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1
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Loycano MA, Pienta KJ, Amend SR. Temporal myc dynamics permit mitotic bypass, promoting polyploid phenotypes. Cancer Lett 2025; 613:217526. [PMID: 39909233 PMCID: PMC11924244 DOI: 10.1016/j.canlet.2025.217526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 01/29/2025] [Accepted: 02/02/2025] [Indexed: 02/07/2025]
Abstract
High Myc phenotypes are extensively documented in the hyperproliferative cell cycle of cancer cells, as well as non-proliferative endoreplication cycles engaged during normal development and stress response. Notably, endoreplication in cancer produces chemotherapy resistant polyploid cells, necessitating a clearer understanding of altered cell cycle regulation that uncouples DNA replication and mitotic cell division. The c-Myc oncogene is a well-established transcriptional regulator of cell cycle progression and has been extensively published as an essential driver of the G1/S transition. Beyond S phase, Myc transcriptionally activates the proteins that drive mitotic entry. Sustained activation of Myc through the cell cycle transcriptionally couples DNA replication and mitotic cell division. Based on the literature in this field, we propose a new model of temporal regulation of Myc activity that serves to either couple or uncouple these two processes, determining cell cycle fate - proliferation or polyploidy. The mitotic cell cycle requires two pulses of Myc activity - the first driving the G1/S transition and the second driving the G2/M transition. During mitosis, Myc activity must be silenced to achieve high-fidelity division. Absence of the second activity pulse during G2 results in the downregulation of the proteins essential for mitotic entry and permits premature activation of APC/C, inducing mitotic bypass. A subsequent rise of Myc activity following mitotic bypass permits genome re-replication, driving polyploid phenotypes. This model serves to provide a new level of understanding to the global regulation of S phase-mitosis coupling, as well as a new lens to view low Myc phenotypes.
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Affiliation(s)
- Michael A Loycano
- Cancer Ecology Center, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institute, Baltimore, MD, USA; Cellular and Molecular Medicine Graduate Training Program, Johns Hopkins School of Medicine, Baltimore, MD, USA.
| | - Kenneth J Pienta
- Cancer Ecology Center, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institute, Baltimore, MD, USA; Cellular and Molecular Medicine Graduate Training Program, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Sarah R Amend
- Cancer Ecology Center, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institute, Baltimore, MD, USA; Cellular and Molecular Medicine Graduate Training Program, Johns Hopkins School of Medicine, Baltimore, MD, USA
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2
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Fidler E, Dwyer K, Ansari A. Ssu72: a versatile protein with functions in transcription and beyond. Front Mol Biosci 2024; 11:1332878. [PMID: 38304578 PMCID: PMC10830811 DOI: 10.3389/fmolb.2024.1332878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 01/08/2024] [Indexed: 02/03/2024] Open
Abstract
Eukaryotic transcription is a complex process involving a vast network of protein and RNA factors that influence gene expression. The main player in transcription is the RNA polymerase that synthesizes the RNA from the DNA template. RNA polymerase II (RNAPII) transcribes all protein coding genes and some noncoding RNAs in eukaryotic cells. The polymerase is aided by interacting partners that shuttle it along the gene for initiation, elongation and termination of transcription. One of the many factors that assist RNAPII in transcription of genes is Ssu72. It is a carboxy-terminal-domain (CTD)-phosphatase that plays pleiotropic roles in the transcription cycle. It is essential for cell viability in Saccharomyces cerevisiae, the organism in which it was discovered. The homologues of Ssu72 have been identified in humans, mice, plants, flies, and fungi thereby suggesting the evolutionarily conserved nature of the protein. Recent studies have implicated the factor beyond the confines of transcription in homeostasis and diseases.
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Affiliation(s)
| | | | - Athar Ansari
- Department of Biological Sciences, Wayne State University, Detroit, MI, United States
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3
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Wilson SR, Duncan AW. The Ploidy State as a Determinant of Hepatocyte Proliferation. Semin Liver Dis 2023; 43:460-471. [PMID: 37967885 PMCID: PMC10862383 DOI: 10.1055/a-2211-2144] [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: 11/17/2023]
Abstract
The liver's unique chromosomal variations, including polyploidy and aneuploidy, influence hepatocyte identity and function. Among the most well-studied mammalian polyploid cells, hepatocytes exhibit a dynamic interplay between diploid and polyploid states. The ploidy state is dynamic as hepatocytes move through the "ploidy conveyor," undergoing ploidy reversal and re-polyploidization during proliferation. Both diploid and polyploid hepatocytes actively contribute to proliferation, with diploids demonstrating an enhanced proliferative capacity. This enhanced potential positions diploid hepatocytes as primary drivers of liver proliferation in multiple contexts, including homeostasis, regeneration and repopulation, compensatory proliferation following injury, and oncogenic proliferation. This review discusses the influence of ploidy variations on cellular activity. It presents a model for ploidy-associated hepatocyte proliferation, offering a deeper understanding of liver health and disease with the potential to uncover novel treatment approaches.
