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Jiang N, Li G, Luo S, Kong X, Yin S, Peng J, Jiang Y, Tao W, Li C, Xie H, Deng H, Xie B. Single-cell transcriptomics reveals liver developmental trajectory during lineage reprogramming of human induced hepatocyte-like cells. Cell Mol Life Sci 2025; 82:139. [PMID: 40188417 PMCID: PMC11973031 DOI: 10.1007/s00018-025-05677-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 03/11/2025] [Accepted: 03/24/2025] [Indexed: 04/08/2025]
Abstract
Hepatocytes are crucial for drug screening, disease modeling, and clinical transplantation, yet generating functional hepatocytes in vitro is challenging due to the difficulty of establishing their authentic gene regulatory networks (GRNs). We have previously developed a two-step lineage reprogramming strategy to generate functionally competent human induced hepatocytes (hiHeps), providing an effective model for studying the establishment of hepatocyte-specific GRNs. In this study, we utilized high-throughput single-cell RNA sequencing (scRNA-seq) to explore the cell-fate transition and the establishment of hepatocyte-specific GRNs involved in the two-step reprogramming process. Our findings revealed that the late stage of the reprogramming process mimics the natural trajectory of liver development, exhibiting similar transcriptional waves of developmental genes. CD24 and DLK1 were identified as surface markers enriching two distinct hepatic progenitor populations respectively. Lipid metabolism emerged as a key enhancer of hiHeps maturation. Furthermore, transcription factors HNF4A and HHEX were identified as pivotal gatekeepers directing cell fate decisions between hepatocytes and intestinal cells. Collectively, this study provides valuable insights into the establishment of hepatocyte-specific GRNs during hiHeps induction at single-cell resolution, facilitating more efficient production of functional hepatocytes for therapeutic applications.
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Affiliation(s)
- Nan Jiang
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou, China
- Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China
| | - Guangya Li
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Sen Luo
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou, China
- Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China
| | - Xi Kong
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou, China
- Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China
| | - Shigang Yin
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou, China
- Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China
| | - Jianhua Peng
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou, China
- Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China
| | - Yong Jiang
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou, China
- Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China
| | - Wei Tao
- Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
| | - Cheng Li
- School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China
| | - Huangfan Xie
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou, China.
- Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China.
| | - Hongkui Deng
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
- Changping Laboratory, Beijing, China.
| | - Bingqing Xie
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou, China.
- Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China.
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Zhao X, Wang S, Liu Q, Wei W, Sun X, Song H, Xu J, Zhang S, Wang H, Fu J. Single-cell landscape of the intrahepatic ecosystem in alcohol-related liver disease. Clin Transl Med 2025; 15:e70198. [PMID: 39834100 PMCID: PMC11746962 DOI: 10.1002/ctm2.70198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 01/05/2025] [Accepted: 01/10/2025] [Indexed: 01/22/2025] Open
Abstract
Alcohol-related liver disease (ALD) is a common chronic liver disease caused by long-term excessive alcohol consumption and responsible for more than half of all liver-related deaths worldwide. The molecular mechanisms associated with ALD were not fully understood. In this study, we performed single-cell RNA sequencing on liver tissues obtained from ALD patients and healthy liver donors. We identified an ALB+KRT7+ epithelial population that expressed both hepatocyte and biliary markers significantly expanded in ALD livers. The ALB+KRT7+ epithelial cells were demonstrated to have stem cell properties and malignant transformation potentials. Moreover, ALB+KRT7+ epithelium-derived ALD organoids promote the tumour growth by activating Wnt/β-catenin signalling of liver cancer cells. Most importantly, blocking the Wnt protein secretion or knockdown the Wnt receptor suppressed the tumour promoting effect of ALD organoids. Our study provides important insights that Wnt signalling can be targeted in patients with advanced alcohol-related cirrhosis to prevent malignant transformation. In addition, our results also uncovered the important alterations of nonparenchymal cells, especially macrophages and T/NK populations that responsible for active inflammation responses in alcohol-related hepatitis and immunosuppressive microenvironment in advanced cirrhosis livers, which likely facilitated the malignant progression of ALD. KEY POINTS: This study provides single-cell landscape of human liver samples across different ALD stages. The ALB+ KRT7+ epithelium were enriched in ALD patients, and the function of this epithelial population varied significantly across ALD stages. ALB+KRT7+ epithelium from advanced alcohol-related cirrhosis had malignant transformation potential and tumour promotion activity. The comprehensive changes of parenchymal and nonparenchymal cells in the ALD livers lay a hidden danger for the further malignant progression.
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Affiliation(s)
- Xiaofang Zhao
- Translational Medicine CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepatobiliary Tumor BiologyEastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical UniversityShanghaiChina
| | - Senyan Wang
- Translational Medicine CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Qi Liu
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Wenjuan Wei
- Translational Medicine CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Xiaoyan Sun
- Translational Medicine CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Hao Song
- Translational Medicine CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Jing Xu
- Translational Medicine CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Hongyang Wang
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepatobiliary Tumor BiologyEastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical UniversityShanghaiChina
| | - Jing Fu
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepatobiliary Tumor BiologyEastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical UniversityShanghaiChina
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Xu C, Fang X, Song Y, Xiang Z, Xu X, Wei X. Transcriptional Control: A Directional Sign at the Crossroads of Adult Hepatic Progenitor Cells' Fates. Int J Biol Sci 2024; 20:3544-3556. [PMID: 38993564 PMCID: PMC11234216 DOI: 10.7150/ijbs.93739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 05/31/2024] [Indexed: 07/13/2024] Open
Abstract
Hepatic progenitor cells (HPCs) have a bidirectional potential to differentiate into hepatocytes and bile duct epithelial cells and constitute a second barrier to liver regeneration in the adult liver. They are usually located in the Hering duct in the portal vein region where various cells, extracellular matrix, cytokines, and communication signals together constitute the niche of HPCs in homeostasis to maintain cellular plasticity. In various types of liver injury, different cellular signaling streams crosstalk with each other and point to the inducible transcription factor set, including FoxA1/2/3, YB-1, Foxl1, Sox9, HNF4α, HNF1α, and HNF1β. These transcription factors exert different functions by binding to specific target genes, and their products often interact with each other, with diverse cascades of regulation in different molecular events that are essential for homeostatic regulation, self-renewal, proliferation, and selective differentiation of HPCs. Furthermore, the tumor predisposition of adult HPCs is found to be significantly increased under transcriptional factor dysregulation in transcriptional analysis, and the altered initial commitment of the differentiation pathway of HPCs may be one of the sources of intrahepatic tumors. Related transcription factors such as HNF4α and HNF1 are expected to be future targets for tumor treatment.
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Affiliation(s)
- Chenhao Xu
- Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Xixi Fang
- Hangzhou Normal University, Hangzhou 310006, China
| | - Yisu Song
- Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Ze Xiang
- Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Xuyong Wei
- Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
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Zhao H, Ling Y, He J, Dong J, Mo Q, Wang Y, Zhang Y, Yu H, Tang C. Potential targets and therapeutics for cancer stem cell-based therapy against drug resistance in hepatocellular carcinoma. Drug Resist Updat 2024; 74:101084. [PMID: 38640592 DOI: 10.1016/j.drup.2024.101084] [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: 02/26/2024] [Revised: 03/22/2024] [Accepted: 04/06/2024] [Indexed: 04/21/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most common digestive malignancyin the world, which is frequently diagnosed at late stage with a poor prognosis. For most patients with advanced HCC, the therapeutic options arelimiteddue to cancer occurrence of drug resistance. Hepatic cancer stem cells (CSCs) account for a small subset of tumor cells with the ability of self-renewal and differentiationin HCC. It is widely recognized that the presence of CSCs contributes to primary and acquired drug resistance. Therefore, hepatic CSCs-targeted therapy is considered as a promising strategy to overcome drug resistance and improve therapeutic outcome in HCC. In this article, we review drug resistance in HCC and provide a summary of potential targets for CSCs-based therapy. In addition, the development of CSCs-targeted therapeuticsagainst drug resistance in HCC is summarized in both preclinical and clinical trials. The in-depth understanding of CSCs-related drug resistance in HCC will favor optimization of the current therapeutic strategies and gain encouraging therapeutic outcomes.
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Affiliation(s)
- Hongxing Zhao
- Department of Radiology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Yuhang Ling
- Central Laboratory, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Huzhou Key Laboratory of Translational Medicine, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Jie He
- Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Jinling Dong
- Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Qinliang Mo
- Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Yao Wang
- Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Ying Zhang
- Central Laboratory, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Hongbin Yu
- Department of General Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Chengwu Tang
- Huzhou Key Laboratory of Translational Medicine, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China.
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Ping D, Qi J, Li M, Sun X, Peng Y, Liu C. Fuzheng Huayu recipe alleviates liver fibrosis via inhibiting NLRP3 inflammasome activation in macrophages. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:117001. [PMID: 37544346 DOI: 10.1016/j.jep.2023.117001] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 07/26/2023] [Accepted: 08/02/2023] [Indexed: 08/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Fuzheng Huayu recipe (FZHY) is a commonly used Traditional Chinese Medicine formula for treating liver fibrosis in clinical settings. Despite its widespread use, the specific curative effects and underlying pharmacological mechanisms of FZHY in treating liver fibrosis are not yet fully understood. AIM AND STUDY This study aims to investigate the antifibrotic mechanism of FZHY treatment by exploring its effects on the activation of NOD-like receptor protein 3 (NLRP3) inflammasome in macrophages. MATERIALS AND METHODS In order to investigate the impact of FZHY on the activation and priming of NLRP3 inflammasome in clinical trials and animal experiments using immunohistochemistry and Western blotting. Twenty-four C57BL/6 mice were used to induce liver fibrosis by feeding a diet that contained 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). To study inflammasome function, Lipopolysaccharide (LPS)/adenine triphosphate (ATP) induced NLRP3 inflammasome activation was induced in bone marrow-derived macrophages (BMDMs) isolated from wild mice. The effects of macrophage NLRP3 inflammasome activation on the function of hepatic stellate cells (HSCs) were explored by treating primary HSCs with preconditioned media from BMDMs culture. RESULTS FZHY treatment resulted in the downregulation of NLRP3 protein expression and inhibition of its priming and activation in both human fibrotic livers and DDC-induced liver fibrosis. Furthermore, FZHY was observed to block the activation of the NLRP3 inflammasome pathway, which can lead to excessive inflammatory cytokine release in supernatants and cell lysates in response to LPS and ATP. Lastly, treatment with FZHY was able to inhibit the activation of HSCs induced by supernatants from macrophages. CONCLUSIONS FZHY has been shown to potentially prevent NLRP3 inflammasome activation in macrophages which can result in the suppression of HSCs activation. Ultimately, these effects may lead to the improvement of liver fibrosis. The ability of FZHY to act on this novel mechanism represents an important aspect of its therapeutic potential for liver fibrosis.
