensitive lineage tracing system specific for the detection of BEC-derived hepatocytes. The BEC-to-hepatocyte transdifferentiation occurred and became minor contributors to hepatocyte homeostasis in a portion of adult individuals. The BEC-derived hepatocytes distributed in clusters in the liver. When a fibrotic liver underwent extreme hepatocyte damages, BEC-to-hepatocyte transdifferentiation acted as the major origin of regenerating hepatocytes. In contrast, partial hepatectomy failed to induce the BEC-to-hepatocyte conversion. In conclusion, based on a sensitive lineage tracing system, our results suggest that BECs are able to transdifferentiate into hepatocytes and contribute to both physiological hepatocyte homeostasis and pathological regeneration.
Developed sensitivity system to trace BECs derived hepatocytes in liver homeostasis BECs convert to hepatocytes in liver homeostasis but are individually heterogeneous BECs are the primary regeneration sources in the extreme injury of the fibrotic liver BECs fail to contribute to new hepatocytes after partial hepatectomy
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Affiliation(s)
- Wenfeng Zhang
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, 2 Tiansheng Road, Beibei, 400715 Chongqing, China
| | - Jingying Chen
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, 2 Tiansheng Road, Beibei, 400715 Chongqing, China.,University of Chinese Academy of Sciences (Chongqing), Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Beibei, 400714 Chongqing, China
| | - Rui Ni
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, 2 Tiansheng Road, Beibei, 400715 Chongqing, China
| | - Qifen Yang
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, 2 Tiansheng Road, Beibei, 400715 Chongqing, China
| | - Lingfei Luo
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, 2 Tiansheng Road, Beibei, 400715 Chongqing, China
| | - Jianbo He
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, 2 Tiansheng Road, Beibei, 400715 Chongqing, China
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25
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Jung DJ, Byeon JH, Jeong GS. Flow enhances phenotypic and maturation of adult rat liver organoids. Biofabrication 2020; 12:045035. [PMID: 33000764 DOI: 10.1088/1758-5090/abb538] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A biologically relevant in vitro model of hepatic microtissue would be a valuable tool for the preclinical study of pharmacokinetics and metabolism. Although considerable advances have been made in recent years in the establishment of alternative in vitro culture systems that mimic liver tissue, generating an effective liver model remains challenging. Specifically, existing model systems still exhibit limited functions for hepatocellular differentiation potential and cellular complexity. It is essential to improve the in vitro differentiation of liver progenitor cells (LPCs) for disease modeling and preclinical pharmatoxicological research. Here, we describe a rat liver organoid culture system under in vivo-like steady-state flow conditions; this system is capable of controlling the expansion and differentiation of rat liver organoids over 10-15 d. LPCs cultured in medium flow conditions become self-assembled liver organoids that exhibit phenotypic and functional hepato-biliary modeling. In addition, hepatocytes that are differentiated using liver organoids produced albumin and maintained polygonal morphology, which is characteristic of mature hepatocytes.
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Affiliation(s)
- Da Jung Jung
- Biomedical Engineering Research Center, Asan Institute for Life Sciences, Asan Medical Center, 88 Olympic-Ro, Songpa-Gu, Seoul 05505, Republic of Korea
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26
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Abstract
Following injury, the liver's epithelial cells regenerate efficiently with rapid proliferation of hepatocytes and biliary cells. However, when proliferation of resident epithelial cells is impaired, alternative regeneration mechanisms can occur. Intricate lineage-tracing strategies and experimental models of regenerative stress have revealed a degree of plasticity between hepatocytes and biliary cells. New technologies such as single-cell omics, in combination with functional studies, will be instrumental to uncover the remaining unknowns in the field. In this review, we evaluate the experimental and clinical evidence for epithelial plasticity in the liver and how this influences the development of therapeutic strategies for chronic liver disease.
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Affiliation(s)
- Victoria L Gadd
- Centre for Regenerative Medicine, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Niya Aleksieva
- Centre for Regenerative Medicine, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Stuart J Forbes
- Centre for Regenerative Medicine, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, EH16 4UU, UK.
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27
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Pastore N, Huynh T, Herz NJ, Calcagni' A, Klisch TJ, Brunetti L, Kim KH, De Giorgi M, Hurley A, Carissimo A, Mutarelli M, Aleksieva N, D'Orsi L, Lagor WR, Moore DD, Settembre C, Finegold MJ, Forbes SJ, Ballabio A. TFEB regulates murine liver cell fate during development and regeneration. Nat Commun 2020; 11:2461. [PMID: 32424153 PMCID: PMC7235048 DOI: 10.1038/s41467-020-16300-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 04/20/2020] [Indexed: 12/29/2022] Open
Abstract
It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes. However, the signaling pathways implicated in the differentiation of LPCs are still incompletely understood. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is known to be involved in osteoblast and myeloid differentiation, but its role in lineage commitment in the liver has not been investigated. Here we show that during development and upon regeneration TFEB drives the differentiation status of murine LPCs into the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation. Genetic interaction studies show that Sox9, a marker of precursor and biliary cells, is a direct transcriptional target of TFEB and a primary mediator of its effects on liver cell fate. In summary, our findings identify an unexplored pathway that controls liver cell lineage commitment and whose dysregulation may play a role in biliary cancer.
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Affiliation(s)
- Nunzia Pastore
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA.
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
| | - Tuong Huynh
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Niculin J Herz
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Alessia Calcagni'
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Tiemo J Klisch
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Lorenzo Brunetti
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, 77030, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Kangho Ho Kim
- Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Marco De Giorgi
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Ayrea Hurley
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Annamaria Carissimo
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, NA, 80078, Italy
| | | | - Niya Aleksieva
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Luca D'Orsi
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, NA, 80078, Italy
| | - William R Lagor
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - David D Moore
- Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Carmine Settembre
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, NA, 80078, Italy
- Department of Translational Medicine, Medical Genetics, Federico II University, Naples, 80131, Italy
| | - Milton J Finegold
- Department of Pathology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Stuart J Forbes
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Andrea Ballabio
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA.
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, NA, 80078, Italy.
- Department of Translational Medicine, Medical Genetics, Federico II University, Naples, 80131, Italy.