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Affiliation(s)
- Sierra R. Wilson
- Department of Pathology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Andrew W. Duncan
- Department of Pathology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
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4
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Wen Z, Lin YH, Wang S, Fujiwara N, Rong R, Jin KW, Yang DM, Yao B, Yang S, Wang T, Xie Y, Hoshida Y, Zhu H, Xiao G. Deep-Learning-Based Hepatic Ploidy Quantification Using H&E Histopathology Images. Genes (Basel) 2023; 14:921. [PMID: 37107679 PMCID: PMC10137944 DOI: 10.3390/genes14040921] [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: 03/01/2023] [Revised: 03/28/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023] Open
Abstract
Polyploidy, the duplication of the entire genome within a single cell, is a significant characteristic of cells in many tissues, including the liver. The quantification of hepatic ploidy typically relies on flow cytometry and immunofluorescence (IF) imaging, which are not widely available in clinical settings due to high financial and time costs. To improve accessibility for clinical samples, we developed a computational algorithm to quantify hepatic ploidy using hematoxylin-eosin (H&E) histopathology images, which are commonly obtained during routine clinical practice. Our algorithm uses a deep learning model to first segment and classify different types of cell nuclei in H&E images. It then determines cellular ploidy based on the relative distance between identified hepatocyte nuclei and determines nuclear ploidy using a fitted Gaussian mixture model. The algorithm can establish the total number of hepatocytes and their detailed ploidy information in a region of interest (ROI) on H&E images. This is the first successful attempt to automate ploidy analysis on H&E images. Our algorithm is expected to serve as an important tool for studying the role of polyploidy in human liver disease.
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Affiliation(s)
- Zhuoyu Wen
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yu-Hsuan Lin
- Children’s Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Shidan Wang
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Naoto Fujiwara
- Division of Digestive and Liver Diseases, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ruichen Rong
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Kevin W. Jin
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Donghan M. Yang
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Bo Yao
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Shengjie Yang
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Tao Wang
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Center for the Genetics of Host Defense, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yang Xie
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Hamon Center for Regenerative Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Bioinformatics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yujin Hoshida
- Division of Digestive and Liver Diseases, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Hao Zhu
- Children’s Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Children’s Research Institute Mouse Genome Engineering Core, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Guanghua Xiao
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Hamon Center for Regenerative Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Bioinformatics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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5
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Zhang L, Ma XJN, Fei YY, Han HT, Xu J, Cheng L, Li X. Stem cell therapy in liver regeneration: Focus on mesenchymal stem cells and induced pluripotent stem cells. Pharmacol Ther 2022; 232:108004. [PMID: 34597754 DOI: 10.1016/j.pharmthera.2021.108004] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/11/2021] [Accepted: 09/23/2021] [Indexed: 02/07/2023]
Abstract
The liver has the ability to repair itself after injury; however, a variety of pathological changes in the liver can affect its ability to regenerate, and this could lead to liver failure. Mesenchymal stem cells (MSCs) are considered a good source of cells for regenerative medicine, as they regulate liver regeneration through different mechanisms, and their efficacy has been demonstrated by many animal experiments and clinical studies. Induced pluripotent stem cells, another good source of MSCs, have also made great progress in the establishment of organoids, such as liver disease models, and in drug screening. Owing to the recent developments in MSCs and induced pluripotent stem cells, combined with emerging technologies including graphene, nano-biomaterials, and gene editing, precision medicine and individualized clinical treatment may be realized in the near future.
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Affiliation(s)
- Lu Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Xiao-Jing-Nan Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Yuan-Yuan Fei
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China
| | - Heng-Tong Han
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Jun Xu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Lu Cheng
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China
| | - Xun Li
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China; Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China.
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6
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Orekhova NA, Modorov MV. Effects of environmental low-dose irradiation on functional-metabolic organ responses in a natural mouse population (Apodemus agrarius Pallas, 1771) within the East Urals Radioactive Trace (EURT) area, Russia. Int J Radiat Biol 2022; 98:1414-1423. [DOI: 10.1080/09553002.2022.2033340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Natal´ya A. Orekhova
- Institute of Plant and Animal Ecology, Ural Branch, Russian Academy of Sciences, st. Vos’mogo Marta 202, Yekaterinburg, 620144 Russia
| | - Makar V. Modorov
- Institute of Plant and Animal Ecology, Ural Branch, Russian Academy of Sciences, st. Vos’mogo Marta 202, Yekaterinburg, 620144 Russia
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7
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Abstract
Polyploidy is a common and dynamic feature of mature rodent and human hepatocytes. While polyploidization occurs naturally during growth, alterations in the distribution of diploid and polyploid cells in the liver can be indicative of tissue stress or a pathologic state. Here, we describe a method for flow cytometric quantification of ploidy distribution by staining with propidium iodide. We first outline a hepatocyte isolation procedure from mouse liver through a two-step perfusion system for analysis of cellular ploidy. In an alternative approach, we employ a nuclei isolation protocol to assess nuclear ploidy. Finally, we describe how the use of fluorescent cell markers is compatible with these methods and helps retain information on cellular position within the tissue.
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Affiliation(s)
- Yinhua Jin
- Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Teni Anbarchian
- Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Roel Nusse
- Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
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8
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Donne R, Sangouard F, Celton-Morizur S, Desdouets C. Hepatocyte Polyploidy: Driver or Gatekeeper of Chronic Liver Diseases. Cancers (Basel) 2021; 13:cancers13205151. [PMID: 34680300 PMCID: PMC8534039 DOI: 10.3390/cancers13205151] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/11/2021] [Accepted: 10/11/2021] [Indexed: 12/25/2022] Open
Abstract
Polyploidy, also known as whole-genome amplification, is a condition in which the organism has more than two basic sets of chromosomes. Polyploidy frequently arises during tissue development and repair, and in age-associated diseases, such as cancer. Its consequences are diverse and clearly different between systems. The liver is a particularly fascinating organ in that it can adapt its ploidy to the physiological and pathological context. Polyploid hepatocytes are characterized in terms of the number of nuclei per cell (cellular ploidy; mononucleate/binucleate hepatocytes) and the number of chromosome sets in each nucleus (nuclear ploidy; diploid, tetraploid, octoploid). The advantages and disadvantages of polyploidy in mammals are not fully understood. About 30% of the hepatocytes in the human liver are polyploid. In this review, we explore the mechanisms underlying the development of polyploid cells, our current understanding of the regulation of polyploidization during development and pathophysiology and its consequences for liver function. We will also provide data shedding light on the ways in which polyploid hepatocytes cope with centrosome amplification. Finally, we discuss recent discoveries highlighting the possible roles of liver polyploidy in protecting against tumor formation, or, conversely, contributing to liver tumorigenesis.