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Affiliation(s)
- Dabing Ping
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jingshu Qi
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Meng Li
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xin Sun
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yuan Peng
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Chenghai Liu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China; Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai, 201203, China.
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Jeong J, Tanaka M, Yang Y, Arefyev N, DiRito J, Tietjen G, Zhang X, McConnell MJ, Utsumi T, Iwakiri Y. An optimized visualization and quantitative protocol for in-depth evaluation of lymphatic vessel architecture in the liver. Am J Physiol Gastrointest Liver Physiol 2023; 325:G379-G390. [PMID: 37605828 PMCID: PMC10887843 DOI: 10.1152/ajpgi.00139.2023] [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: 07/07/2023] [Revised: 08/11/2023] [Accepted: 08/11/2023] [Indexed: 08/23/2023]
Abstract
The liver lymphatic system is essential for maintaining tissue fluid balance and immune function. The detailed structure of lymphatic vessels (LVs) in the liver remains to be fully demonstrated. The aim of this study is to reveal LV structures in normal and diseased livers by developing a tissue-clearing and coimmunolabeling protocol optimized for the tissue size and the processing time for three-dimensional (3-D) visualization and quantification of LVs in the liver. We showed that our optimized protocol enables in-depth exploration of lymphatic networks in the liver, consisting of LVs along the portal tract (deep lymphatic system) and within the collagenous Glisson's capsule (superficial lymphatic system) in different species. With this protocol, we have shown 3-D LVs configurations in relation to blood vessels and bile ducts in cholestatic mouse livers, in which LVs were highly dilated and predominantly found around highly proliferating bile ducts and peribiliary vascular plexuses in the portal tract. We also established a quantification method using a 3-D volume-rendering approach. We observed a 1.6-fold (P < 0.05) increase in the average diameter of LVs and a 2.4-fold increase (P < 0.05) in the average branch number of LVs in cholestatic/fibrotic livers compared with control livers. Furthermore, cholestatic/fibrotic livers showed a 4.3-fold increase (P < 0.05) in total volume of LVs compared with control livers. Our optimized protocol and quantification method demonstrate an efficient and simple liver tissue-clearing procedure that allows the comprehensive analysis of liver lymphatic system.NEW & NOTEWORTHY This article showed a comprehensive 3-D-structural analysis of liver lymphatic vessel (LV) in normal and diseased livers in relation to blood vessels and bile ducts. In addition to the LVs highly localized at the portal tract, we revealed capsular LVs in mouse, rat, and human livers. In cholestatic livers, LVs are significantly increased and dilated compared with normal livers. Our optimized protocol provides detailed spatial information for LVs remodeling in normal and pathological conditions.
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Affiliation(s)
- Jain Jeong
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Masatake Tanaka
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
- Division of Pathophysiology, Medical Institute of Bioregulation and Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yilin Yang
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Nikolai Arefyev
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Jenna DiRito
- Department of Surgery, Section of Organ Transplantation and Immunology, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Gregory Tietjen
- Department of Surgery, Section of Organ Transplantation and Immunology, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Xuchen Zhang
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Matthew J McConnell
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Teruo Utsumi
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Yasuko Iwakiri
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
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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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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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Li L, Xun C, Yu CH. Role of microRNA-regulated cancer stem cells in recurrent hepatocellular carcinoma. World J Hepatol 2022; 14:1985-1996. [PMID: 36618329 PMCID: PMC9813843 DOI: 10.4254/wjh.v14.i12.1985] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/24/2022] [Accepted: 11/22/2022] [Indexed: 12/23/2022] Open
Abstract
Among the most common cancers, hepatocellular carcinoma (HCC) has a high rate of tumor recurrence, tumor dormancy, and drug resistance after initial successful chemotherapy or radiotherapy. A small subset of cancer cells, cancer stem cells (CSCs), exhibit stem cell characteristics and are present in various cancers, including HCC. The dysregulation of microRNAs (miRNAs) often accompanies the occurrence and development of HCC. miRNAs can influence tumorigenesis, progression, recurrence, and drug resistance by regulating CSCs properties, which supports their clinical utility in managing and treating HCC. This review summarizes the regulatory effects of miRNAs on CSCs in HCC with a special focus on their impact on HCC recurrence.
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Affiliation(s)
- Lei Li
- Department of Pathology, University of Otago, Dunedin 9016, New Zealand
| | - Chen Xun
- Department of Hepatobiliary Surgery, Zhuzhou Central Hospital, Zhuzhou 412000, Hunan Province, China
| | - Chun-Hong Yu
- School of Engineering Medicine, Beihang University, Beijing 100191, China.
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Liang Y, Kaneko K, Xin B, Lee J, Sun X, Zhang K, Feng GS. Temporal analyses of postnatal liver development and maturation by single-cell transcriptomics. Dev Cell 2022; 57:398-414.e5. [PMID: 35134346 PMCID: PMC8842999 DOI: 10.1016/j.devcel.2022.01.004] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 11/10/2021] [Accepted: 01/05/2022] [Indexed: 02/09/2023]
Abstract
The postnatal development and maturation of the liver, the major metabolic organ, are inadequately understood. We have analyzed 52,834 single-cell transcriptomes and identified 31 cell types or states in mouse livers at postnatal days 1, 3, 7, 21, and 56. We observe unexpectedly high levels of hepatocyte heterogeneity in the developing liver and the progressive construction of the zonated metabolic functions from pericentral to periportal hepatocytes, which is orchestrated with the development of sinusoid endothelial, stellate, and Kupffer cells. Trajectory and gene regulatory analyses capture 36 transcription factors, including a circadian regulator, Bhlhe40, in programming liver development. Remarkably, we identified a special group of macrophages enriched at day 7 with a hybrid phenotype of macrophages and endothelial cells, which may regulate sinusoidal construction and Treg-cell function. This study provides a comprehensive atlas that covers all hepatic cell types and is instrumental for further dissection of liver development, metabolism, and disease.
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Affiliation(s)
- Yan Liang
- Department of Pathology, Division of Biological Sciences, and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
| | - Kota Kaneko
- Department of Pathology, Division of Biological Sciences, and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
| | - Bing Xin
- Department of Pathology, Division of Biological Sciences, and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
| | - Jin Lee
- Department of Pathology, Division of Biological Sciences, and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
| | - Xin Sun
- Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
| | - Kun Zhang
- Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA
| | - Gen-Sheng Feng
- Department of Pathology, Division of Biological Sciences, and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
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11
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Bram Y, Nguyen DHT, Gupta V, Park J, Richardson C, Chandar V, Schwartz RE. Cell and Tissue Therapy for the Treatment of Chronic Liver Disease. Annu Rev Biomed Eng 2021; 23:517-546. [PMID: 33974812 PMCID: PMC8864721 DOI: 10.1146/annurev-bioeng-112619-044026] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
Liver disease is an important clinical problem, impacting 600 million people worldwide. It is the 11th-leading cause of death in the world. Despite constant improvement in treatment and diagnostics, the aging population and accumulated risk factors led to increased morbidity due to nonalcoholic fatty liver disease and steatohepatitis. Liver transplantation, first established in the 1960s, is the second-most-common solid organ transplantation and is the gold standard for the treatment of liver failure. However, less than 10% of the global need for liver transplantation is met at the current rates of transplantation due to the paucity of available organs. Cell- and tissue-based therapies present an alternative to organ transplantation. This review surveys the approaches and tools that have been developed, discusses the distinctive challenges that exist for cell- and tissue-based therapies, and examines the future directions of regenerative therapies for the treatment of liver disease.
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Affiliation(s)
- Yaron Bram
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA;
| | - Duc-Huy T Nguyen
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA;
| | - Vikas Gupta
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA;
| | - Jiwoon Park
- Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medical College, New York, NY 10065, USA
| | - Chanel Richardson
- Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA
| | - Vasuretha Chandar
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA;
| | - Robert E Schwartz
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; .,Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medical College, New York, NY 10065, USA
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12
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Fatma H, Siddique HR. Pluripotency inducing Yamanaka factors: role in stemness and chemoresistance of liver cancer. Expert Rev Anticancer Ther 2021; 21:853-864. [PMID: 33832395 DOI: 10.1080/14737140.2021.1915137] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction: Liver cancer is a major cause of mortality and is characterized by the transformation of cells into an uncontrolled mass of tumor cells with many genetic and epigenetic changes, which lead to the development of tumors. A small subpopulation of cell population known as Cancer Stem Cells (CSCs) is responsible for cancer stemness and chemoresistance. Yamanaka factors [octamer-binding transcription factor 4 (OCT4), SRY (sex-determining region Y)-box 2 (SOX2), kruppel-like factor 4 (KLF4), and Myelocytomatosis (MYC); OSKM] are responsible for cancer cell stemness, chemoresistance, and recurrence.Area covered: We cover recent discoveries and investigate the role of OSKM in inducing pluripotency and stem cell-like properties in various cancers with special emphasis on liver cancer. We review Yamanaka factors' role in stemness and chemoresistance of liver cancer.Expert opinion: In CSCs, including liver CSCs, the deregulation of various signaling pathways is one of the major reasons for stemness and drug resistance and is primarily due to OSKM. OSKM are responsible for tumor heterogeneity which renders targeting drug useless after a certain period. These factors can be exploited to understand the underlying mechanism of cancer stemness and resistance to chemotherapeutic drugs.