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28
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Diao L, Yousuf Y, Amini‐Nik S, Jeschke MG. Increased proliferation of hepatic periportal ductal progenitor cells contributes to persistent hypermetabolism after trauma. J Cell Mol Med 2020; 24:1578-1587. [PMID: 31793707 PMCID: PMC6991656 DOI: 10.1111/jcmm.14845] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Revised: 10/16/2019] [Accepted: 10/28/2019] [Indexed: 12/13/2022] Open
Abstract
Prolonged and persistent hypermetabolism and excessive inflammatory response after severe trauma is detrimental and associated with poor outcome. The predisposing pathology or signals mediating this complex response are essentially unknown. As the liver is the central organ mediating the systemic metabolic responses and considering that adult hepatic stem cells are on top of the hierarchy of cell differentiation and may pass epigenetic information to their progeny, we asked whether liver progenitor cells are activated, signal hypermetabolism upon post-traumatic cellular stress responses, and pass this to differentiated progeny. We generated Sox9CreERT2 : ROSA26 EYFP mice to lineage-trace the periportal ductal progenitor cells (PDPCs) and verify the fate of these cells post-burn. We observed increased proliferation of PDPCs and their progeny peaking around two weeks post-burn, concomitant with the hepatomegaly and the cellular stress responses. We then sorted out PDPCs, PDPC-derived hepatocytes and mature hepatocytes, compared their transcriptome and showed that PDPCs and their progeny present a significant up-regulation in signalling pathways associated with inflammation and metabolic activation, contributing to persistent hypermetabolic and hyper-inflammatory state. Furthermore, concomitant down-regulation of LXR signalling in PDPCs and their progeny implicates the therapeutic potential of early and short-term administration of LXR agonists in ameliorating such persistent hypermetabolism.
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Affiliation(s)
- Li Diao
- Sunnybrook Research InstituteTorontoONCanada
| | | | - Saeid Amini‐Nik
- Sunnybrook Research InstituteTorontoONCanada
- Division of Plastic SurgeryDepartment of SurgeryUniversity of TorontoTorontoONCanada
- Department of Laboratory Medicine and Pathobiology (LMP)University of TorontoTorontoONCanada
| | - Marc G. Jeschke
- Sunnybrook Research InstituteTorontoONCanada
- Division of Plastic SurgeryDepartment of SurgeryUniversity of TorontoTorontoONCanada
- Department of ImmunologyUniversity of TorontoTorontoONCanada
- Ross Tilley Burn CentreSunnybrook Health Sciences CentreTorontoONCanada
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29
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Jewell ML, Gibson JR, Guy CD, Hyun J, Du K, Oh SH, Premont RT, Hsu DS, Ribar T, Gregory SG, Diehl AME. Single-Cell RNA Sequencing Identifies Yes-Associated Protein 1-Dependent Hepatic Mesothelial Progenitors in Fibrolamellar Carcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:93-107. [PMID: 31669305 PMCID: PMC10069284 DOI: 10.1016/j.ajpath.2019.09.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 08/23/2019] [Accepted: 09/26/2019] [Indexed: 12/29/2022]
Abstract
Fibrolamellar carcinoma (FLC) is characterized by in-frame fusion of DnaJ heat shock protein family (Hsp40) member B1 (DNAJB1) with protein kinase cAMP-activated catalytic subunit α (PRKACA) and by dense desmoplasia. Surgery is the only effective treatment because mechanisms supporting tumor survival are unknown. We used single-cell RNA sequencing to characterize a patient-derived FLC xenograft model and identify therapeutic targets. Human FLC cells segregated into four discrete clusters that all expressed the oncogene Yes-associated protein 1 (YAP1). The two communities most enriched with cells coexpressing FLC markers [CD68, A-kinase anchoring protein 12 (AKAP12), cytokeratin 7, epithelial cell adhesion molecule (EPCAM), and carbamoyl palmitate synthase-1] also had the most cells expressing YAP1 and its proproliferative target genes (AREG and CCND1), suggesting these were proliferative FLC cell clusters. The other two clusters were enriched with cells expressing profibrotic YAP1 target genes, ACTA2, ELN, and COL1A1, indicating these were fibrogenic FLC cells. All clusters expressed the YAP1 target gene and mesothelial progenitor marker mesothelin, and many mesothelin-positive cells coexpressed albumin. Trajectory analysis predicted that the four FLC communities were derived from a single cell type transitioning among phenotypic states. After establishing a novel FLC cell line that harbored the DNAJB1-PRKACA fusion, YAP1 was inhibited, which significantly reduced expression of known YAP1 target genes as well as cell growth and migration. Thus, both FLC epithelial and stromal cells appear to arise from DNAJB1-PRKACA fusion in a YAP1-dependent liver mesothelial progenitor, identifying YAP1 as a target for FLC therapy.
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Affiliation(s)
- Mark L Jewell
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina
| | - Jason R Gibson
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - Cynthia D Guy
- Department of Pathology, Duke University, Durham, North Carolina
| | - Jeongeun Hyun
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina
| | - Kuo Du
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina
| | - Seh-Hoon Oh
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina
| | - Richard T Premont
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina
| | - David S Hsu
- Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Thomas Ribar
- Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Simon G Gregory
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - Anna Mae E Diehl
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina.
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30
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Wakasa Y, Kimura N, Yamada T, Shimizu T, Hakamada K, Tsuchida S. Delay in hepatocyte proliferation and prostaglandin D2 synthase expression for cholestasis due to endotoxin during partial hepatectomy in rats. Mol Med Rep 2019; 20:4367-4375. [PMID: 31545425 PMCID: PMC6797974 DOI: 10.3892/mmr.2019.10681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 08/22/2019] [Indexed: 11/05/2022] Open
Abstract
Infection is a frequent complication of liver transplantation or partial hepatectomy (PH) and sometimes results in cholestasis. We examined factors involved in infection‑induced cholestasis after PH, employing a rat PH model and lipopolysaccharide (LPS) as a bacterial toxin. Male Sprague‑Dawley rats were subjected to 70% PH and/or LPS injection, and tissues were harvested at 0, 24, 72 and 168 h. Gene expression was analyzed by microarray analysis and reverse transcription‑quantitative polymerase chain reaction, and protein levels and localization were analyzed by western blotting and immunohistochemistry, respectively. Plasma bile acid levels were significantly higher in the LPS + PH group than in the PH group. Ribonucleotide reductase regulatory subunit M2 and proliferating cell nuclear antigen peaked at 24 and 72 h in the PH group and LPS + PH group, respectively, indicating a delay in cell proliferation in the latter group. The sodium‑dependent taurocholate cotransporting polypeptide and organic‑anion‑transporting polypeptide 1a1 and 1a2 were reduced in the PH group at 24 h, and were not further decreased in the LPS + PH group. Chemokine ligand 9 (Cxcl9), a chemokine involved in M2 macrophage polarization, increased after 24 h in the LPS and the LPS + PH groups. The number and shape of Cxcl9‑positive cells were similar to CD163‑positive cells, suggesting that such cells produced the chemokine. Hematopoietic prostaglandin D2 synthase (Ptgds2) was only detected in hepatocytes of the LPS + PH group exhibiting a delay in cell proliferation. Thus, Kupffer cells activated with LPS were suggested to be responsible for a delay in hepatocyte proliferation after PH.