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Affiliation(s)
- Romain Donne
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY 10029, USA
- Icahn School of Medicine at Mount Sinai, The Precision Immunology Institute, New York, NY 10029, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Flora Sangouard
- Laboratory of Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, F-75006 Paris, France;
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006 Paris, France
| | - Séverine Celton-Morizur
- Laboratory of Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, F-75006 Paris, France;
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006 Paris, France
- Correspondence: (S.C.-M.); (C.D.)
| | - Chantal Desdouets
- Laboratory of Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, F-75006 Paris, France;
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006 Paris, France
- Correspondence: (S.C.-M.); (C.D.)
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9
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Wang X, Zhang W, Yang Y, Wang J, Qiu H, Liao L, Oikawa T, Wauthier E, Sethupathy P, Reid LM, Liu Z, He Z. A MicroRNA-Based Network Provides Potential Predictive Signatures and Reveals the Crucial Role of PI3K/AKT Signaling for Hepatic Lineage Maturation. Front Cell Dev Biol 2021; 9:670059. [PMID: 34141708 PMCID: PMC8204022 DOI: 10.3389/fcell.2021.670059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 04/07/2021] [Indexed: 11/13/2022] Open
Abstract
Background Functions of miRNAs involved in tumorigenesis are well reported, yet, their roles in normal cell lineage commitment remain ambiguous. Here, we investigated a specific "transcription factor (TF)-miRNA-Target" regulatory network during the lineage maturation of biliary tree stem cells (BTSCs) into adult hepatocytes (hAHeps). Method Bioinformatic analysis was conducted based on our RNA-seq and microRNA-seq datasets with four human hepatic-lineage cell lines, including hBTSCs, hepatic stem cells (hHpSCs), hepatoblasts (hHBs), and hAHeps. Short time-series expression miner (STEM) analysis was performed to reveal the time-dependent dynamically changed miRNAs and mRNAs. GO and KEGG analyses were applied to reveal the potential function of key miRNAs and mRNAs. Then, the miRDB, miRTarBase, TargetScan, miRWalk, and DIANA-microT-CDS databases were adopted to predict the potential targets of miRNAs while the TransmiR v2.0 database was used to obtain the experimentally supported TFs that regulate miRNAs. The TCGA, Kaplan-Meier Plotter, and human protein atlas (HPA) databases and more than 10 sequencing data, including bulk RNA-seq, microRNA-seq, and scRNA-seq data related to hepatic development or lineage reprogramming, were obtained from both our or other published studies for validation. Results STEM analysis showed that during the maturation from hBTSCs to hAHeps, 52 miRNAs were downwardly expressed and 928 mRNA were upwardly expressed. Enrichment analyses revealed that those 52 miRNAs acted as pluripotency regulators for stem cells and participated in various novel signaling pathways, including PI3K/AKT, MAPK, and etc., while 928 mRNAs played important roles in liver-functional metabolism. With an extensive sorting of those key miRNAs and mRNAs based on the target prediction results, 23 genes were obtained which not only functioned as the targets of 17 miRNAs but were considered critical for the hepatic lineage commitment. A "TF-miRNA-Target" regulatory network for hepatic lineage commitment was therefore established and had been well validated by various datasets. The network revealed that the PI3K/AKT pathway was gradually suppressed during the hepatic commitment. Conclusion A total of 17 miRNAs act as suppressors during hepatic maturation mainly by regulating 23 targets and modulating the PI3K/AKT signaling pathway. The regulatory network uncovers possible signatures and guidelines enabling us to identify or obtain the functional hepatocytes for future study.
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Affiliation(s)
- Xicheng Wang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai, China.,Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Wencheng Zhang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai, China.,Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Yong Yang
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jiansong Wang
- Department of Traumatology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hua Qiu
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Lijun Liao
- Department of Anesthesiology and Pain Management, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Eliane Wauthier
- Department of Cell Biology and Physiology, UNC School of Medicine, Chapel Hill, NC, United States
| | - Praveen Sethupathy
- Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, United States
| | - Lola M Reid
- Department of Cell Biology and Physiology, UNC School of Medicine, Chapel Hill, NC, United States
| | - Zhongmin Liu
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai, China.,Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Zhiying He
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai, China.,Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
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10
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Hwang S, Kim MH, Lee CW. Ssu72 Dual-Specific Protein Phosphatase: From Gene to Diseases. Int J Mol Sci 2021; 22:3791. [PMID: 33917542 PMCID: PMC8038829 DOI: 10.3390/ijms22073791] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/02/2021] [Accepted: 04/05/2021] [Indexed: 12/22/2022] Open
Abstract
More than 70% of eukaryotic proteins are regulated by phosphorylation. However, the mechanism of dephosphorylation that counteracts phosphorylation is less studied. Phosphatases are classified into 104 distinct groups based on substrate-specific features and the sequence homologies in their catalytic domains. Among them, dual-specificity phosphatases (DUSPs) that dephosphorylate both phosphoserine/threonine and phosphotyrosine are important for cellular homeostasis. Ssu72 is a newly studied phosphatase with dual specificity that can dephosphorylate both phosphoserine/threonine and phosphotyrosine. It is important for cell-growth signaling, metabolism, and immune activation. Ssu72 was initially identified as a phosphatase for the Ser5 and Ser7 residues of the C-terminal domain of RNA polymerase II. It prefers the cis configuration of the serine-proline motif within its substrate and regulates Pin1, different from other phosphatases. It has recently been reported that Ssu72 can regulate sister chromatid cohesion and the separation of duplicated chromosomes during the cell cycle. Furthermore, Ssu72 appears to be involved in the regulation of T cell receptor signaling, telomere regulation, and even hepatocyte homeostasis in response to a variety of stress and damage signals. In this review, we aim to summarize various functions of the Ssu72 phosphatase, their implications in diseases, and potential therapeutic indications.