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Affiliation(s)
- Homa Fatma
- Molecular Cancer Genetics & Translational Research Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh-Uttar Pradesh, India
| | - Hifzur Rahman Siddique
- Molecular Cancer Genetics & Translational Research Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh-Uttar Pradesh, India
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13
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Liu L, Borlak J. Advances in Liver Cancer Stem Cell Isolation and their Characterization. Stem Cell Rev Rep 2021; 17:1215-1238. [PMID: 33432485 DOI: 10.1007/s12015-020-10114-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/28/2020] [Indexed: 12/24/2022]
Abstract
Over the last decade research on cancer stem cells (CSC) significantly contributed to a better understanding of tumor biology. Given their similarity to normal stem cells, i.e. self-renewal and pluripotency the need arises to develop robust protocols for the isolation and characterization of CSCs. As with other malignancies, hepatic tumors are composed of a heterogeneous population of cells including liver cancer stem cells (LCSC). Yet, a precise understanding of why stem cells become cancerous is still lacking. There is unmet need to develop robust protocols for the successful isolation of LCSCs from human tissue resection material as to assist in the development of molecular targeted therapies. Here we review the research progress made in the isolation and characterization of LCSCs by considering a wide range of cell surface markers and sorting methods, as applied to side populations, microsphere cultures and the gradient centrifugation method. We emphasize the different fluorescence activated cell sorting methods and the possibility to enrich LCSCs by immunomagnetic beads. We review the specificity of functional assays by considering ABCG transporter and ALDH1 enzyme activities and evaluate the in vivo tumorigenicity of LCSCs in highly sensitive bioassays. Finally, we evaluate different LCSC markers in association with viral and non-viral liver disease and explore the potential of novel drug delivery systems targeting CD133, EpCAM, CD13 and CD90 for the development of molecular targeted therapies. Graphical Abstract.
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Affiliation(s)
- Lu Liu
- Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Jürgen Borlak
- Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
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14
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Wei S, Tang J, Cai X. Founder cells for hepatocytes during liver regeneration: from identification to application. Cell Mol Life Sci 2020; 77:2887-2898. [PMID: 32060582 PMCID: PMC11105049 DOI: 10.1007/s00018-020-03457-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 01/02/2020] [Accepted: 01/10/2020] [Indexed: 12/12/2022]
Abstract
Liver regeneration (LR) capacity in vertebrates developed through natural selection over a hundred million years of evolution. To maintain homeostasis or recover from various injuries, liver cells must regenerate; this process includes the renewal of parenchymal and nonparenchymal cells as well as the formation of liver structures. The cellular origin of newly grown tissue is one of the critical questions in this area and has been a subject of prolonged debate. The regenerative tissue may derive from either hepatocyte self-duplication or liver stem/progenitor cells (LSPCs). Recently, hepatocyte subpopulations and cholangiocytes were also described as important founder cells. The niche that triggers the proliferation of hepatocytes and the differentiation of LSPCs has been extensively studied. Meanwhile, in vitro culture systems for liver founder cells and organoids have been developed rapidly for mechanistic studies and potential therapeutic purposes. This review summarizes the cellular sources and niches that give rise to renewed hepatocytes during LR, and it also describes in vitro culture studies of those founder cells for future applications, as well as current reports for stem cell-based therapies for liver diseases.
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Affiliation(s)
- Saisai Wei
- Key Laboratory of Endoscopic Technique Research of Zhejiang Province, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China
| | - Jiacheng Tang
- Key Laboratory of Endoscopic Technique Research of Zhejiang Province, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China
| | - Xiujun Cai
- Key Laboratory of Endoscopic Technique Research of Zhejiang Province, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.
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15
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Liu YC, Yeh CT, Lin KH. Cancer Stem Cell Functions in Hepatocellular Carcinoma and Comprehensive Therapeutic Strategies. Cells 2020; 9:cells9061331. [PMID: 32466488 PMCID: PMC7349579 DOI: 10.3390/cells9061331] [Citation(s) in RCA: 186] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 05/22/2020] [Accepted: 05/22/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant cause of cancer-related mortality owing to resistance to traditional treatments and tumor recurrence after therapy, which leads to poor therapeutic outcomes. Cancer stem cells (CSC) are a small subset of tumor cells with the capability to influence self-renewal, differentiation, and tumorigenesis. A number of surface markers for liver cancer stem cell (LCSC) subpopulations (EpCAM, CD133, CD44, CD13, CD90, OV-6, CD47, and side populations) in HCC have been identified. LCSCs play critical roles in regulating HCC stemness, self-renewal, tumorigenicity, metastasis, recurrence, and therapeutic resistance via genetic mutations, epigenetic disruption, signaling pathway dysregulation, or alterations microenvironment. Accumulating studies have shown that biomarkers for LCSCs contribute to diagnosis and prognosis prediction of HCC, supporting their utility in clinical management and development of therapeutic strategies. Preclinical and clinical analyses of therapeutic approaches for HCC using small molecule inhibitors, oncolytic measles viruses, and anti-surface marker antibodies have demonstrated selective, efficient, and safe targeting of LCSC populations. The current review focuses on recent reports on the influence of LCSCs on HCC stemness, tumorigenesis, and multiple drug resistance (MDR), along with LCSC-targeted therapeutic strategies for HCC.
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Affiliation(s)
- Yu-Chin Liu
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan;
- Department of Biomedical Sciences, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan;
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan;
- Department of Biomedical Sciences, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan;
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Correspondence: ; Tel./Fax: +886-3-211-8263
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16
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Afify SM, Sanchez Calle A, Hassan G, Kumon K, Nawara HM, Zahra MH, Mansour HM, Khayrani AC, Alam MJ, Du J, Seno A, Iwasaki Y, Seno M. A novel model of liver cancer stem cells developed from induced pluripotent stem cells. Br J Cancer 2020; 122:1378-1390. [PMID: 32203212 PMCID: PMC7188674 DOI: 10.1038/s41416-020-0792-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 02/10/2020] [Accepted: 02/24/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Liver cancer is the second most common cause of cancer-related death. Every type of tumours including liver cancer contains cancer stem cells (CSCs). To date, the molecular mechanism regulating the development of liver CSCs remains unknown. METHODS In this study, we tried to generate a new model of liver CSCs by converting mouse induced pluripotent stem cells (miPSCs) with hepatocellular carcinoma (HCC) cell line Huh7 cells conditioned medium (CM). miPSCs treated with CM were injected into the liver of BALB/c nude mice. The developed tumours were then excised and analysed. RESULTS The primary cultured cells from the malignant tumour possessed self-renewal capacity, differentiation potential and tumorigenicity in vivo, which were found rich in liver cancer-associated markers as well as CSC markers. CONCLUSIONS We established a model of liver CSCs converting from miPS and showed different stages of stemness during conversion process. Our CSC model will be important to assess the molecular mechanisms necessary to develop liver CSCs and could help in defeating liver cancer.
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Affiliation(s)
- Said M Afify
- Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama, 700-8530, Japan.
- Division of Biochemistry, Chemistry Department, Faculty of Science, Menoufia University, Shebin ElKoum Menoufia, 32511, Egypt.
| | - Anna Sanchez Calle
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, 104- 0045, Japan
| | - Ghmkin Hassan
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, 700-8530, Japan
- Department of Microbiology and Biochemistry, Faculty of Pharmacy, Damascus University, Damascus, 10769, Syria
| | - Kazuki Kumon
- Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama, 700-8530, Japan
| | - Hend M Nawara
- Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama, 700-8530, Japan
| | - Maram H Zahra
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, 700-8530, Japan
| | - Hager M Mansour
- Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama, 700-8530, Japan
| | - Apriliana Cahya Khayrani
- Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama, 700-8530, Japan
| | - Md Jahangir Alam
- Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama, 700-8530, Japan
| | - Juan Du
- Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama, 700-8530, Japan
| | - Akimasa Seno
- Okayama University Research Laboratory of Stem Cell Engineering in Detroit, IBio, Wayne State University, Detroit, MI, 48202, USA
| | - Yoshiaki Iwasaki
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Okayama University, Okayama, 700-8558, Japan
| | - Masaharu Seno
- Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama, 700-8530, Japan.
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, 700-8530, Japan.
- Okayama University Research Laboratory of Stem Cell Engineering in Detroit, IBio, Wayne State University, Detroit, MI, 48202, USA.
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17
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Reduced DAXX Expression Is Associated with Reduced CD24 Expression in Colorectal Cancer. Cells 2019; 8:cells8101242. [PMID: 31614769 PMCID: PMC6830082 DOI: 10.3390/cells8101242] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/23/2019] [Accepted: 10/11/2019] [Indexed: 12/14/2022] Open
Abstract
The presence of an activating mutation of the Wnt/β-catenin signaling pathway is found in ~90% of colorectal cancer (CRC) cases. Death domain-associated protein (DAXX), a nuclear protein, interacts with β-catenin in CRC cells. We investigated DAXX expression in 106 matched sample pairs of CRC and adjacent normal tissue by Western blotting. This study evaluated DAXX expression and its clinical implications in CRC. The results revealed that DAXX expression was significantly lower in the patients with the positive serum carcinoembryonic antigen (CEA) screening results compared to the patients with negative CEA screening levels (p < 0.001). It has been reported that CD24 is a Wnt target in CRC cells. Here, we further revealed that DAXX expression was significantly correlated with CD24 expression (rho = 0.360, p < 0.001) in 106 patients. Consistent with this, in the CEA-positive subgroup, of which the carcinomas expressed DAXX at low levels, they were significantly correlated with CD24 expression (rho = 0.461, p < 0.005). Therefore, reduced DAXX expression is associated with reduced CD24 expression in CRC. Notably, in the Hct116 cells, DAXX knockdown using short-hairpin RNA against DAXX (shDAXX) not only caused significant cell proliferation, but also promoted metastasis. The DAXX-knockdown cells also demonstrated significantly decreased CD24 expression, however the intracellular localization of CD24 did not change. Thus, DAXX might be considered as a potential regulator of CD24 or β-catenin expression, which might be correlated with proliferative and metastatic potential of CRC.
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18
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Tsuchiya A, Ogawa M, Watanabe T, Takeuchi S, Kojima Y, Watanabe Y, Kimura N, Hayashi K, Yokoyama J, Terai S. Diverse perspectives to address for the future treatment of heterogeneous hepatocellular carcinoma. Heliyon 2019; 5:e01325. [PMID: 30911692 PMCID: PMC6416651 DOI: 10.1016/j.heliyon.2019.e01325] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 10/05/2018] [Accepted: 03/04/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinomas (HCCs), which often arise from chronic liver damage, have poor conditional 5-year survival and are recognized as heterogeneous tumors. Considering the heterogeneity of HCCs, diverse perspectives need to be addressed for treating such tumors, besides the findings of conventional imaging modalities and tumor markers. Data from the latest technologies, such as liquid biopsy, and the detection of the presence of cancer cells with stem/progenitor cell markers, gene mutations and diverse pathways, crosstalk with immune cells and cancer-associated fibroblasts, and mechanisms of epithelial–mesenchymal transition provide diverse lines of information. Integration of these data with clinical data might be necessary to develop effective therapies for precision medicine. Here, we review several aspects of dealing with the complexity of heterogeneous HCCs.