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Affiliation(s)
- Yusuke Wakasa
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan
| | - Norihisa Kimura
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan
| | - Toshiyuki Yamada
- Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan
| | - Takeshi Shimizu
- Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan
| | - Kenichi Hakamada
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan
| | - Shigeki Tsuchida
- Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan
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31
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A critical role of autophagy in regulating the mesenchymal transition of ductular cells in liver cirrhosis. Sci Rep 2019; 9:10673. [PMID: 31337842 PMCID: PMC6650611 DOI: 10.1038/s41598-019-46764-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Accepted: 07/05/2019] [Indexed: 02/07/2023] Open
Abstract
Our previous studies have shown that autophagy mediates the link between ductular reaction (DR) and liver cirrhosis. Whether the subsequent fibrogenic response is regulated by increased autophagy in DR remains unclear. Here, using both human liver specimens and a rat model of liver cirrhosis induced by 2-acetylaminofluorene (AAF) and carbon tetrachloride (CCL4), we explored the involvement of autophagy in regulating mesenchymal transition of ductular cells. Ductular cells from AAF/CCL4 livers exhibited increased autophagy compared to those of normal livers. These cells showed morphological and functional characteristics of mesenchymal cells. Blocking autophagy using bafilomycin A1 or siRNA targeting ATG7 reduced the expression of mesenchymal markers in these ductular cells from AAF/CCL4 livers, indicating a role for autophagy in regulating the mesenchymal phenotype of ductular cells. Furthermore, we show that the mesenchymal transition in DR requires the activation of transforming growth factor-β (TGF-β) signaling in an autophagy-dependent manner. Importantly, in cirrhotic human livers, ductular cells that are positive for LC3B also showed increased expression of TGF-β and fibroblast-specific protein-1. Our data suggest activation of autophagy in ductular cells, and also demonstrate that it is required for the mesenchymal transition during the DR, processes that are critically involved in the pathogenesis of cirrhosis.
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32
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Almalé L, García-Álvaro M, Martínez-Palacián A, García-Bravo M, Lazcanoiturburu N, Addante A, Roncero C, Sanz J, de la O López M, Bragado P, Mikulits W, Factor VM, Thorgeirsson SS, Casal JI, Segovia JC, Rial E, Fabregat I, Herrera B, Sánchez A. c-Met Signaling Is Essential for Mouse Adult Liver Progenitor Cells Expansion After Transforming Growth Factor-β-Induced Epithelial-Mesenchymal Transition and Regulates Cell Phenotypic Switch. Stem Cells 2019; 37:1108-1118. [PMID: 31108004 DOI: 10.1002/stem.3038] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 04/08/2019] [Accepted: 04/29/2019] [Indexed: 01/10/2023]
Abstract
Adult hepatic progenitor cells (HPCs)/oval cells are bipotential progenitors that participate in liver repair responses upon chronic injury. Recent findings highlight HPCs plasticity and importance of the HPCs niche signals to determine their fate during the regenerative process, favoring either fibrogenesis or damage resolution. Transforming growth factor-β (TGF-β) and hepatocyte growth factor (HGF) are among the key signals involved in liver regeneration and as component of HPCs niche regulates HPCs biology. Here, we characterize the TGF-β-triggered epithelial-mesenchymal transition (EMT) response in oval cells, its effects on cell fate in vivo, and the regulatory effect of the HGF/c-Met signaling. Our data show that chronic treatment with TGF-β triggers a partial EMT in oval cells based on coexpression of epithelial and mesenchymal markers. The phenotypic and functional profiling indicates that TGF-β-induced EMT is not associated with stemness but rather represents a step forward along hepatic lineage. This phenotypic transition confers advantageous traits to HPCs including survival, migratory/invasive and metabolic benefit, overall enhancing the regenerative potential of oval cells upon transplantation into a carbon tetrachloride-damaged liver. We further uncover a key contribution of the HGF/c-Met pathway to modulate the TGF-β-mediated EMT response. It allows oval cells expansion after EMT by controlling oxidative stress and apoptosis, likely via Twist regulation, and it counterbalances EMT by maintaining epithelial properties. Our work provides evidence that a coordinated and balanced action of TGF-β and HGF are critical for achievement of the optimal regenerative potential of HPCs, opening new therapeutic perspectives. Stem Cells 2019;37:1108-1118.
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Affiliation(s)
- Laura Almalé
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
| | - María García-Álvaro
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
| | - Adoración Martínez-Palacián
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
| | - María García-Bravo
- Cell Differentiation and Cytometry Unit, Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Advanced Therapies Mixed Unit, CIEMAT/IIS Fundación Jiménez Díaz, Madrid, Spain
| | - Nerea Lazcanoiturburu
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
| | - Annalisa Addante
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
| | - Cesáreo Roncero
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
| | - Julián Sanz
- Department of Pathology, Hospital Clínico San Carlos, Madrid, Spain
| | - María de la O López
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
| | - Paloma Bragado
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
| | - Wolfgang Mikulits
- Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Valentina M Factor
- Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Snorri S Thorgeirsson
- Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.,Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - J Ignacio Casal
- Department of Functional Proteomics, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | - José-Carlos Segovia
- Cell Differentiation and Cytometry Unit, Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Advanced Therapies Mixed Unit, CIEMAT/IIS Fundación Jiménez Díaz, Madrid, Spain
| | - Eduardo Rial
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | - Isabel Fabregat
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) and University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.,Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain
| | - Blanca Herrera
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
| | - Aránzazu Sánchez
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
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33
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Anderson N, Borlak J. Hepatobiliary Events in Migraine Therapy with Herbs-The Case of Petadolex, A Petasites Hybridus Extract. J Clin Med 2019; 8:jcm8050652. [PMID: 31083451 PMCID: PMC6572430 DOI: 10.3390/jcm8050652] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 04/29/2019] [Accepted: 05/03/2019] [Indexed: 12/28/2022] Open
Abstract
Petadolex®, a defined butterbur extract has clinically proven efficacy against migraine attacks. However, spontaneous reports indicate cases of herbal induced liver injury (HILI). While most HILI patients presented mild serum biochemistry changes (<3 ULN, dose range 50 to 225 mg/day; treatment duration 4–730 days) nine developed severe HILI (average time-to-onset 103 days, ALT-range 3–153; AST 2–104-fold ULN). HILI cases resolved after medication withdrawal though two patients required liver transplantation. Liver biopsies revealed an inconsistent injury pattern, i.e. necrosis, macrovesicular steatosis, inflammation, cholestasis, and bile duct proliferation. Causality assessment rated 3 cases likely, 13 possible, 8 unlikely and 24 as unclassifiable/unclassified. Note, 22 patients reported hepatotoxic co-medications especially during periods of pain. A no-observable-adverse-effect-level at 15-fold of the maximal clinical dose (3 mg/kg/day MCD) was established for rats. At >45 and 90-fold MCD bile duct hyperplasia was observed but could not be confirmed in an explorative minipig study at 218-fold MCD. Human hepatocyte studies at 49-fold Cmax serum petasins (=active ingredient) and therapeutic Ibuprofen, Paracetamol and Naratriptan concentrations evidenced liver transaminase and CYP-monooxygenase changes. Collectively, Petadolex® HILI cases are rare, idiosyncratic and frequently confounded by co-medications. A physician-supervised self-medication plan with herbs and pain relief medication is needed to minimize risk for HILI.