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Affiliation(s)
- Soeun Hwang
- Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon 16419, Korea; (S.H.); (M.-H.K.)
| | - Min-Hee Kim
- Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon 16419, Korea; (S.H.); (M.-H.K.)
| | - Chang-Woo Lee
- Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon 16419, Korea; (S.H.); (M.-H.K.)
- SKKU Institute for Convergence, Sungkyunkwan University, Suwon 16419, Korea
- Curogen Technology, Suwon 16419, Korea
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11
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Barbutti I, Laurentino JC, Va da Silva N, Deoclécio VS, Ferrucci D, Carvalho HF. Dietary Fat Quality in Normolipidic Diets Affects Hepatocyte's Nuclear Phenotypes. Nutr Metab Insights 2021; 13:1178638820982003. [PMID: 33414640 PMCID: PMC7750749 DOI: 10.1177/1178638820982003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 11/23/2020] [Indexed: 11/16/2022] Open
Abstract
Dietary fat quality affects overall systemic parameters and produce hepatic accumulation
of fat and inflammation (steatohepatitis). In this communication we have assessed how
mouse liver nuclear phenotypes are influenced by diets containing 7% lipid prepared with
lard, linseed oil or soybean oil for 32 weeks. Liver specimens were imprinted on glass
slides, fixed and stained with DAPI. 3D confocal images were obtained and employed for the
calculation of nuclear thickness, nuclear volume and DAPI-DNA intensity. Hepatocytes’
nuclei could be classified as diploid A, diploid B, tetraploid and higher ploidy levels.
Linseed oil in the diet resulted in increased frequency of diploid A (more compact) and
less polyploidy, while lard caused increased volume and more polyploidy. Soybean oil
produced intermediate nuclear sizes. The results suggest a high demand on liver physiology
promoted by lard, which has a predominance of saturated fatty acids, while linseed oil
promoted the opposite effect.
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Affiliation(s)
- Isabella Barbutti
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, São Paulo, Brazil
| | - Jesse C Laurentino
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, São Paulo, Brazil
| | - Natalia Va da Silva
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, São Paulo, Brazil
| | - Vinicius S Deoclécio
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, São Paulo, Brazil
| | - Danilo Ferrucci
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, São Paulo, Brazil
| | - Hernandes F Carvalho
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, São Paulo, Brazil
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12
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Wilkinson PD, Duncan AW. Differential Roles for Diploid and Polyploid Hepatocytes in Acute and Chronic Liver Injury. Semin Liver Dis 2021; 41:42-49. [PMID: 33764484 PMCID: PMC8056861 DOI: 10.1055/s-0040-1719175] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocytes are the primary functional cells of the liver that perform essential roles in homeostasis, regeneration, and injury. Most mammalian somatic cells are diploid and contain pairs of each chromosome, but there are also polyploid cells containing additional sets of chromosomes. Hepatocytes are among the best described polyploid cells, with polyploids comprising more than 25 and 90% of the hepatocyte population in humans and mice, respectively. Cellular and molecular mechanisms that regulate hepatic polyploidy have been uncovered, and in recent years, diploid and polyploid hepatocytes have been shown to perform specialized functions. Diploid hepatocytes accelerate liver regeneration induced by resection and may accelerate compensatory regeneration after acute injury. Polyploid hepatocytes protect the liver from tumor initiation in hepatocellular carcinoma and promote adaptation to tyrosinemia-induced chronic injury. This review describes how ploidy variations influence cellular activity and presents a model for context-specific functions for diploid and polyploid hepatocytes.
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Affiliation(s)
- Patrick D Wilkinson
- Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Andrew W Duncan
- Department of Pathology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
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13
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Therapy-induced polyploidization and senescence: Coincidence or interconnection? Semin Cancer Biol 2020; 81:83-95. [DOI: 10.1016/j.semcancer.2020.11.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/23/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023]
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Abstract
Polyploidy (or whole-genome duplication) is the condition of having more than two basic sets of chromosomes. Polyploidization is well tolerated in many species and can lead to specific biological functions. In mammals, programmed polyploidization takes place during development in certain tissues, such as the heart and placenta, and is considered a feature of differentiation. However, unscheduled polyploidization can cause genomic instability and has been observed in pathological conditions, such as cancer. Polyploidy of the liver parenchyma was first described more than 100 years ago. The liver is one of the few mammalian organs that display changes in polyploidy during homeostasis, regeneration and in response to damage. In the human liver, approximately 30% of hepatocytes are polyploid. The polyploidy of hepatocytes results from both nuclear polyploidy (an increase in the amount of DNA per nucleus) and cellular polyploidy (an increase in the number of nuclei per cell). In this Review, we discuss the regulation of polyploidy in liver development and pathophysiology. We also provide an overview of current knowledge about the mechanisms of hepatocyte polyploidization, its biological importance and the fate of polyploid hepatocytes during liver tumorigenesis.