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Affiliation(s)
- Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Takayuki Watanabe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Suguru Takeuchi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Yuichi Kojima
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Yusuke Watanabe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Naruhiro Kimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Kazunao Hayashi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Junji Yokoyama
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
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19
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Afify SM, Seno M. Conversion of Stem Cells to Cancer Stem Cells: Undercurrent of Cancer Initiation. Cancers (Basel) 2019; 11:E345. [PMID: 30862050 PMCID: PMC6468812 DOI: 10.3390/cancers11030345] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/02/2019] [Accepted: 03/06/2019] [Indexed: 12/13/2022] Open
Abstract
Cancer stem cells (CSCs) also known as cancer-initiating cells (CIC), are responsible for the sustained and uncontrolled growth of malignant tumors and are proposed to play significant roles in metastasis and recurrence. Several hypotheses have proposed that the events in either stem and/or differentiated cells, such as genomic instability, inflammatory microenvironment, cell fusion, and lateral gene transfer, should be considered as the possible origin of CSCs. However, until now, the exact origin of CSC has been obscure. The development of induced pluripotent stem cells (iPSCs) in 2007, by Yamanaka's group, has been met with much fervency and hailed as a breakthrough discovery by the scientific and research communities, especially in regeneration therapy. The studies on the development of CSC from iPSCs should also open a new page of cancer research, which will help in designing new therapies applicable to CSCs. Currently most reviews have focused on CSCs and CSC niches. However, the insight into the niche before the CSC niche should also be of keen interest. This review introduces the novel concept of cancer initiation introducing the conversion of iPSCs to CSCs and proposes a relationship between the inflammatory microenvironment and cancer initiation as the key concept of the cancer-inducing niche responsible for the development of CSC.
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Affiliation(s)
- Said M Afify
- Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan.
- Division of Biochemistry, Faculty of Science, Menoufia University, Shebin El Koum-Menoufia 32511, Egypt.
| | - Masaharu Seno
- Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan.
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan.
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20
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Tsuchiya A, Lu WY. Liver stem cells: Plasticity of the liver epithelium. World J Gastroenterol 2019; 25:1037-1049. [PMID: 30862993 PMCID: PMC6406190 DOI: 10.3748/wjg.v25.i9.1037] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 01/21/2019] [Accepted: 01/26/2019] [Indexed: 02/06/2023] Open
Abstract
The liver has a high regenerative capacity after acute liver injury, but this is often impaired during chronic liver injury. The existence of a dedicated liver stem cell population that acts as a source of regeneration during chronic liver injury has been controversial. Recent advances in transgenic models and cellular reprogramming have provided new insights into the plasticity of the liver epithelium and directions for the development of future therapies. This article will highlight recent findings about the cellular source of regeneration during liver injury and the advances in promoting liver regeneration.
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Affiliation(s)
- Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate school of medical and dental sciences, Niigata University, Chuo-ku, Niigata 951-8510, Japan
| | - Wei-Yu Lu
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, the University of Birmingham, Birmingham B15 2TT, United Kingdom
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21
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Sato K, Marzioni M, Meng F, Francis H, Glaser S, Alpini G. Ductular Reaction in Liver Diseases: Pathological Mechanisms and Translational Significances. Hepatology 2019; 69:420-430. [PMID: 30070383 PMCID: PMC6324973 DOI: 10.1002/hep.30150] [Citation(s) in RCA: 276] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 06/20/2018] [Indexed: 12/12/2022]
Abstract
Ductular reaction (DR) is characterized by the proliferation of reactive bile ducts induced by liver injuries. DR is pathologically recognized as bile duct hyperplasia and is commonly observed in biliary disorders. It can also be identified in various liver disorders including nonalcoholic fatty liver disease. DR is associated with liver fibrosis and damage, and the extent of DR parallels to patient mortality. DR raises scientific interests because it is associated with transdifferentiation of liver cells and may play an important role in hepatic regeneration. The origin of active cells during DR can be cholangiocytes, hepatocytes, or hepatic progenitor cells, and associated signaling pathways could differ depending on the specific liver injury or animal models used in the study. Although further studies are needed to elucidate detailed mechanisms and the functional roles in liver diseases, DR can be a therapeutic target to inhibit liver fibrosis and to promote liver regeneration. This review summarizes previous studies of DR identified in patients and animal models as well as currently understood mechanisms of DR.
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Affiliation(s)
- Keisaku Sato
- Research, Central Texas Veterans Health Care System, Temple, TX 76504
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, TX 76504
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Healthcare, Temple, TX 76504
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ospedali Riuniti - University Hospital, Ancona, Italy
| | - Fanyin Meng
- Research, Central Texas Veterans Health Care System, Temple, TX 76504
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Healthcare, Temple, TX 76504
- Academic Research Integration, Baylor Scott & White Healthcare, Temple, TX 76504
| | - Heather Francis
- Research, Central Texas Veterans Health Care System, Temple, TX 76504
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, TX 76504
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Healthcare, Temple, TX 76504
| | - Shannon Glaser
- Research, Central Texas Veterans Health Care System, Temple, TX 76504
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, TX 76504
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Healthcare, Temple, TX 76504
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, Temple, TX 76504
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, TX 76504
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Healthcare, Temple, TX 76504
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22
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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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23
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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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Involvement of inflammation and its related microRNAs in hepatocellular carcinoma. Oncotarget 2017; 8:22145-22165. [PMID: 27888618 PMCID: PMC5400654 DOI: 10.18632/oncotarget.13530] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 11/02/2016] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most commonly diagnosed type of cancer. The tumor inflammatory microenvironment regulates almost every step towards liver tumorigenesis and subsequent progression, and regulation of the inflammation-related signaling pathways, cytokines, chemokines and non-coding RNAs influences the proliferation, migration and metastasis of liver tumor cells. Inflammation fine-tunes the cancer microenvironment to favor epithelial-mesenchymal transition, in which cancer stem cells maintain tumorigenic potential. Emerging evidence points to inflammation-related microRNAs as crucial molecules to integrate the complex cellular and molecular crosstalk during HCC progression. Thus understanding the mechanisms by which inflammation regulates microRNAs might provide novel and admissible strategies for preventing, diagnosing and treating HCC. In this review, we will update three hypotheses of hepatocarcinogenesis and elaborate the most predominant inflammation signaling pathways, i.e. IL-6/STAT3 and NF-κB. We also try to summarize the crucial tumor-promoting and tumor-suppressing microRNAs and detail how they regulate HCC initiation and progression and collaborate with other critical modulators in this review.
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Flores-Téllez TNJ, Villa-Treviño S, Piña-Vázquez C. Road to stemness in hepatocellular carcinoma. World J Gastroenterol 2017; 23:6750-6776. [PMID: 29085221 PMCID: PMC5645611 DOI: 10.3748/wjg.v23.i37.6750] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Revised: 05/27/2017] [Accepted: 07/24/2017] [Indexed: 02/06/2023] Open
Abstract
Carcinogenic process has been proposed to relay on the capacity to induce local tissue damage and proliferative repair. Liver has a great regeneration capacity and currently, most studies point towards the dominant role of hepatocytes in regeneration at all levels of liver damage. The most frequent liver cancer is hepatocellular carcinoma (HCC). Historical findings originally led to the idea that the cell of origin of HCC might be a progenitor cell. However, current linage tracing studies put the progenitor hypothesis of HCC origin into question. In agreement with their dominant role in liver regeneration, mature hepatocytes are emerging as the cell of origin of HCC, although, the specific hepatocyte subpopulation of origin is yet to be determined. The relationship between the cancer cell of origin (CCO) and cancer-propagating cells, known as hepatic cancer stem cell (HCSC) is unknown. It has been challenging to identify the definitive phenotypic marker of HCSC, probably due to the existence of different cancer stem cells (CSC) subpopulations with different functions within HCC. There is a dynamic interconversion among different CSCs, and between CSC and non-CSCs. Because of that, CSC-state is currently defined as a description of a highly adaptable and dynamic intrinsic property of tumor cells, instead of a static subpopulation of a tumor. Altered conditions could trigger the gain of stemness, some of them include: EMT-MET, epigenetics, microenvironment and selective stimulus such as chemotherapy. This CSC heterogeneity and dynamism makes them out reach from therapeutic protocols directed to a single target. A further avenue of research in this line will be to uncover mechanisms that trigger this interconversion of cell populations within tumors and target it.
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Affiliation(s)
- Teresita NJ Flores-Téllez
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Av. IPN No. 2508 Col. San Pedro Zacatenco CP 07360, Ciudad de México, México
| | - Saúl Villa-Treviño
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Av. IPN No. 2508 Col. San Pedro Zacatenco CP 07360, Ciudad de México, México
| | - Carolina Piña-Vázquez
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Av. IPN No. 2508 Col. San Pedro Zacatenco CP 07360, Ciudad de México, México
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Lee CW, Huang WC, Huang HD, Huang YH, Ho JH, Yang MH, Yang VW, Lee OK. DNA Methyltransferases Modulate Hepatogenic Lineage Plasticity of Mesenchymal Stromal Cells. Stem Cell Reports 2017; 9:247-263. [PMID: 28602611 PMCID: PMC5511371 DOI: 10.1016/j.stemcr.2017.05.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 05/04/2017] [Accepted: 05/05/2017] [Indexed: 12/20/2022] Open
Abstract
The irreversibility of developmental processes in mammalian cells has been challenged by rising evidence that de-differentiation of hepatocytes occurs in adult liver. However, whether reversibility exists in mesenchymal stromal cell (MSC)-derived hepatocytes (dHeps) remains elusive. In this study, we find that hepatogenic differentiation (HD) of MSCs is a reversible process and is modulated by DNA methyltransferases (DNMTs). DNMTs are regulated by transforming growth factor β1 (TGFβ1), which in turn controls hepatogenic differentiation and de-differentiation. In addition, a stepwise reduction in TGFβ1 concentrations in culture media increases DNMT1 and decreases DNMT3 in primary hepatocytes (Heps) and confers Heps with multi-differentiation potentials similarly to MSCs. Hepatic lineage reversibility of MSCs and lineage conversion of Heps are regulated by DNMTs in response to TGFβ1. This previously unrecognized TGFβ1-DNMTs-MSC-HD axis may further increase the understanding the normal and pathological processes in the liver, as well as functions of MSCs after transplantation to treat liver diseases.