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Affiliation(s)
- Nora Anderson
- Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
| | - Jürgen Borlak
- Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
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Dynamism, Sensitivity, and Consequences of Mesenchymal and Stem-Like Phenotype of Cancer Cells. Stem Cells Int 2018; 2018:4516454. [PMID: 30405720 PMCID: PMC6199882 DOI: 10.1155/2018/4516454] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 08/17/2018] [Indexed: 12/16/2022] Open
Abstract
There are remarkable similarities in the description of cancer stem cells (CSCs) and cancer cells with mesenchymal phenotype. Both cell types are highly tumorigenic, resistant against common anticancer treatment, and thought to cause metastatic growth. Moreover, cancer cells are able to switch between CSC and non-CSC phenotypes and vice versa, to ensure the necessary balance within the tumor. Likewise, cancer cells can switch between epithelial and mesenchymal phenotypes via well-described transition (EMT/MET) that is thought to be crucial for tumor propagation. In this review, we discuss whether, and to which extend, the CSCs and mesenchymal cancer cells are overlapping phenomena in terms of mechanisms, origin, and implication for cancer treatment. As well, we describe the dynamism of both phenotypes and involvement of the tumor microenvironment in CSC reversion and in EMT.
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35
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Jolly MK, Somarelli JA, Sheth M, Biddle A, Tripathi SC, Armstrong AJ, Hanash SM, Bapat SA, Rangarajan A, Levine H. Hybrid epithelial/mesenchymal phenotypes promote metastasis and therapy resistance across carcinomas. Pharmacol Ther 2018; 194:161-184. [PMID: 30268772 DOI: 10.1016/j.pharmthera.2018.09.007] [Citation(s) in RCA: 215] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cancer metastasis and therapy resistance are the major unsolved clinical challenges, and account for nearly all cancer-related deaths. Both metastasis and therapy resistance are fueled by epithelial plasticity, the reversible phenotypic transitions between epithelial and mesenchymal phenotypes, including epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET). EMT and MET have been largely considered as binary processes, where cells detach from the primary tumor as individual units with many, if not all, traits of a mesenchymal cell (EMT) and then convert back to being epithelial (MET). However, recent studies have demonstrated that cells can metastasize in ways alternative to traditional EMT paradigm; for example, they can detach as clusters, and/or occupy one or more stable hybrid epithelial/mesenchymal (E/M) phenotypes that can be the end point of a transition. Such hybrid E/M cells can integrate various epithelial and mesenchymal traits and markers, facilitating collective cell migration. Furthermore, these hybrid E/M cells may possess higher tumor-initiation and metastatic potential as compared to cells on either end of the EMT spectrum. Here, we review in silico, in vitro, in vivo and clinical evidence for the existence of one or more hybrid E/M phenotype(s) in multiple carcinomas, and discuss their implications in tumor-initiation, tumor relapse, therapy resistance, and metastasis. Together, these studies drive the emerging notion that cells in a hybrid E/M phenotype may occupy 'metastatic sweet spot' in multiple subtypes of carcinomas, and pathways linked to this (these) hybrid E/M state(s) may be relevant as prognostic biomarkers as well as a promising therapeutic targets.
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Affiliation(s)
- Mohit Kumar Jolly
- Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.
| | - Jason A Somarelli
- Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, USA
| | - Maya Sheth
- Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, USA
| | - Adrian Biddle
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Satyendra C Tripathi
- Department of Clinical Cancer Prevention, UT MD Anderson Cancer Center, Houston, USA
| | - Andrew J Armstrong
- Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, USA
| | - Samir M Hanash
- Department of Clinical Cancer Prevention, UT MD Anderson Cancer Center, Houston, USA
| | - Sharmila A Bapat
- National Center for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, India
| | - Annapoorni Rangarajan
- Department of Molecular Reproduction, Development & Genetics, Indian Institute of Science, Bangalore, India
| | - Herbert Levine
- Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.
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Modeling of mesenchymal hybrid epithelial state and phenotypic transitions in EMT and MET processes of cancer cells. Sci Rep 2018; 8:14323. [PMID: 30254295 PMCID: PMC6156327 DOI: 10.1038/s41598-018-32737-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 09/12/2018] [Indexed: 02/06/2023] Open
Abstract
Based on the transcriptional regulatory mechanisms between microRNA-200 and transcription factor ZEB in an individual cancer cell, a minimal dynamic model is proposed to study the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) processes of cancer cells. It is shown that each cancer cell can exit in any of three phenotypic states: the epithelial (E) state, the mesenchymal (M) state, and the epithelial/mesenchymal (E/M) hybrid state, and the state of cancer cell can interconvert between different states. The phase diagram shows that there are monostable, bistable, and tristable phenotypic states regions in a parameters plane. It is found that different pathway in the phase diagram can correspond to the EMT or the MET process of cancer cells, and there are two possible EMT processes. It is important that the experimental phenomenon of E/M hybrid state appearing in the EMT process but rather in the MET process can be understood through different pathways in the phase diagram. Our numerical simulations show that the effects of noise are opposite to these of time delay on the expression of transcription factor ZEB, and there is competition between noise and time delay in phenotypic transitions process of cancer cells.