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15
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de Gregorio E, Colell A, Morales A, Marí M. Relevance of SIRT1-NF-κB Axis as Therapeutic Target to Ameliorate Inflammation in Liver Disease. Int J Mol Sci 2020; 21:E3858. [PMID: 32485811 PMCID: PMC7312021 DOI: 10.3390/ijms21113858] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/26/2020] [Accepted: 05/27/2020] [Indexed: 12/12/2022] Open
Abstract
Inflammation is an adaptive response in pursuit of homeostasis reestablishment triggered by harmful conditions or stimuli, such as an infection or tissue damage. Liver diseases cause approximately 2 million deaths per year worldwide and hepatic inflammation is a common factor to all of them, being the main driver of hepatic tissue damage and causing progression from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH), cirrhosis and, ultimately, hepatocellular carcinoma (HCC). The metabolic sensor SIRT1, a class III histone deacetylase with strong expression in metabolic tissues such as the liver, and transcription factor NF-κB, a master regulator of inflammatory response, show an antagonistic relationship in controlling inflammation. For this reason, SIRT1 targeting is emerging as a potential strategy to improve different metabolic and/or inflammatory pathologies. In this review, we explore diverse upstream regulators and some natural/synthetic activators of SIRT1 as possible therapeutic treatment for liver diseases.
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Affiliation(s)
- Estefanía de Gregorio
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain;
| | - Anna Colell
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 08036 Barcelona, Spain;
| | - Albert Morales
- Department of Cell Death and Proliferation, IIBB-CSIC, Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic of Barcelona, University of Barcelona, CIBEREHD, 08036 Barcelona, Spain;
| | - Montserrat Marí
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain;
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16
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Orekhova NYA. Hepatic effects of low-dose rate radiation in natural mouse populations ( Apodemus uralensis and Apodemus agrarius): comparative interspecific analysis. Int J Radiat Biol 2020; 96:1038-1050. [PMID: 32412327 DOI: 10.1080/09553002.2020.1770362] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Hypothesis: Natural mouse populations in radioactive contamination zone provide adequate information about dose loads and biological effects for 'non-human biota'. The comparative analysis of the responses of different species of mice allows us to reveal the possible variation in the effects of low-dose rate radiation relative to the ecological-physiological and functional-metabolic features of the species.Materials and methods: Objects of study - two sympatric rodent species [pygmy wood mouse (Apodemus uralensis Pallas, 1811) and striped field mouse (Apodemus agrarius Pallas, 1771)] caught on the territory of the East-Ural radioactive trace (EURT). The EURT zone is consequence the Kyshtym accident in South Urals in 1957. Nowadays, the main dose-forming radionuclide is β-emitting 90Sr. The individual dose rate of impacted mice caused by internal exposure to 90Sr varied from 0.021 to 0.152 mGy/day. The baseline functional-metabolic characteristics of the liver were researched: protein-, lipid-, and glycogen-synthesizing processes; glycolysis; aerobic synthesis of ATP; lipid peroxidation; and the H2O2-scavenging enzymatic status; and the functional activity of the genome.Results: The hepatic shifts for impacted populations are amplified with increasing dose rate of irradiation, regardless of which species is considered. But, the response of closely related species of rodents to irradiation is different both in the vector and the level (in A. agrarius sample was 2 time higher than that for A. uralensis).Conclusion: The radiation-induced hepatic shifts in A. uralensis from the EURT area correspond to the chronic response under stressful environmental conditions. The impacted population of A. agrarius can be considered the more reactive species to the radiation burden, demonstrating an acute effect. The interspecies contrast in the radiation response is associated with the original interspecies differences (background rodents' samples in 28 km from the impact study site), and also the degree of residency of the species in the impact plots.
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Affiliation(s)
- Natal Ya A Orekhova
- Institute of Plant and Animal Ecology, Ural Branch, Russian Academy of Sciences, Yekaterinburg, Russia
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17
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Bou-Nader M, Caruso S, Donne R, Celton-Morizur S, Calderaro J, Gentric G, Cadoux M, L’Hermitte A, Klein C, Guilbert T, Albuquerque M, Couchy G, Paradis V, Couty JP, Zucman-Rossi J, Desdouets C. Polyploidy spectrum: a new marker in HCC classification. Gut 2020; 69:355-364. [PMID: 30979717 PMCID: PMC6984053 DOI: 10.1136/gutjnl-2018-318021] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 02/25/2019] [Accepted: 03/24/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Polyploidy is a fascinating characteristic of liver parenchyma. Hepatocyte polyploidy depends on the DNA content of each nucleus (nuclear ploidy) and the number of nuclei per cell (cellular ploidy). Which role can be assigned to polyploidy during human hepatocellular carcinoma (HCC) development is still an open question. Here, we investigated whether a specific ploidy spectrum is associated with clinical and molecular features of HCC. DESIGN Ploidy spectra were determined on surgically resected tissues from patients with HCC as well as healthy control tissues. To define ploidy profiles, a quantitative and qualitative in situ imaging approach was used on paraffin tissue liver sections. RESULTS We first demonstrated that polyploid hepatocytes are the major components of human liver parenchyma, polyploidy being mainly cellular (binuclear hepatocytes). Across liver lobules, polyploid hepatocytes do not exhibit a specific zonation pattern. During liver tumorigenesis, cellular ploidy is drastically reduced; binuclear polyploid hepatocytes are barely present in HCC tumours. Remarkably, nuclear ploidy is specifically amplified in HCC tumours. In fact, nuclear ploidy is amplified in HCCs harbouring a low degree of differentiation and TP53 mutations. Finally, our results demonstrated that highly polyploid tumours are associated with a poor prognosis. CONCLUSIONS Our results underline the importance of quantification of cellular and nuclear ploidy spectra during HCC tumorigenesis.