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Affiliation(s)
- Chien-Wei Lee
- Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 11221, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan
| | - Wei-Chih Huang
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, HsinChu 30010, Taiwan
| | - Hsien-Da Huang
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, HsinChu 30010, Taiwan; Department of Biological Science and Technology, National Chiao Tung University, HsinChu 30010, Taiwan; Center for Bioinformatics Research, National Chiao Tung University, HsinChu 30010, Taiwan; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11221, Taiwan
| | - Jennifer H Ho
- Center for Stem Cell Research, Taipei Medical University-Wan Fang Hospital, Taipei 11031, Taiwan
| | - Muh-Hwa Yang
- Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei 11221, Taiwan; Genome Research Center, National Yang-Ming University, Taipei 11221, Taiwan; Immunity and Inflammation Research Center, National Yang-Ming University, Taipei 11221, Taiwan; Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - Vincent W Yang
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Oscar K Lee
- Taipei City Hospital, Taipei 10341, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan; Stem Cell Research Center, National Yang-Ming University, Taipei 11221, Taiwan; Department of Medical Research, Taipei Veterans General Hospital, Taipei 11221, Taiwan.
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Abstract
Liver cancer is an often fatal malignant tumor with a high recurrence rate and chemoresistance. The major malignant phenotypes of cancer, including recurrence, metastasis, and chemoresistance, are related to the presence of cancer stem cells (CSCs). In the past few decades, CSCs have been identified and characterized in many tumors including liver cancer. Accumulated evidence has revealed many aspects of the biological behavior of liver CSCs and the mechanism of their regulation. Based on these findings, a number of studies have investigated eradication of liver CSCs. This review focuses on the recent advances in our understanding of the biology of liver CSCs and the development of strategies for their treatment.
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28
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Progressive induction of hepatocyte progenitor cells in chronically injured liver. Sci Rep 2017; 7:39990. [PMID: 28051157 PMCID: PMC5209740 DOI: 10.1038/srep39990] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 11/30/2016] [Indexed: 12/19/2022] Open
Abstract
Differentiated epithelial cells show substantial lineage plasticity upon severe tissue injuries. In chronically injured mouse livers, part of hepatocytes become Sry-HMG box containing 9 (Sox9) (+) epithelial cell adhesion molecule (−) hepatocyte nuclear factor 4 α (+) biphenotypic hepatocytes. However, it is not clear whether all Sox9+ hepatocytes uniformly possess cellular properties as hepatocyte progenitors. Here, we examined the microarray data comparing Sox9+ hepatocytes with mature hepatocytes and identified CD24 as a novel marker for biphenotypic hepatocytes. Immunohistochemical analyses showed that part of Sox9+ hepatocytes near expanded ductular structures expressed CD24 in the liver injured by 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC) diet and by bile duct ligation. Indeed, Sox9+ hepatocytes could be separated into CD24− and CD24+ cells by fluorescence activated cell sorting. The ratio of CD24+ cells against CD24− ones in Sox9+ hepatocytes gradually increased while DDC-injury progressed and colony-forming capability mostly attributed to CD24+ cells. Although hepatocyte markers were remarkably downregulated in of Sox9+ CD24+ hepatocytes, they re-differentiated into mature hepatocytes in vitro and in vivo. Our current results demonstrate that the emergence of biphenotypic hepatocytes is a sequential event including the transition from CD24− and CD24+ status, which may be a crucial step for hepatocytes to acquire progenitor properties.
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Comparison of stem cell behaviors between indigenous high and low-CD24 percentage expressing cells of stem cells from apical papilla (SCAPs). Tissue Cell 2016; 48:397-406. [DOI: 10.1016/j.tice.2016.08.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 08/23/2016] [Accepted: 08/23/2016] [Indexed: 01/06/2023]
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30
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Analysis of the structure, evolution, and expression of CD24, an important regulator of cell fate. Gene 2016; 590:324-37. [DOI: 10.1016/j.gene.2016.05.038] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 05/23/2016] [Accepted: 05/29/2016] [Indexed: 12/11/2022]
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Rodrigues‐Pinto R, Berry A, Piper‐Hanley K, Hanley N, Richardson SM, Hoyland JA. Spatiotemporal analysis of putative notochordal cell markers reveals CD24 and keratins 8, 18, and 19 as notochord-specific markers during early human intervertebral disc development. J Orthop Res 2016; 34:1327-40. [PMID: 26910849 PMCID: PMC5021113 DOI: 10.1002/jor.23205] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 02/17/2016] [Indexed: 02/04/2023]
Abstract
In humans, the nucleus pulposus (NP) is composed of large vacuolated notochordal cells in the fetus but, soon after birth, becomes populated by smaller, chondrocyte-like cells. Although animal studies indicate that notochord-derived cells persist in the adult NP, the ontogeny of the adult human NP cell population is still unclear. As such, identification of unique notochordal markers is required. This study was conducted to determine the spatiotemporal expression of putative human notochordal markers to aid in the elucidation of the ontogeny of adult human NP cells. Human embryos and fetuses (3.5-18 weeks post-conception (WPC)) were microdissected to isolate the spine anlagens (notochord and somites/sclerotome). Morphology of the developing IVD was assessed using hematoxylin and eosin. Expression of keratin (KRT) 8, KRT18, KRT19, CD24, GAL3, CD55, BASP1, CTGF, T, CD90, Tie2, and E-cadherin was assessed using immunohistochemistry. KRT8, KRT18, KRT19 were uniquely expressed by notochordal cells at all spine levels at all stages studied; CD24 was expressed at all stages except 3.5 WPC. While GAL3, CD55, BASP1, CTGF, and T were expressed by notochordal cells at specific stages, they were also co-expressed by sclerotomal cells. CD90, Tie2, and E-cadherin expression was not detectable in developing human spine cells at any stage. This study has identified, for the first time, the consistent expression of KRT8, KRT18, KRT19, and CD24 as human notochord-specific markers during early IVD development. Thus, we propose that these markers can be used to help ascertain the ontogeny of adult human NP cells. © 2016 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. J Orthop Res 34:1327-1340, 2016.
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Affiliation(s)
- Ricardo Rodrigues‐Pinto
- Centre For Tissue Injury and Repair, Institute of Inflammation and Repair, Faculty of Medical and Human SciencesUniversity of ManchesterStopford Building, Oxford RoadManchesterM13 9PTUnited Kingdom
- Department of OrthopaedicsCentro Hospitalar do Porto—Hospital de Santo AntónioLargo Prof. Abel SalazarPorto4099‐001Portugal
| | - Andrew Berry
- Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human SciencesUniversity of ManchesterAV Hill Building—3rd Floor, Oxford RoadManchesterM13 9PTUnited Kingdom
| | - Karen Piper‐Hanley
- Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human SciencesUniversity of ManchesterAV Hill Building—3rd Floor, Oxford RoadManchesterM13 9PTUnited Kingdom
| | - Neil Hanley
- Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human SciencesUniversity of ManchesterAV Hill Building—3rd Floor, Oxford RoadManchesterM13 9PTUnited Kingdom
| | - Stephen M. Richardson
- Centre For Tissue Injury and Repair, Institute of Inflammation and Repair, Faculty of Medical and Human SciencesUniversity of ManchesterStopford Building, Oxford RoadManchesterM13 9PTUnited Kingdom
| | - Judith A. Hoyland
- Centre For Tissue Injury and Repair, Institute of Inflammation and Repair, Faculty of Medical and Human SciencesUniversity of ManchesterStopford Building, Oxford RoadManchesterM13 9PTUnited Kingdom
- NIHR Manchester Musculoskeletal Biomedical Research UnitManchester Academic Health Science CentreManchesterUnited Kingdom
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32
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Huch M, Dollé L. The plastic cellular states of liver cells: Are EpCAM and Lgr5 fit for purpose? Hepatology 2016; 64:652-62. [PMID: 26799921 PMCID: PMC4973669 DOI: 10.1002/hep.28469] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Revised: 12/25/2015] [Accepted: 01/17/2016] [Indexed: 12/14/2022]
Abstract
Adult liver cells have been considered restricted regarding their fate and lineage potential. That is, hepatocytes have been thought able only to generate hepatocytes and duct cells, only duct cells. While this may be the case for the majority of scenarios in a state of quiescence or homeostasis, evidence suggests that liver cells are capable of interconverting between cellular states of distinct phenotypic traits. This interconversion or plasticity had been suggested by classical studies using cellular markers, but recently lineage tracing approaches have proven that cells are highly plastic and retain an extraordinary ability to respond differently to normal tissue homeostasis, to tissue repair, or when challenged to expand ex vivo or to differentiate upon transplantation. Stemness, as "self-renewal and multipotency," seems not to be limited to a particular cell type but rather to a cellular state in which cells exhibit a high degree of plasticity and can move back and forth in different phenotypic states. For instance, upon damage cells can dedifferentiate to acquire stem cell potential that allows them to self-renew, repopulate a damaged tissue, and then undergo differentiation. In this review, we will discuss the evidence on cellular plasticity in the liver, focusing our attention on two markers, epithelial cell adhesion molecule and leucine-rich repeat-containing G protein-coupled receptor 5, which identify cells with stem cell potential. (Hepatology 2016;64:652-662).
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Affiliation(s)
- Meritxell Huch
- Wellcome Trust/Cancer Research UK‐Gurdon Institutethe Wellcome Trust‐Medical Research Council Stem Cell Institute, and Physiology, Development, and Neuroscience, University of CambridgeCambridgeUK
| | - Laurent Dollé
- Laboratory of Liver Cell BiologyDepartment of Basic Biomedical SciencesFaculty of Medicine and PharmacyFree University BrusselsBrusselsBelgium
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Silencing of hepatic fate-conversion factors induce tumorigenesis in reprogrammed hepatic progenitor-like cells. Stem Cell Res Ther 2016; 7:96. [PMID: 27460218 PMCID: PMC4962402 DOI: 10.1186/s13287-016-0349-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 06/02/2016] [Accepted: 06/21/2016] [Indexed: 11/17/2022] Open
Abstract
Background Several studies have reported the direct conversion of mouse fibroblasts to hepatocyte-like cells with different degrees of maturation by expression of hepatic fate-conversion factors. Methods We have used a combination of lentiviral vectors expressing hepatic fate-conversion factors with Oct4, Sox2, Klf4, and Myc to convert mouse embryonic fibroblasts into hepatic cells. Results We have generated hepatic cells with progenitor-like features (iHepL cells). iHepL cells displayed basic hepatocyte functions but failed to perform functions characteristic of mature hepatocytes such as significant Cyp450 or urea cycle activities. iHepL cells expressed multiple hepatic-specific transcription factors and functional genes characteristic of immature hepatocytes and cholangiocytes, as well as high levels of Foxl1, Cd24a, and Lgr5, specific markers of hepatic progenitor cells. When transplanted into partial hepatectomized and hepatic irradiated mice, they differentiated into hepatocytes and cholangiocytes. However, iHepL cells formed malignant non-teratoma cell aggregations in one out of five engrafted livers and five out of five xenografts assays. All the cells in these tumors had silenced key hepatic fate-conversion factors, and lost hepatic features. Conclusions This study highlights the dangers of using pluripotency factors in reprogramming strategies when fate-conversion factors are silenced in vivo, and urges us to perform extensive tumorigenic tests in reprogrammed cells. Electronic supplementary material The online version of this article (doi:10.1186/s13287-016-0349-5) contains supplementary material, which is available to authorized users.