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37
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Chen J, Chen CY, Nguyen C, Chen L, Lee K, Stiles BL. Emerging signals regulating liver tumor initiating cells. LIVER RESEARCH 2018. [DOI: 10.1016/j.livres.2018.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Wu Y, Ding ZY, Jin GN, Xiong YX, Yu B, Sun YM, Wang W, Liang HF, Zhang B, Chen XP. Autocrine transforming growth factor-β/activin A-Smad signaling induces hepatic progenitor cells undergoing partial epithelial-mesenchymal transition states. Biochimie 2018; 148:87-98. [PMID: 29544731 DOI: 10.1016/j.biochi.2018.03.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Accepted: 03/05/2018] [Indexed: 12/17/2022]
Abstract
Hepatic progenitor cells (HPCs) are a subpopulation of cells which was usually expanded in chronic liver injury and are contributed to liver regeneration through differentiating into hepatocytes and cholangiocytes. Epithelial-mesenchymal transition is a dynamic process which is important for the progression of liver fibrosis and cancer initiation. This study demonstrated that LE/6 and WB-F344 cells, both of which were HPC derived cell lines, were undergoing partial epithelial-mesenchymal transition states, which was indicated by the co-expression of epithelial markers (E-cadherin and zona occludin 1), and mesenchymal markers (vimentin, fibronectin, collagen 1and α-SMA). Furthermore, autocrine TGF-β and activin A signaling contributed to the maintenance of partial EMT in HPCs. In addition, Smad signaling, a classic downstream signaling cascade of both TGF-β and activin A, also participated in the partial EMT. These findings revealed the existence of partial EMT states in HPCs and confirmed some partial EMT related autocrine signaling cascades, and may help to further the understanding and explore the functional role of HPCs in the process of hepatic fibrosis and liver cancer initiation.
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Affiliation(s)
- Yu Wu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
| | - Ze-Yang Ding
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
| | - Guan-Nan Jin
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
| | - Yi-Xiao Xiong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
| | - Bin Yu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
| | - Yi-Min Sun
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
| | - Wei Wang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
| | - Hui-Fang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
| | - Xiao-Ping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
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Chien CS, Chen YH, Chen HL, Wang CP, Wu SH, Ho SL, Huang WC, Yu CH, Chang MH. Cells responsible for liver mass regeneration in rats with 2-acetylaminofluorene/partial hepatectomy injury. J Biomed Sci 2018; 25:39. [PMID: 29695258 PMCID: PMC5937839 DOI: 10.1186/s12929-018-0441-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 04/20/2018] [Indexed: 12/17/2022] Open
Abstract
Background Whether hepatic progenitor cells (HPCs)/oval cells regenerate liver mass upon chronic liver injury is controversial in mice and has not been conclusively proven in humans and rats. In this study, we examined which cell type—hepatocytes or oval cells—mediates liver regeneration in the classic rat 2-acetylaminofluorene (AAF)/partial hepatectomy (PH) injury where AAF reversibly blocks hepatocyte proliferation, thereby inducing oval cell expansion after the regenerative stimulus of PH. Methods We employed lineage tracing of dipeptidyl peptidase IV (DPPIV, a hepatocyte canalicular enzyme)-positive hepatocytes by subjecting rats with DPPIV-chimeric livers to AAF/PH, AAF/PH/AAF (continuous AAF after AAF/PH to nonselectively inhibit regenerating hepatocytes), or AAF/PH/retrorsine injury (2-dose retrorsine after AAF/PH to specifically and irreversibly block existing hepatocytes); through these methods, we determined hepatocyte contribution to liver regeneration. To determine the oval cell contribution to hepatocyte regeneration, we performed DPPIV(+) oval cell transplantation combined with AAF/PH injury or AAF/PH/retrorsine injury in DPPIV-deficient rats to track the fate of DPPIV(+) oval cells. Results DPPIV-chimeric livers demonstrated typical oval cell activation upon AAF/PH injury. After cessation of AAF, DPPIV(+) hepatocytes underwent extensive proliferation to regenerate the liver mass, whereas oval cells underwent hepatocyte differentiation. Upon AAF/PH/AAF injury where hepatocyte proliferation was inhibited by continuous AAF treatment following AAF/PH, oval cells extensively expanded in an undifferentiated state but did not produce hepatocytes. By substituting retrorsine for AAF administration following AAF/PH (AAF/PH/retrorsine), oval cells regenerated large-scale hepatocytes. Conclusions Hepatocyte self-replication provides the majority of hepatocyte regeneration, with supplementary contribution from oval cells in rats under AAF/PH injury. Oval cells expand and maintain in an undifferentiated state upon continuously nonselective liver injury, whereas they can significantly regenerate hepatocytes in a noncompetitive environment.
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Affiliation(s)
- Chin-Sung Chien
- Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation. No.289, Jianguo Rd., Xindian Dist, New Taipei City, 23142, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University . No.7, Chung Shan South Rd., Zhongzheng Dist, Taipei, 10002, Taiwan
| | - Ya-Hui Chen
- Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation. No.289, Jianguo Rd., Xindian Dist, New Taipei City, 23142, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University . No.7, Chung Shan South Rd., Zhongzheng Dist, Taipei, 10002, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital. No.1, Changde St., Zhongzheng Dist, Taipei, 10048, Taiwan
| | - Hui-Ling Chen
- Hepatitis Research Center, National Taiwan University Hospital. No.1, Changde St., Zhongzheng Dist, Taipei, 10048, Taiwan
| | - Chiu-Ping Wang
- Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation. No.289, Jianguo Rd., Xindian Dist, New Taipei City, 23142, Taiwan
| | - Shang-Hsin Wu
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University . No.7, Chung Shan South Rd., Zhongzheng Dist, Taipei, 10002, Taiwan
| | - Shu-Li Ho
- Hepatitis Research Center, National Taiwan University Hospital. No.1, Changde St., Zhongzheng Dist, Taipei, 10048, Taiwan
| | - Wen-Cheng Huang
- Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation. No.289, Jianguo Rd., Xindian Dist, New Taipei City, 23142, Taiwan
| | - Chun-Hsien Yu
- Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation. No.289, Jianguo Rd., Xindian Dist, New Taipei City, 23142, Taiwan. .,Department of Pediatrics, School of Medicine, Tzu Chi University, No.701, Sec. 3, Zhongyang Rd, Hualien, 97004, Taiwan.