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Affiliation(s)
- Myriam Bou-Nader
- Team Proliferation Stress and Liver Physiopathology, Genome and Cancer, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
| | - Stefano Caruso
- Team Functional Genomics of Solid Tumors, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Équipe Labellisée Ligue Contre le Cancer, Paris, France
| | - Romain Donne
- Team Proliferation Stress and Liver Physiopathology, Genome and Cancer, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
| | - Séverine Celton-Morizur
- Team Proliferation Stress and Liver Physiopathology, Genome and Cancer, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
| | - Julien Calderaro
- INSERM U1162, Paris, France,Department of Pathology, Hopital Henri Mondor, Creteil, France
| | - Géraldine Gentric
- Stress and Cancer Laboratory, Équipe Labelisée LNCC, Institut Curie, Paris, France,INSERM U830, Paris, France
| | - Mathilde Cadoux
- Team Proliferation Stress and Liver Physiopathology, Genome and Cancer, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
| | - Antoine L’Hermitte
- Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
| | - Christophe Klein
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, Paris, France
| | | | | | - Gabrielle Couchy
- Team Functional Genomics of Solid Tumors, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Équipe Labellisée Ligue Contre le Cancer, Paris, France
| | | | - Jean-Pierre Couty
- Team Proliferation Stress and Liver Physiopathology, Genome and Cancer, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
| | - Jessica Zucman-Rossi
- Team Functional Genomics of Solid Tumors, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Équipe Labellisée Ligue Contre le Cancer, Paris, France
| | - Chantal Desdouets
- Team Proliferation Stress and Liver Physiopathology, Genome and Cancer, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
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18
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Viswanathan P, Sharma Y, Maisuradze L, Tchaikovskaya T, Gupta S. Ataxia telangiectasia mutated pathway disruption affects hepatic DNA and tissue damage in nonalcoholic fatty liver disease. Exp Mol Pathol 2020; 113:104369. [PMID: 31917286 DOI: 10.1016/j.yexmp.2020.104369] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 11/27/2019] [Accepted: 01/03/2020] [Indexed: 12/26/2022]
Abstract
To overcome the rising burdens of nonalcoholic fatty liver disease, mechanistic linkages in mitochondrial dysfunction, inflammation and hepatic injury are critical. As ataxia telangiectasia mutated (ATM) gene oversees DNA integrity and mitochondrial homeostasis, we analyzed mRNAs and total proteins or phosphoproteins related to ATM gene by arrays in subjects with healthy liver, fatty liver or nonalcoholic steatohepatitis. Functional genomics approaches were used to query DNA damage or cell growth events. The effects of fatty acid-induced toxicity in mitochondrial health, DNA integrity and cell proliferation were validated in HuH-7 cells, including by inhibiting ATM kinase activity or knckdown of its mRNA. In fatty livers, DNA damage and ATM pathway activation was observed. During induced steatosis in HuH-7 cells, lowering of ATM activity produced mitochondrial dysregulation, DNA damage and cell growth inhibition. In livers undergoing steatohepatitis, ATM was depleted with increased hepatic DNA damage and growth-arrest due to cell cycle checkpoint activations. Moreover, molecular signatures of oncogenesis were associated with upstream mechanistic networks directing cell metabolism, inflammation or growth that were either activated (in fatty liver) or inactivated (in steatohepatitis). To compensate for hepatic growth arrest, preoncogenic oval cell populations expressing connexin-43 and/or albumin emerged. These oval cells avoided DNA damage and proliferated actively. We concluded that ATM is a major contributor to the onset and progression of nonalcoholic fatty liver disease. Therefore, specific markers for ATM pathway dysregulation will allow prospective segregation of cohorts for disease susceptibility and progression from steatosis to steatohepatitis. This will offer superior design and evaluation parameters for clinical trials. Restoration of ATM activity with targeted therapies should be appropriate for nonalcoholic fatty liver disease.
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Affiliation(s)
- Preeti Viswanathan
- Department of Pediatrics, Albert Einstein College of Medicine and Children's Hospital at Montefiore, Bronx, NY, United States
| | - Yogeshwar Sharma
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Luka Maisuradze
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Tatyana Tchaikovskaya
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States; Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Sanjeev Gupta
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States; Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, United States; Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, United States; Diabetes Center, Albert Einstein College of Medicine, Bronx, NY, United States; Irwin S. and Sylvia Chanin Institute for Cancer Research, and Albert Einstein College of Medicine, Bronx, NY, United States; Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY, United States.
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19
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Suvorov A, Naumov V, Shtratnikova V, Logacheva M, Shershebnev A, Wu H, Gerasimov E, Zheludkevich A, Pilsner JR, Sergeyev O. Rat liver epigenome programing by perinatal exposure to 2,2',4'4'-tetrabromodiphenyl ether. Epigenomics 2019; 12:235-249. [PMID: 31833787 DOI: 10.2217/epi-2019-0315] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Perinatal exposures to polybrominated diphenyl ethers permanently reprogram liver metabolism and induce a nonalcoholic fatty liver disease-like phenotype and insulin resistance in rodents. Aim: To test if these changes are associated with altered liver epigenome. Materials & methods: Expression of small RNA and changes in DNA methylation in livers of adult rats were analyzed following perinatal exposure to 2,2',4,4'-tetrabromodiphenyl ether, the polybrominated diphenyl ether congener most prevalent in human tissues. Results: We identified 33 differentially methylated DNA regions and 15 differentially expressed miRNAs. These changes were enriched for terms related to lipid and carbohydrate metabolism, insulin signaling, Type-2 diabetes and nonalcoholic fatty liver disease. Conclusion: Changes in the liver epigenome are a likely candidate mechanism of long-term maintenance of an aberrant metabolic phenotype.