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Liu WH, Ren LN, Wang T, Navarro-Alvarez N, Tang LJ. The Involving Roles of Intrahepatic and Extrahepatic Stem/Progenitor Cells (SPCs) to Liver Regeneration. Int J Biol Sci 2016; 12:954-963. [PMID: 27489499 PMCID: PMC4971734 DOI: 10.7150/ijbs.15715] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 05/09/2016] [Indexed: 12/17/2022] Open
Abstract
Liver regeneration is usually attributed to mature hepatocytes, which possess a remarkable potential to proliferate under mild to moderate injury. However, when the liver is severely damaged or hepatocyte proliferation is greatly inhibited, liver stem/progenitor cells (LSPCs) will contribute to the liver regeneration process. LSPCs in the developing liver have been extensively characterized, however, their contributing role to liver regeneration has not been completely understood. In addition to the restoration of the liver parenchymal tissue by hepatocytes or/and LSPCs, or in some cases bone marrow (BM) derived cells, such as hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), the wound healing after injury in terms of angiopoiesis by liver sinusoidal endothelial cells (LSECs) or/and sinusoidal endothelial progenitor cells (SEPCs) is another important aspect taking place during regeneration. To conclude, liver regeneration can be mainly divided into three distinct restoring levels according to the cause and severity of injury: hepatocyte dominant regeneration, LSPCs mediated regeneration, extrahepatic stem cells participative regeneration. In this review, we focus on the recent findings of liver regeneration, especially on those related to stem/progenitor cells (SPCs)-mediated regeneration and their potential clinical applications and challenges.
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Affiliation(s)
- Wei-hui Liu
- 1. General Surgery Center, Chengdu Military General Hospital; Chengdu, Sichuan Province, 610083
| | - Li-na Ren
- 1. General Surgery Center, Chengdu Military General Hospital; Chengdu, Sichuan Province, 610083
| | - Tao Wang
- 1. General Surgery Center, Chengdu Military General Hospital; Chengdu, Sichuan Province, 610083
| | - Nalu Navarro-Alvarez
- 2. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Li-jun Tang
- 1. General Surgery Center, Chengdu Military General Hospital; Chengdu, Sichuan Province, 610083
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35
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The potential role of liver stem cells in initiation of primary liver cancer. Hepatol Int 2016; 10:893-901. [PMID: 27139191 DOI: 10.1007/s12072-016-9730-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 04/01/2016] [Indexed: 02/06/2023]
Abstract
Identification of the cellular origin of primary liver cancer remains challenging. Some data point toward liver stem cells (LSCs) or liver progenitor cells (LPCs) not only as propagators of liver regeneration, but also as initiators of liver cancer. LSCs exhibit a long lifespan and strong duplicative potential upon activation and are inclined to accumulate more mutations that can be passed down to the next generations. Recent evidence shows that dysregulation of signaling pathways associated with self-renewal of LSCs can drive their aberrant proliferation and even malignant transformation. If LSCs could be proved to be an initiator of liver carcinogenesis, they would be promising for ultra-early diagnosis and targeting therapy of liver cancer. This review mainly summarizes the potential role of LSCs in the carcinogenesis of primary liver cancer.
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Zhang H, Siegel CT, Shuai L, Lai J, Zeng L, Zhang Y, Lai X, Bie P, Bai L. Repair of liver mediated by adult mouse liver neuro-glia antigen 2-positive progenitor cell transplantation in a mouse model of cirrhosis. Sci Rep 2016; 6:21783. [PMID: 26905303 PMCID: PMC4764864 DOI: 10.1038/srep21783] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 02/01/2016] [Indexed: 02/07/2023] Open
Abstract
NG2-expressing cells are a population of periportal vascular stem/progenitors (MLpvNG2(+) cells) that were isolated from healthy adult mouse liver by using a "Percoll-Plate-Wait" procedure. We demonstrated that isolated cells are able to restore liver function after transplantation into a cirrhotic liver, and co-localized with the pericyte marker (immunohistochemistry: PDGFR-β) and CK19. Cells were positive for: stem cell (Sca-1, CD133, Dlk) and liver stem cell markers (EpCAM, CD14, CD24, CD49f); and negative for: hematopoietic (CD34, CD45) and endothelial markers (CD31, vWf, von Willebrand factor). Cells were transplanted (1 × 10(6) cells) in mice with diethylnitrosamine-induced cirrhosis at week 6. Cells showed increased hepatic associated gene expression of alpha-fetoprotein (AFP), Albumin (Alb), Glucose-6-phosphatase (G6Pc), SRY (sex determining region Y)-box 9 (Sox9), hepatic nuclear factors (HNF1a, HNF1β, HNF3β, HNF4α, HNF6, Epithelial cell adhesion molecule (EpCAM), Leucine-rich repeated-containing G-protein coupled receptor 5-positive (Lgr5) and Tyrosine aminotransferase (TAT). Cells showed decreased fibrogenesis, hepatic stellate cell infiltration, Kupffer cells and inflammatory cytokines. Liver function markers improved. In a cirrhotic liver environment, cells could differentiate into hepatic lineages. In addition, grafted MLpvNG2(+) cells could mobilize endogenous stem/progenitors to participate in liver repair. These results suggest that MLpvNG2(+) cells may be novel adult liver progenitors that participate in liver regeneration.
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Affiliation(s)
- Hongyu Zhang
- Hepatobiliary Institute, Southwestern Hospital, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Christopher T. Siegel
- Department of Surgery, Division of Hepatobiliary and Abdominal Organ Transplantation, Case Western Reserve University Hospital, Cleveland OH 44106, USA
| | - Ling Shuai
- Hepatobiliary Institute, Southwestern Hospital, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Jiejuan Lai
- Hepatobiliary Institute, Southwestern Hospital, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Linli Zeng
- Hepatobiliary Institute, Southwestern Hospital, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Yujun Zhang
- Hepatobiliary Institute, Southwestern Hospital, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Xiangdong Lai
- Hepatobiliary Institute, Southwestern Hospital, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Ping Bie
- Hepatobiliary Institute, Southwestern Hospital, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Lianhua Bai
- Hepatobiliary Institute, Southwestern Hospital, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
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Köhn-Gaone J, Gogoi-Tiwari J, Ramm GA, Olynyk JK, Tirnitz-Parker JEE. The role of liver progenitor cells during liver regeneration, fibrogenesis, and carcinogenesis. Am J Physiol Gastrointest Liver Physiol 2016; 310:G143-54. [PMID: 26608186 DOI: 10.1152/ajpgi.00215.2015] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 11/19/2015] [Indexed: 01/31/2023]
Abstract
The growing worldwide challenge of cirrhosis and hepatocellular carcinoma due to increasing prevalence of excessive alcohol consumption, viral hepatitis, obesity, and the metabolic syndrome has sparked interest in stem cell-like liver progenitor cells (LPCs) as potential candidates for cell therapy and tissue engineering, as an alternative approach to whole organ transplantation. However, LPCs always proliferate in chronic liver diseases with a predisposition to cancer; they have been suggested to play major roles in driving fibrosis, disease progression, and may even represent tumor-initiating cells. Hence, a greater understanding of the factors that govern their activation, communication with other hepatic cell types, and bipotential differentiation as opposed to their potential transformation is needed before their therapeutic potential can be harnessed.
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Affiliation(s)
- Julia Köhn-Gaone
- Curtin Health Innovation Research Institute, Curtin University, Perth Western Australia, Australia
| | - Jully Gogoi-Tiwari
- Curtin Health Innovation Research Institute, Curtin University, Perth Western Australia, Australia
| | - Grant A Ramm
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - John K Olynyk
- Curtin Health Innovation Research Institute, Curtin University, Perth Western Australia, Australia; Fiona Stanley and Fremantle Hospitals, Western Australia, Australia; School of Veterinary and Life Sciences, Murdoch University, Murdoch, Western Australia, Australia; and
| | - Janina E E Tirnitz-Parker
- Curtin Health Innovation Research Institute, Curtin University, Perth Western Australia, Australia; School of Medicine and Pharmacology, University of Western Australia, Fremantle Western Australia, Australia
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Xing LB, Gao YT. Progress in research of surface markers of liver cancer stem cells. Shijie Huaren Xiaohua Zazhi 2016; 24:4231. [DOI: 10.11569/wcjd.v24.i31.4231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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39
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Graumann F, Churin Y, Tschuschner A, Reifenberg K, Glebe D, Roderfeld M, Roeb E. Genomic Methylation Inhibits Expression of Hepatitis B Virus Envelope Protein in Transgenic Mice: A Non-Infectious Mouse Model to Study Silencing of HBV Surface Antigen Genes. PLoS One 2015; 10:e0146099. [PMID: 26717563 PMCID: PMC4696744 DOI: 10.1371/journal.pone.0146099] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 12/14/2015] [Indexed: 02/07/2023] Open
Abstract
Objective The Hepatitis B virus genome persists in the nucleus of virus infected hepatocytes where it serves as template for viral mRNA synthesis. Epigenetic modifications, including methylation of the CpG islands contribute to the regulation of viral gene expression. The present study investigates the effects of spontaneous age dependent loss of hepatitis B surface protein- (HBs) expression due to HBV-genome specific methylation as well as its proximate positive effects in HBs transgenic mice. Methods Liver and serum of HBs transgenic mice aged 5–33 weeks were analyzed by Western blot, immunohistochemistry, serum analysis, PCR, and qRT-PCR. Results From the third month of age hepatic loss of HBs was observed in 20% of transgenic mice. The size of HBs-free area and the relative number of animals with these effects increased with age and struck about 55% of animals aged 33 weeks. Loss of HBs-expression was strongly correlated with amelioration of serum parameters ALT and AST. In addition lower HBs-expression went on with decreased ER-stress. The loss of surface protein expression started on transcriptional level and appeared to be regulated epigenetically by DNA methylation. The amount of the HBs-expression correlated negatively with methylation of HBV DNA in the mouse genome. Conclusions Our data suggest that methylation of specific CpG sites controls gene expression even in HBs-transgenic mice with truncated HBV genome. More important, the loss of HBs expression and intracellular aggregation ameliorated cell stress and liver integrity. Thus, targeted modulation of HBs expression may offer new therapeutic approaches. Furthermore, HBs-transgenic mice depict a non-infectious mouse model to study one possible mechanism of HBs gene silencing by hypermethylation.