| | - Mei-Hwei Chang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University . No.7, Chung Shan South Rd., Zhongzheng Dist, Taipei, 10002, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital. No.1, Changde St., Zhongzheng Dist, Taipei, 10048, Taiwan.,Department of Pediatrics, National Taiwan University Hospital, and College of Medicine, National Taiwan University. No.8, Chung Shan South Rd., Zhongzheng Dist, Taipei, 10041, Taiwan
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40
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function, and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:1-87. [DOI: 10.1016/b978-0-7020-6697-9.00001-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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41
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Abstract
Fibrosis of the liver is an inherent wound healing response to chronic liver injury. Regeneration of liver epithelium and restoration of normal liver structure were generally involved in this process. Although the liver has a striking capacity to adapt to damage through tissue repair, excessive accumulation of extracellular matrix during this process often leads to scar tissue formation and subsequent fibrosis. Epithelial to mesenchymal transition (EMT) enables a polarized epithelial cell to undergo multiple changes biochemically and to bear a mesenchymal cell phenotype. EMT plays a critical role in tissue and organ development and embryogenesis. In the liver, it is proposed that epithelial cells can acquire fibroblastic phonotype via EMT and contribute to fibrogenesis. This made EMT a potential target for antifibrotic strategies. Following an original passion, many investigators devote themselves to exploring this mechanism in liver fibrosis. However, as research continues, this hypothesis became highly controversial. The exact contribution of EMT to fibrogenesis was challenged due to the contradictory results from related studies. In this review, we summarized the recent advances regarding EMT in hepatic fibrosis and discussed the potentially involved liver cell types and pathways in order to reach rational and helpful conclusions.
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Affiliation(s)
- Kangkang Yu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Qian Li
- Department of General Surgery, Qingdao Municipal Hospital, Qingdao, People's Republic of China
| | - Guangfeng Shi
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Ning Li
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China,Address for correspondence: Dr. Ning Li, Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai – 200040, People's Republic of China. E-mail:
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42
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Tomita H, Kanayama T, Niwa A, Noguchi K, Tanaka T, Hara A. The Stem Cells in Liver Cancers and the Controversies. STEM CELLS AND CANCER IN HEPATOLOGY 2018:273-287. [DOI: 10.1016/b978-0-12-812301-0.00013-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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43
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Choi YJ, Kim H, Kim JW, Song CW, Kim DS, Yoon S, Park HJ. Phthalazinone Pyrazole Enhances the Hepatic Functions of Human Embryonic Stem Cell-Derived Hepatocyte-Like Cells via Suppression of the Epithelial-Mesenchymal Transition. Stem Cell Rev Rep 2017; 14:438-450. [PMID: 29238913 DOI: 10.1007/s12015-017-9795-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
During liver development, nonpolarized hepatic progenitor cells differentiate into mature hepatocytes with distinct polarity. This polarity is essential for maintaining the intrinsic properties of hepatocytes. The balance between the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) plays a decisive role in differentiation of polarized hepatocytes. In this study, we found that phthalazinone pyrazole (PP), a selective inhibitor of Aurora-A kinase (Aurora-A), suppressed the EMT during the differentiation of hepatocyte-like cells (HLCs) from human embryonic stem cells. The differentiated HLCs treated with PP at the hepatoblast stage showed enhanced hepatic morphology and functions, particularly with regard to the expression of drug metabolizing enzymes. Moreover, we found that these effects were mediated though suppression of the AKT pathway, which is involved in induction of the EMT, and upregulation of hepatocyte nuclear factor 4α expression rather than Aurora-A inhibition. In conclusion, these findings provided insights into the regulatory role of the EMT on in vitro hepatic maturation, suggesting that inhibition of the EMT may drive transformation of hepatoblast cells into mature and polarized HLCs.
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Affiliation(s)
- Young-Jun Choi
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea
- Human and Environmental Toxicology, School of Engineering, University of Science and Technology, Daejeon, 34113, Republic of Korea
| | - Hyemin Kim
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea
| | - Ji-Woo Kim
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea
| | - Chang-Woo Song
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea
- Human and Environmental Toxicology, School of Engineering, University of Science and Technology, Daejeon, 34113, Republic of Korea
| | - Dae-Sung Kim
- Department of Biotechnology, Brain Korea 21, Korea University, Seoul, 02841, Republic of Korea
| | - Seokjoo Yoon
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea
- Human and Environmental Toxicology, School of Engineering, University of Science and Technology, Daejeon, 34113, Republic of Korea
| | - Han-Jin Park
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
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Jolly MK, Tripathi SC, Jia D, Mooney SM, Celiktas M, Hanash SM, Mani SA, Pienta KJ, Ben-Jacob E, Levine H. Stability of the hybrid epithelial/mesenchymal phenotype. Oncotarget 2017; 7:27067-84. [PMID: 27008704 PMCID: PMC5053633 DOI: 10.18632/oncotarget.8166] [Citation(s) in RCA: 299] [Impact Index Per Article: 37.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 03/07/2016] [Indexed: 12/16/2022] Open
Abstract
Epithelial-to-Mesenchymal Transition (EMT) and its reverse – Mesenchymal to Epithelial Transition (MET) – are hallmarks of cellular plasticity during embryonic development and cancer metastasis. During EMT, epithelial cells lose cell-cell adhesion and gain migratory and invasive traits either partially or completely, leading to a hybrid epithelial/mesenchymal (hybrid E/M) or a mesenchymal phenotype respectively. Mesenchymal cells move individually, but hybrid E/M cells migrate collectively as observed during gastrulation, wound healing, and the formation of tumor clusters detected as Circulating Tumor Cells (CTCs). Typically, the hybrid E/M phenotype has largely been tacitly assumed to be transient and ‘metastable’. Here, we identify certain ‘phenotypic stability factors’ (PSFs) such as GRHL2 that couple to the core EMT decision-making circuit (miR-200/ZEB) and stabilize hybrid E/M phenotype. Further, we show that H1975 lung cancer cells can display a stable hybrid E/M phenotype and migrate collectively, a behavior that is impaired by knockdown of GRHL2 and another previously identified PSF - OVOL. In addition, our computational model predicts that GRHL2 can also associate hybrid E/M phenotype with high tumor-initiating potential, a prediction strengthened by the observation that the higher levels of these PSFs may be predictive of poor patient outcome. Finally, based on these specific examples, we deduce certain network motifs that can stabilize the hybrid E/M phenotype. Our results suggest that partial EMT, i.e. a hybrid E/M phenotype, need not be ‘metastable’, and strengthen the emerging notion that partial EMT, but not necessarily a complete EMT, is associated with aggressive tumor progression.