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Affiliation(s)
- Alexander Suvorov
- Department of Environmental Health Sciences, School of Public Health & Health Sciences, University of Massachusetts 686 North Pleasant Street Amherst, MA 01003, USA.,A.N. Belozersky Research Institute of Physico-Chemical Biology, Moscow State University, Leninskye Gory, House 1, Building 40, 119992, Moscow, Russia
| | - Vladimir Naumov
- Kulakov National Medical Research Center of Obstetrics, Gynecology & Perinatology, Ministry of Health of the Russian Federation, Oparina 4, 117997, Moscow, Russia
| | - Victoria Shtratnikova
- A.N. Belozersky Research Institute of Physico-Chemical Biology, Moscow State University, Leninskye Gory, House 1, Building 40, 119992, Moscow, Russia.,Center for Data-Intensive Biomedicine & Biotechnology, Skolkovo Institute of Science & Technology, 143028, Moscow, Russia
| | - Maria Logacheva
- A.N. Belozersky Research Institute of Physico-Chemical Biology, Moscow State University, Leninskye Gory, House 1, Building 40, 119992, Moscow, Russia.,Center for Data-Intensive Biomedicine & Biotechnology, Skolkovo Institute of Science & Technology, 143028, Moscow, Russia
| | - Alex Shershebnev
- Department of Environmental Health Sciences, School of Public Health & Health Sciences, University of Massachusetts 686 North Pleasant Street Amherst, MA 01003, USA
| | - Haotian Wu
- Department of Environmental Health Sciences, School of Public Health & Health Sciences, University of Massachusetts 686 North Pleasant Street Amherst, MA 01003, USA.,Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, 722 W 168th St, New York, NY 10032, USA
| | - Evgeny Gerasimov
- E.I. Martsinovsky Institute of Medical Parasitology & Tropical Medicine, I.M. Sechenov First Moscow State Medical University, 20 Malaya Pirogovskaya, 119435, Moscow, Russia.,Faculty of Biology, Lomonosov Moscow State University, 119992, Moscow, Russia
| | | | - Jonathan R Pilsner
- Department of Environmental Health Sciences, School of Public Health & Health Sciences, University of Massachusetts 686 North Pleasant Street Amherst, MA 01003, USA
| | - Oleg Sergeyev
- A.N. Belozersky Research Institute of Physico-Chemical Biology, Moscow State University, Leninskye Gory, House 1, Building 40, 119992, Moscow, Russia.,Chapaevsk Medical Association, 3a Meditsinskaya St., Samara region, 446100, Chapaevsk, Russia
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20
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Donné R, Saroul M, Maillet V, Celton-Morizur S, Desdouets C. [Hepatic polyploidy: Dr Jekyll or Mr Hyde]. Med Sci (Paris) 2019; 35:519-526. [PMID: 31274081 DOI: 10.1051/medsci/2019094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Polyploidy (alias whole genome amplification) refers to organisms containing more than two basic sets of chromosomes. Polyploidy was first observed in plants more than a century ago, and it is known that such processes occur in many eukaryotes under a variety of circumstances. In mammals, the development of polyploid cells can contribute to tissue differentiation and therefore possibly a gain of function. Alternately, it can be associated with development of disease such as cancer. Polyploidy can occur because of cell fusion or abnormal cell division. Polyploidy is a common characteristic of the mammalian liver. Polyploidization occurs notably during liver development, but also in adults because of cellular stress. Recent progresses have unraveled the mechanisms and functional consequences of hepatocytes polyploidization during normal and pathological liver growth.
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Affiliation(s)
- Romain Donné
- Centre de Recherche des Cordeliers, Inserm, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, équipe Proliferation, Stress and Liver Physiopathology, 15, rue de l'École de Médecine, 75006 Paris, France
| | - Maëva Saroul
- Centre de Recherche des Cordeliers, Inserm, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, équipe Proliferation, Stress and Liver Physiopathology, 15, rue de l'École de Médecine, 75006 Paris, France
| | - Vanessa Maillet
- Centre de Recherche des Cordeliers, Inserm, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, équipe Proliferation, Stress and Liver Physiopathology, 15, rue de l'École de Médecine, 75006 Paris, France
| | - Séverine Celton-Morizur
- Centre de Recherche des Cordeliers, Inserm, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, équipe Proliferation, Stress and Liver Physiopathology, 15, rue de l'École de Médecine, 75006 Paris, France
| | - Chantal Desdouets
- Centre de Recherche des Cordeliers, Inserm, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, équipe Proliferation, Stress and Liver Physiopathology, 15, rue de l'École de Médecine, 75006 Paris, France
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21
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Bobrov IP, Lepilov AV, Dolgatov AY, Kryuchkova NG, Bakarev MA, Molodykh OP. Relationship between Cooling Medium and Hepatocyte Ploidometric Parameters in Albino Rats. Bull Exp Biol Med 2019; 167:215-219. [PMID: 31236883 DOI: 10.1007/s10517-019-04494-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Indexed: 12/01/2022]
Abstract
Relationship between the method of hypothermic exposure and ploidometric characteristics of hepatocyte nuclei of rats were studied immediately after hypothermic exposure and during the posthypothermic period. The following cooling modes were used: single submersion into 5°C water (until rectal temperature drop to 20-25°C; deep hypothermia) and single exposure at air temperature of -25°C (until rectal temperature drop to 30°C; moderate hypothermia). A manifest destructive effect of deep hypothermia on rat liver was detected: the exposure caused manifest alteration of hepatocytes (alteration index increased 81-fold immediately after the exposure and remained 16-fold higher than normally after 14 days) and an increase of DNA accumulation index with predominance of hepatocytes with 5c-8c nuclei (60% of the population) during the entire period of observation, which indicated intensification of the compensatory and adaptive processes in the liver with predominating high-ploid population of hepatocytes. Hepatocyte alteration processes in response to moderate hypothermia were less intense (hepatocyte alteration index increased 19-fold immediately after the exposure and remained 3-fold higher than normally after 14 days). The DNA accumulation index increased moderately immediately after the exposure and returned to normal after 14 days, with emergence of 2c hepatocytes and an increase in the level of 4c hepatocytes (51% of the population), which indicated realization of a different strategy of liver regeneration - recovery of the cell population intrinsic to intact animals.