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Affiliation(s)
- Franziska Graumann
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany
| | - Yuri Churin
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany
| | | | - Kurt Reifenberg
- Central Laboratory Animal Facility, Johannes Gutenberg University, Mainz, Germany
| | - Dieter Glebe
- Institute of Medical Virology, National Reference Centre for Hepatitis B and D Viruses, Justus Liebig University, Giessen, Germany
| | - Martin Roderfeld
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany
| | - Elke Roeb
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany
- * E-mail:
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Kamiya A, Ito K, Yanagida A, Chikada H, Iwama A, Nakauchi H. MEK-ERK Activity Regulates the Proliferative Activity of Fetal Hepatoblasts Through Accumulation of p16/19cdkn2a. Stem Cells Dev 2015; 24:2525-35. [DOI: 10.1089/scd.2015.0015] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Akihide Kamiya
- Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan
- Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Keiichi Ito
- Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Ayaka Yanagida
- Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Hiromi Chikada
- Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Atsushi Iwama
- Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiromitsu Nakauchi
- Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California
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41
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Marcelo KL, Lin F, Rajapakshe K, Dean A, Gonzales N, Coarfa C, Means AR, Goldie LC, York B. Deciphering hepatocellular responses to metabolic and oncogenic stress. J Biol Methods 2015; 2. [PMID: 26504887 DOI: 10.14440/jbm.2015.77] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Each cell type responds uniquely to stress and fractionally contributes to global and tissue-specific stress responses. Hepatocytes, liver macrophages (MΦ), and sinusoidal endothelial cells (SEC) play functionally important and interdependent roles in adaptive processes such as obesity and tumor growth. Although these cell types demonstrate significant phenotypic and functional heterogeneity, their distinctions enabling disease-specific responses remain understudied. We developed a strategy for the simultaneous isolation and quantification of these liver cell types based on antigenic cell surface marker expression. To demonstrate the utility and applicability of this technique, we quantified liver cell-specific responses to high-fat diet (HFD) or diethylnitrosamine (DEN), a liver-specific carcinogen, and found that while there was only a marginal increase in hepatocyte number, MΦ and SEC populations were quantitatively increased. Global gene expression profiling of hepatocytes, MΦ and SEC identified characteristic gene signatures that define each cell type in their distinct physiological or pathological states. Integration of hepatic gene signatures with available human obesity and liver cancer microarray data provides further insight into the cell-specific responses to metabolic or oncogenic stress. Our data reveal unique gene expression patterns that serve as molecular "fingerprints" for the cell-centric responses to pathologic stimuli in the distinct microenvironment of the liver. The technical advance highlighted in this study provides an essential resource for assessing hepatic cell-specific contributions to metabolic and oncogenic stress, information that could unveil previously unappreciated molecular mechanisms for the cellular crosstalk that underlies the continuum from metabolic disruption to obesity and ultimately hepatic cancer.
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Affiliation(s)
- Kathrina L Marcelo
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Fumin Lin
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Kimal Rajapakshe
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Adam Dean
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Naomi Gonzales
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Cristian Coarfa
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Anthony R Means
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA ; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Lauren C Goldie
- Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA ; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA ; USDA/ARS Children's Nutrition Research Center at Baylor College of Medicine, Houston, TX, USA
| | - Brian York
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA ; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
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42
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Ling L, Camilleri ET, Helledie T, Samsonraj RM, Titmarsh DM, Chua RJ, Dreesen O, Dombrowski C, Rider DA, Galindo M, Lee I, Hong W, Hui JH, Nurcombe V, van Wijnen AJ, Cool SM. Effect of heparin on the biological properties and molecular signature of human mesenchymal stem cells. Gene 2015; 576:292-303. [PMID: 26484394 DOI: 10.1016/j.gene.2015.10.039] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 10/15/2015] [Indexed: 01/12/2023]
Abstract
Chronic use of heparin as an anti-coagulant for the treatment of thrombosis or embolism invokes many adverse systemic events including thrombocytopenia, vascular reactions and osteoporosis. Here, we addressed whether adverse effects might also be directed to mesenchymal stem cells that reside in the bone marrow compartment. Harvested human bone marrow-derived mesenchymal stem cells (hMSCs) were exposed to varying doses of heparin and their responses profiled. At low doses (<200 ng/ml), serial passaging with heparin exerted a variable effect on hMSC proliferation and multipotentiality across multiple donors, while at higher doses (≥ 100 μg/ml), heparin supplementation inhibited cell growth and increased both senescence and cell size. Gene expression profiling using cDNA arrays and RNA-seq analysis revealed pleiotropic effects of low-dose heparin on signaling pathways essential to hMSC growth and differentiation (including the TGFβ/BMP superfamily, FGFs, and Wnts). Cells serially passaged in low-dose heparin possess a donor-dependent gene signature that reflects their altered phenotype. Our data indicate that heparin supplementation during the culturing of hMSCs can alter their biological properties, even at low doses. This warrants caution in the application of heparin as a culture supplement for the ex vivo expansion of hMSCs. It also highlights the need for careful evaluation of the bone marrow compartment in patients receiving chronic heparin treatment.
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Affiliation(s)
- Ling Ling
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore
| | - Emily T Camilleri
- Department of Orthopedic Surgery & Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Torben Helledie
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore
| | - Rebekah M Samsonraj
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore; Department of Orthopedic Surgery & Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Drew M Titmarsh
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore
| | - Ren Jie Chua
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore
| | - Oliver Dreesen
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore
| | - Christian Dombrowski
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore
| | - David A Rider
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore
| | - Mario Galindo
- Millennium Institute on Immunology and Immunotherapy, University of Chile, Chile; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Casilla 70061, Correo 7, Santiago, Chile
| | - Ian Lee
- Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673, Singapore
| | - Wanjin Hong
- Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673, Singapore
| | - James H Hui
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore
| | - Victor Nurcombe
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore
| | - Andre J van Wijnen
- Department of Orthopedic Surgery & Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
| | - Simon M Cool
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore; Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore.
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Abstract
The liver is a central regulator of metabolism, and liver failure thus constitutes a major health burden. Understanding how this complex organ develops during embryogenesis will yield insights into how liver regeneration can be promoted and how functional liver replacement tissue can be engineered. Recent studies of animal models have identified key signaling pathways and complex tissue interactions that progressively generate liver progenitor cells, differentiated lineages and functional tissues. In addition, progress in understanding how these cells interact, and how transcriptional and signaling programs precisely coordinate liver development, has begun to elucidate the molecular mechanisms underlying this complexity. Here, we review the lineage relationships, signaling pathways and transcriptional programs that orchestrate hepatogenesis.
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Affiliation(s)
- Miriam Gordillo
- Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA
| | - Todd Evans
- Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA
| | - Valerie Gouon-Evans
- Department of Developmental and Regenerative Biology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Abstract
In recent years, hepatic oval cells (HOC) have gradually become a research hotspot, and their participation in the reconstruction of liver structure and function has been preliminarily confirmed. This provides a new direction for the study of the pathogenesis and treatment of liver injury, hepatitis, liver fibrosis, cirrhosis, liver neoplasms and other liver diseases. This paper will discuss the relationship between hepatic oval cells and liver diseases.
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45
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Lu WY, Bird TG, Boulter L, Tsuchiya A, Cole AM, Hay T, Guest RV, Wojtacha D, Man TY, Mackinnon A, Ridgway RA, Kendall T, Williams MJ, Jamieson T, Raven A, Hay DC, Iredale JP, Clarke AR, Sansom OJ, Forbes SJ. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat Cell Biol 2015; 17:971-983. [PMID: 26192438 PMCID: PMC4612439 DOI: 10.1038/ncb3203] [Citation(s) in RCA: 365] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 06/09/2015] [Indexed: 12/13/2022]
Abstract
Hepatocytes and cholangiocytes self-renew following liver injury. Following severe injury hepatocytes are increasingly senescent, but whether hepatic progenitor cells (HPCs) then contribute to liver regeneration is unclear. Here, we describe a mouse model where the E3 ubiquitin ligase Mdm2 is inducibly deleted in more than 98% of hepatocytes, causing apoptosis, necrosis and senescence with nearly all hepatocytes expressing p21. This results in florid HPC activation, which is necessary for survival, followed by complete, functional liver reconstitution. HPCs isolated from genetically normal mice, using cell surface markers, were highly expandable and phenotypically stable in vitro. These HPCs were transplanted into adult mouse livers where hepatocyte Mdm2 was repeatedly deleted, creating a non-competitive repopulation assay. Transplanted HPCs contributed significantly to restoration of liver parenchyma, regenerating hepatocytes and biliary epithelia, highlighting their in vivo lineage potency. HPCs are therefore a potential future alternative to hepatocyte or liver transplantation for liver disease.