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Affiliation(s)
- Mohit Kumar Jolly
- Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.,Department of Bioengineering, Rice University, Houston, TX, USA
| | - Satyendra C Tripathi
- Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dongya Jia
- Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.,Graduate Program in Systems, Synthetic and Physical Biology, Rice University, Houston, TX, USA
| | - Steven M Mooney
- Department of Biology, University of Waterloo, Waterloo, ON, Canada
| | - Muge Celiktas
- Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Samir M Hanash
- Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Red and Charline McCombs Institute for The Early Detection and Treatment of Cancer, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sendurai A Mani
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kenneth J Pienta
- The James Brady Urological Institute, and Departments of Urology, Oncology, Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Eshel Ben-Jacob
- Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.,Graduate Program in Systems, Synthetic and Physical Biology, Rice University, Houston, TX, USA.,School of Physics and Astronomy and The Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel
| | - Herbert Levine
- Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.,Department of Bioengineering, Rice University, Houston, TX, USA.,Department of Physics and Astronomy, Rice University, Houston, TX, USA.,Department of Biosciences, Rice University, Houston, TX, USA
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Li YW, Zhang C, Sheng QJ, Bai H, Ding Y, Dou XG. Mesenchymal stem cells rescue acute hepatic failure by polarizing M2 macrophages. World J Gastroenterol 2017; 23:7978-7988. [PMID: 29259373 PMCID: PMC5725292 DOI: 10.3748/wjg.v23.i45.7978] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 10/01/2017] [Accepted: 11/01/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate whether M1 or M2 polarization contributes to the therapeutic effects of mesenchymal stem cells (MSCs) in acute hepatic failure (AHF).
METHODS MSCs were transfused into rats with AHF induced by D-galactosamine (DGalN). The therapeutic effects of MSCs were evaluated based on survival rate and hepatocyte proliferation and apoptosis. Hepatocyte regeneration capacity was evaluated by the expression of the hepatic progenitor surface marker epithelial cell adhesion molecule (EpCAM). Macrophage polarization was analyzed by M1 markers [CD68, tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ), inducible nitric oxide synthase (INOS)] and M2 markers [CD163, interleukin (IL)-4, IL-10, arginase-1 (Arg-1)] in the survival and death groups after MSC transplantation.
RESULTS The survival rate in the MSC-treated group was increased compared with the DPBS-treated control group (37.5% vs 10%). MSC treatment protected rats with AHF by reducing apoptotic hepatocytes and promoting hepatocyte regeneration. Immunohistochemical analysis showed that MSC treatment significantly increased the expression of EpCAM compared with the control groups (P < 0.001). Expression of EpCAM in the survival group was significantly up-regulated compared with the death group after MSC transplantation (P = 0.003). Transplantation of MSCs significantly improved the expression of CD163 and increased the gene expression of IL-10 and Arg-1 in the survival group. IL-4 concentrations were significantly increased compared to the death group after MSC transplantation (88.51 ± 24.51 pg/mL vs 34.61 ± 6.6 pg/mL, P < 0.001). In contrast, macrophages showed strong expression of CD68, TNF-α, and INOS in the death group. The concentration of IFN-γ was significantly increased compared to the survival group after MSC transplantation (542.11 ± 51.59 pg/mL vs 104.07 ± 42.80 pg/mL, P < 0.001).
CONCLUSION M2 polarization contributes to the therapeutic effects of MSCs in AHF by altering levels of anti-inflammatory and pro-inflammatory factors.
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Affiliation(s)
- Yan-Wei Li
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Chong Zhang
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Qiu-Ju Sheng
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Han Bai
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Yang Ding
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Xiao-Guang Dou
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
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Bria A, Marda J, Zhou J, Sun X, Cao Q, Petersen BE, Pi L. Hepatic progenitor cell activation in liver repair. LIVER RESEARCH (BEIJING, CHINA) 2017; 1:81-87. [PMID: 29276644 PMCID: PMC5739327 DOI: 10.1016/j.livres.2017.08.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The liver possesses an extraordinary ability to regenerate after injury. Hepatocyte-driven liver regeneration is the default pathway in response to mild-to-moderate acute liver damage. When replication of mature hepatocytes is blocked, facultative hepatic progenitor cells (HPCs), also referred to as oval cells (OCs) in rodents, are activated. HPC/OCs have the ability to proliferate clonogenically and differentiate into several lineages including hepatocytes and bile ductal epithelia. This is a conserved liver injury response that has been studied in many species ranging from mammals (rat, mouse, and human) to fish. In addition, improper HPC/OC activation is closely associated with fibrotic responses, characterized by myofibroblast activation and extracellular matrix production, in many chronic liver diseases. Matrix remodeling and metalloprotease activities play an important role in the regulation of HPC/OC proliferation and fibrosis progression. Thus, understanding molecular mechanisms underlying HPC/OC activation has therapeutic implications for rational design of anti-fibrotic therapies.
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Affiliation(s)
- Adam Bria
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Jorgessen Marda
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Junmei Zhou
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Xiaowei Sun
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Qi Cao
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Bryon E. Petersen
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Liya Pi
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
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Chen J, Chen L, Zern MA, Theise ND, Diehl AM, Liu P, Duan Y. The diversity and plasticity of adult hepatic progenitor cells and their niche. Liver Int 2017; 37:1260-1271. [PMID: 28135758 PMCID: PMC5534384 DOI: 10.1111/liv.13377] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Accepted: 01/23/2017] [Indexed: 12/12/2022]
Abstract
The liver is a unique organ for homoeostasis with regenerative capacities. Hepatocytes possess a remarkable capacity to proliferate upon injury; however, in more severe scenarios liver regeneration is believed to arise from at least one, if not several facultative hepatic progenitor cell compartments. Newly identified pericentral stem/progenitor cells residing around the central vein is responsible for maintaining hepatocyte homoeostasis in the uninjured liver. In addition, hepatic progenitor cells have been reported to contribute to liver fibrosis and cancers. What drives liver homoeostasis, regeneration and diseases is determined by the physiological and pathological conditions, and especially the hepatic progenitor cell niches which influence the fate of hepatic progenitor cells. The hepatic progenitor cell niches are special microenvironments consisting of different cell types, releasing growth factors and cytokines and receiving signals, as well as the extracellular matrix (ECM) scaffold. The hepatic progenitor cell niches maintain and regulate stem cells to ensure organ homoeostasis and regeneration. In recent studies, more evidence has been shown that hepatic cells such as hepatocytes, cholangiocytes or myofibroblasts can be induced to be oval cell-like state through transitions under some circumstance, those transitional cell types as potential liver-resident progenitor cells play important roles in liver pathophysiology. In this review, we describe and update recent advances in the diversity and plasticity of hepatic progenitor cell and their niches and discuss evidence supporting their roles in liver homoeostasis, regeneration, fibrosis and cancers.
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Affiliation(s)
- Jiamei Chen
- Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases of Ministry of Education of China, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai key laboratory of Traditional Chinese Medicine, Shanghai 201203, China
- E-institutes of Shanghai Municipal Education Commission, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Internal Medicine, University of California Davis Medical Center, Sacramento, California, USA
- Institute for Regenerative Cures, University of California Davis Medical Center, Sacramento, California, USA
| | - Long Chen
- Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases of Ministry of Education of China, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai key laboratory of Traditional Chinese Medicine, Shanghai 201203, China
| | - Mark A Zern
- Department of Internal Medicine, University of California Davis Medical Center, Sacramento, California, USA
- Institute for Regenerative Cures, University of California Davis Medical Center, Sacramento, California, USA
| | - Neil D. Theise
- Departments of Pathology and Medicine, Beth Israel Medical Center of Albert Einstein College of Medicine, New York, New York, USA
| | - Ann Mae Diehl
- Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina, USA
| | - Ping Liu
- Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases of Ministry of Education of China, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai key laboratory of Traditional Chinese Medicine, Shanghai 201203, China
- E-institutes of Shanghai Municipal Education Commission, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuyou Duan
- Department of Internal Medicine, University of California Davis Medical Center, Sacramento, California, USA
- Institute for Regenerative Cures, University of California Davis Medical Center, Sacramento, California, USA
- Department of Dermatology, University of California Davis Medical Center, Sacramento, California, USA
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Dysregulation of miR-223 constitutes a promising biomarker that informs about clinical outcomes of acute liver failure. Clin Sci (Lond) 2017; 131:2059-2062. [PMID: 28729435 DOI: 10.1042/cs20171129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 06/30/2017] [Accepted: 07/07/2017] [Indexed: 12/24/2022]
Abstract
In this issue of Clinical Science, Schueller et al. [Clin. Sci. (2017) 131, 1971-1987] evaluated the role of miR-223 across multiple etiologies of acute and chronic liver insults in murine models and clinical samples. The authors find that while miR-223 is not mechanistically involved in liver injury, its intracellular levels in hepatocytes are increased upon hepatic damage in a broad panel of mechanistically distinct injury models. Furthermore, the authors provide evidence that circulating miR-223 levels provide a promising minimally invasive biomarker for acute liver failure (ALF) that defines a distinct subset of ALF cases and correlates with clinical outcomes. Combined, the highlighted study suggests that miR-223 constitutes a promising biomarker whose clinical validity and utility warrant further investigations.
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Ultrastructural Characteristics of Rat Hepatic Oval Cells and Their Intercellular Contacts in the Model of Biliary Fibrosis: New Insights into Experimental Liver Fibrogenesis. Gastroenterol Res Pract 2017; 2017:2721547. [PMID: 28769978 PMCID: PMC5523291 DOI: 10.1155/2017/2721547] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 05/02/2017] [Indexed: 12/23/2022] Open
Abstract
PURPOSE Recently, it has been emphasized that hepatic progenitor/oval cells (HPCs) are significantly involved in liver fibrogenesis. We evaluated the multipotential population of HPCs by transmission electron microscope (TEM), including relations with adherent hepatic nonparenchymal cells (NPCs) in rats with biliary fibrosis induced by bile duct ligation (BDL). METHODS The study used 6-week-old Wistar Crl: WI(Han) rats after BDL for 1, 6, and 8 weeks. RESULTS Current ultrastructural analysis showed considerable proliferation of HPCs in experimental intensive biliary fibrosis. HPCs formed proliferating bile ductules and were scattered in periportal connective tissue. We distinguished 4 main types of HPCs: 0, I, II (bile duct-like cells; most common), and III (hepatocyte-like cells). We observed, very seldom presented in literature, cellular interactions between HPCs and adjacent NPCs, especially commonly found transitional hepatic stellate cells (T-HSCs) and Kupffer cells/macrophages. We showed the phenomenon of penetration of the basement membrane of proliferating bile ductules by cytoplasmic processes sent by T-HSCs and the formation of direct cell-cell contact with ductular epithelial cells related to HPCs. CONCLUSIONS HPC proliferation induced by BDL evidently promotes portal fibrogenesis. Better understanding of the complex cellular interactions between HPCs and adjacent NPCs, especially T-HSCs, may help develop antifibrotic therapies in the future.
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50
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Chen J, Li X, Hu Y, Liu W, Zhou Q, Zhang H, Mu Y, Liu P. Gypenosides Ameliorate Carbon Tetrachloride-Induced Liver Fibrosis by Inhibiting the Differentiation of Hepatic Progenitor Cells into Myofibroblasts. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2017; 45:1061-1074. [PMID: 28659031 DOI: 10.1142/s0192415x17500574] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Gypenosides (GPs), the predominant components of Gynostemma pentaphyllum, exert antifibrotic effects; however, the mechanisms underlying their ability to ameliorate liver fibrosis are unclear. Liver fibrosis was induced in C57BL/6 mice via subcutaneous injection of 10% carbon tetrachloride (CCl[Formula: see text] three times a week for two weeks. Then, CCl4 was administered in conjunction with intragastric GPs for another three weeks. For in vitro analyses, WB-F344, hepatatic progenitor cells (HPCs) were treated with transforming growth factor beta 1 (TGF-[Formula: see text]1) with or without GPs for 48[Formula: see text]h. The results showed that alanine aminotransferase (ALT) and aspartate transaminase (AST) activity, deposition of collagen, hydroxyproline content, and expression of alpha-smooth muscle actin ([Formula: see text]-SMA) and collagen type I (Col I) were significantly decreased after treatment with GPs ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text]). In the 5M CCl4 group, the expression of HPC markers, Sox9 and cytokeratin 19 (CK19), was significantly increased compared with the normal or GPs-treated group ([Formula: see text], [Formula: see text]). Immunostaining showed that the number of Sox9 and [Formula: see text]-SMA double-positive cells was higher in the 5M CCl4 group than in the normal group, but the addition of GPs caused this cell number to decrease. In WB-F344 cells, the expression of [Formula: see text]-SMA and Col I was significantly increased after treatment with TGF-[Formula: see text], whereas in the GPs treatment group, expression was markedly decreased ([Formula: see text]). The levels of TGF-[Formula: see text] and TGF-[Formula: see text]R1 were markedly reduced after GPs treatment both in vivo and in vitro. In conclusion, GPs ameliorated CCl4-induced liver fibrosis via the inhibition of TGF-[Formula: see text] signaling, consequently inhibiting the differentiation of HPCs into myofibroblasts.
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Affiliation(s)
- Jiamei Chen
- * Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- † Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xuewei Li
- * Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- † Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yonghong Hu
- * Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- † Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wei Liu
- * Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- † Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qun Zhou
- * Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- † Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hua Zhang
- * Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- † Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yongping Mu
- * Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- † Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ping Liu
- * Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- † Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai 201203, China
- ‡ E-Institute of Shanghai Municipal Education Commission, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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