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Affiliation(s)
- Wei-Yu Lu
- MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU
| | - Thomas G Bird
- MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, EH4 2XU
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata, Japan
| | - Alicia M Cole
- The CRUK Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow, G61 1BD
| | - Trevor Hay
- European Cancer Stem Cell Research Institute, Cardiff School of Biosciences, CF24 4HQ
| | - Rachel V Guest
- MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU
| | - Davina Wojtacha
- MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU
| | - Tak Yung Man
- MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU
| | - Alison Mackinnon
- MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU
| | - Rachel A Ridgway
- The CRUK Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow, G61 1BD
| | - Timothy Kendall
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, EH4 2XU
| | - Michael J Williams
- MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU
| | - Thomas Jamieson
- The CRUK Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow, G61 1BD
| | - Alex Raven
- MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU
| | - David C Hay
- MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU
| | - John P Iredale
- MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, United Kingdom
| | - Alan R Clarke
- European Cancer Stem Cell Research Institute, Cardiff School of Biosciences, CF24 4HQ
| | - Owen J Sansom
- The CRUK Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow, G61 1BD
| | - Stuart J Forbes
- MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU
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Tsuruya K, Chikada H, Ida K, Anzai K, Kagawa T, Inagaki Y, Mine T, Kamiya A. A Paracrine Mechanism Accelerating Expansion of Human Induced Pluripotent Stem Cell-Derived Hepatic Progenitor-Like Cells. Stem Cells Dev 2015; 24:1691-1702. [PMID: 25808356 PMCID: PMC4499795 DOI: 10.1089/scd.2014.0479] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 03/21/2015] [Indexed: 01/08/2023] Open
Abstract
Hepatic stem/progenitor cells in liver development have a high proliferative potential and the ability to differentiate into both hepatocytes and cholangiocytes. In this study, we focused on the cell surface molecules of human induced pluripotent stem (iPS) cell-derived hepatic progenitor-like cells (HPCs) and analyzed how these molecules modulate expansion of these cells. Human iPS cells were differentiated into immature hepatic lineage cells by cytokines. In addition to hepatic progenitor markers (CD13 and CD133), the cells were coimmunostained for various cell surface markers (116 types). The cells were analyzed by flow cytometry and in vitro colony formation culture with feeder cells. Twenty types of cell surface molecules were highly expressed in CD13(+)CD133(+) cells derived from human iPS cells. Of these molecules, CD221 (insulin-like growth factor receptor), which was expressed in CD13(+)CD133(+) cells, was quickly downregulated after in vitro expansion. The proliferative ability was suppressed by a neutralizing antibody and specific inhibitor of CD221. Overexpression of CD221 increased colony-forming ability. We also found that inhibition of CD340 (erbB2) and CD266 (fibroblast growth factor-inducible 14) signals suppressed proliferation. In addition, both insulin-like growth factor (a ligand of CD221) and tumor necrosis factor-like weak inducer of apoptosis (a ligand of CD266) were provided by feeder cells in our culture system. This study revealed the expression profiles of cell surface molecules in human iPS cell-derived HPCs and that the paracrine interactions between HPCs and other cells through specific receptors are important for proliferation.
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Affiliation(s)
- Kota Tsuruya
- Laboratory of Stem Cell Therapy, Institute of Innovative Science and Technology, Tokai University, Isehara, Japan
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Tokai University, Isehara, Japan
| | - Hiromi Chikada
- Laboratory of Stem Cell Therapy, Institute of Innovative Science and Technology, Tokai University, Isehara, Japan
| | - Kinuyo Ida
- Laboratory of Stem Cell Therapy, Institute of Innovative Science and Technology, Tokai University, Isehara, Japan
| | - Kazuya Anzai
- Laboratory of Stem Cell Therapy, Institute of Innovative Science and Technology, Tokai University, Isehara, Japan
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Tokai University, Isehara, Japan
| | - Tatehiro Kagawa
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Tokai University, Isehara, Japan
| | - Yutaka Inagaki
- Department of Regenerative Medicine, School of Medicine and Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan
| | - Tetsuya Mine
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Tokai University, Isehara, Japan
| | - Akihide Kamiya
- Laboratory of Stem Cell Therapy, Institute of Innovative Science and Technology, Tokai University, Isehara, Japan
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Liu K, Guo MG, Lou XL, Li XY, Xu Y, Ji WD, Huang XD, Yang JH, Duan JC. Hepatocyte nuclear factor 4α induces a tendency of differentiation and activation of rat hepatic stellate cells. World J Gastroenterol 2015; 21:5856-5866. [PMID: 26019449 PMCID: PMC4438019 DOI: 10.3748/wjg.v21.i19.5856] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 01/15/2015] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of hepatocyte nuclear factor 4α (HNF4α) on the differentiation and transformation of hepatic stellate cells (HSCs).
METHODS: By constructing the recombinant adenovirus vector expressing HNF4α and HNF4α shRNA vector, and manipulating HNF4α expression in HSC-T6 cells, we explored the influence of HNF4α and its induction capacity in the differentiation of rat HSCs into hepatocytes.
RESULTS: With increased expression of HNF4α mediated by AdHNF4α, the relative expression of Nanog was downregulated in HSC-T6 cells (98.33 ± 12.33 vs 41.33 ± 5.67, P < 0.001). Consequently, the expression of G-P-6 and PEPCK was upregulated (G-P-6: 14.34 ± 3.33 vs 42.53 ± 5.87, P < 0.01; PEPCK: 10.10 ± 4.67 vs 56.56 ± 5.25, P < 0.001), the expression of AFP and ALB was positive, and the expression of Nanog, Type I collagen, α-SMA, and TIMP-1 was significantly decreased. HNF4α also downregulated vimentin expression and enhanced E-cadherin expression. The ultrastructure of HNF4α-induced cells had more mitochondria and ribosomes compared with the parental cells. After silencing HNF4α expression, EPCK, E-cadherin, AFP, and ALB were downregulated and α-SMA and vimentin were upregulated.
CONCLUSION: HNF4α can induce a tendency of differentiation of HSCs into hepatocyte-like cells. These findings may provide an effective way for the treatment of liver diseases.
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Swiderska-Syn M, Syn WK, Xie G, Krüger L, Machado MV, Karaca G, Michelotti GA, Choi SS, Premont RT, Diehl AM. Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy. Gut 2014; 63:1333-44. [PMID: 24173292 PMCID: PMC4006344 DOI: 10.1136/gutjnl-2013-305962] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVE Smoothened (SMO), a coreceptor of the Hedgehog (Hh) pathway, promotes fibrogenic repair of chronic liver injury. We investigated the roles of SMO+ myofibroblast (MF) in liver regeneration by conditional deletion of SMO in α smooth muscle actin (αSMA)+ cells after partial hepatectomy (PH). DESIGN αSMA-Cre-ER(T2)×SMO/flox mice were treated with vehicle (VEH) or tamoxifen (TMX), and sacrificed 24-96 h post-PH. Regenerating livers were analysed for proliferation, progenitors and fibrosis by qRT-PCR and quantitative immunohistochemistry (IHC). Results were normalised to liver segments resected at PH. For lineage-tracing studies, αSMA-Cre-ER(T2)×ROSA-Stop-flox-yellow fluorescent protein (YFP) mice were treated with VEH or TMX; livers were stained for YFP, and hepatocytes isolated 48 and 72 h post-PH were analysed for YFP by flow cytometric analysis (FACS). RESULTS Post-PH, VEH-αSMA-SMO mice increased expression of Hh-genes, transiently accumulated MF, fibrosis and liver progenitors, and ultimately exhibited proliferation of hepatocytes and cholangiocytes. In contrast, TMX-αSMA-SMO mice showed loss of whole liver SMO expression, repression of Hh-genes, enhanced accumulation of quiescent HSC but reduced accumulation of MF, fibrosis and progenitors, as well as inhibition of hepatocyte and cholangiocyte proliferation, and reduced recovery of liver weight. In TMX-αSMA-YFP mice, many progenitors, cholangiocytes and up to 25% of hepatocytes were YFP+ by 48-72 h after PH, indicating that liver epithelial cells were derived from αSMA-YFP+ cells. CONCLUSIONS Hh signalling promotes transition of quiescent hepatic stellate cells to fibrogenic MF, some of which become progenitors that regenerate the liver epithelial compartment after PH. Hence, scarring is a component of successful liver regeneration.
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Affiliation(s)
- M Swiderska-Syn
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC
| | - WK Syn
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC,Regeneration and Repair, Institute of Hepatology, Foundation for Liver Research, London
| | - G Xie
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC
| | - L Krüger
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC
| | - MV Machado
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC
| | - G Karaca
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC
| | - GA Michelotti
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC
| | - SS Choi
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC,Section of Gastroenterology, Durham Veterans Affairs Medical Center, Durham, NC
| | - RT Premont
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC
| | - AM Diehl
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC,Corresponding author: Anna Mae Diehl, MD, Division of Gastroenterology, Duke University Medical Center, 595 LaSalle Street, Snyderman Building, Suite 1073, Durham, NC 27710, 919-684-4173,
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Yamashita T, Kaneko S. Orchestration of hepatocellular carcinoma development by diverse liver cancer stem cells. J Gastroenterol 2014; 49:1105-10. [PMID: 24647548 DOI: 10.1007/s00535-014-0951-1] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 03/09/2014] [Indexed: 02/04/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the world's most aggressive diseases and carries a poor prognosis for patients. Recent evidence suggests that HCC is organized by cancer stem cells (CSCs), which are a subset of cells with stem cell-like features. CSCs are considered a pivotal target for the eradication of cancer, and liver CSCs have been investigated using various stem cell markers. Several hepatic stem/progenitor markers have been shown to be useful for isolating putative CSCs from HCC, although the expression patterns and phenotypic diversity of CSCs purified by these markers remain obscure. Recently, we found that liver CSCs defined by different markers show unique features of tumorigenicity and metastasis, with phenotypes closely associated with committed liver lineages. Furthermore, our data suggest that these distinct CSCs collaborate to orchestrate the tumorigenicity and metastasis of HCC. In this review article, we summarize the recent advances in understanding the pathogenesis and heterogeneity of liver CSCs.
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Affiliation(s)
- Taro Yamashita
- Departments of General Medicine, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan,
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50
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Kruitwagen HS, Spee B, Schotanus BA. Hepatic progenitor cells in canine and feline medicine: potential for regenerative strategies. BMC Vet Res 2014; 10:137. [PMID: 24946932 PMCID: PMC4089933 DOI: 10.1186/1746-6148-10-137] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Accepted: 12/31/2013] [Indexed: 12/17/2022] Open
Abstract
New curative therapies for severe liver disease are urgently needed in both the human and veterinary clinic. It is important to find new treatment modalities which aim to compensate for the loss of parenchymal tissue and to repopulate the liver with healthy hepatocytes. A prime focus in regenerative medicine of the liver is the use of adult liver stem cells, or hepatic progenitor cells (HPCs), for functional recovery of liver disease. This review describes recent developments in HPC research in dog and cat and compares these findings to experimental rodent studies and human pathology. Specifically, the role of HPCs in liver regeneration, key components of the HPC niche, and HPC activation in specific types of canine and feline liver disease will be reviewed. Finally, the potential applications of HPCs in regenerative medicine of the liver are discussed and a potential role is suggested for dogs as first target species for HPC-based trials.
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Affiliation(s)
- Hedwig S Kruitwagen
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, 3584 CM, Utrecht, The Netherlands.
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