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Affiliation(s)
- I P Bobrov
- Altai State Medical University, Ministry of Health of Russia, Barnaul, Russia.
| | - A V Lepilov
- Altai State Medical University, Ministry of Health of Russia, Barnaul, Russia
| | - A Yu Dolgatov
- Altai State Medical University, Ministry of Health of Russia, Barnaul, Russia
| | - N G Kryuchkova
- Altai State Medical University, Ministry of Health of Russia, Barnaul, Russia
| | - M A Bakarev
- Institute of Molecular Pathology and Pathomorphology, Federal Research Center of Fundamental and Translation Medicine, Novosibirsk, Russia
| | - O P Molodykh
- Institute of Molecular Pathology and Pathomorphology, Federal Research Center of Fundamental and Translation Medicine, Novosibirsk, Russia
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22
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Advances in heart regeneration based on cardiomyocyte proliferation and regenerative potential of binucleated cardiomyocytes and polyploidization. Clin Sci (Lond) 2019; 133:1229-1253. [PMID: 31175264 DOI: 10.1042/cs20180560] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 05/23/2019] [Accepted: 05/24/2019] [Indexed: 12/12/2022]
Abstract
One great achievement in medical practice is the reduction in acute mortality of myocardial infarction due to identifying risk factors, antiplatelet therapy, optimized hospitalization and acute percutaneous coronary intervention. Yet, the prevalence of heart failure is increasing presenting a major socio-economic burden. Thus, there is a great need for novel therapies that can reverse damage inflicted to the heart. In recent years, data have accumulated suggesting that induction of cardiomyocyte proliferation might be a future option for cardiac regeneration. Here, we review the relevant literature since September 2015 concluding that it remains a challenge to verify that a therapy induces indeed cardiomyocyte proliferation. Most importantly, it is unclear that the detected increase in cardiomyocyte cell cycle activity is required for an associated improved function. In addition, we review the literature regarding the evidence that binucleated and polyploid mononucleated cardiomyocytes can divide, and put this in context to other cell types. Our analysis shows that there is significant evidence that binucleated cardiomyocytes can divide. Yet, it remains elusive whether also polyploid mononucleated cardiomyocytes can divide, how efficient proliferation of binucleated cardiomyocytes can be induced, what mechanism regulates cell cycle progression in these cells, and what fate and physiological properties the daughter cells have. In summary, we propose to standardize and independently validate cardiac regeneration studies, encourage the field to study the proliferative potential of binucleated and polyploid mononucleated cardiomyocytes, and to determine whether induction of polyploidization can enhance cardiac function post-injury.
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23
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Kakabadze Z, Karalashvili L, Chakhunashvili D, Havlioglu N, Janelidze M, Kakabadze A, Sharma Y, Gupta S. Decellularized bovine placentome for portacavally-interposed heterotopic liver transplantation in rats. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2018; 97:293-301. [PMID: 30678914 DOI: 10.1016/j.msec.2018.12.025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 11/19/2018] [Accepted: 12/09/2018] [Indexed: 02/06/2023]
Abstract
Scaffolds from healthy placentae offer advantages for tissue engineering with undamaged matrix, associated cytoprotective molecules, and embedded vessels for revascularization. As size disparities in human placenta and small recipients hamper preclinical studies, we studied alternative of bovine placentomes in smaller size ranges. Multiple cow placentomes were decellularized and anatomical integrity was analyzed. Tissue engineering used inbred donor rat livers. Placentomes were hepatized and immediately transplanted in rats with perfusion from portal vein and drainage into inferior vena cava. Cows yielded 99 ± 16 placentomes each. Of these, approximately 25% had 3 to 9 cm diameter and 7 to 63 ml volume, which was suitable for transplantation. After decellularization, angiography and casts documented 100% of vessels and vascular networks were well-perfused without disruptions or leaks. The residual matrix also remained intact for transplantation of placentomes. Perfusion in transplanted placentomes was maintained over up to 30 days. Liver tissue reassembled with restoration of hepatic acinar and sinusoidal structure. Transplanted tissue was intact without apoptosis, or necrosis. Hepatic functions were maintained. Preservation of hepatic homeostasis was verified by cytofluorimetric analysis of hepatocyte ploidy. The prevalence in healthy and transplanted liver of diploid, tetraploid and higher ploidy classes was similar with 57%, 41% and 2% versus 51%, 46.5% and 2.6%, respectively, p = 0.77, ANOVA. CONCLUSIONS: Cow placentomes will allow therapeutic development with disease models in small animals. This will also advance drug or toxicology studies. Portasystemic interposition of engineered liver will be particularly suitable for treating hepatic insufficiencies (metabolic, secretory or detoxification needs), including for children or smaller adults.
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Affiliation(s)
- Zurab Kakabadze
- Department of Clinical Anatomy, Tbilisi State Medical University, 33 V. PshavelaAvenue, 0177 Tbilisi, Georgia.
| | - Lia Karalashvili
- Department of Clinical Anatomy, Tbilisi State Medical University, 33 V. PshavelaAvenue, 0177 Tbilisi, Georgia
| | - David Chakhunashvili
- Department of Clinical Anatomy, Tbilisi State Medical University, 33 V. PshavelaAvenue, 0177 Tbilisi, Georgia
| | - Necat Havlioglu
- Department of Veterans Affairs, Pathology and Laboratory Services, VA Medical Center, Saint Louis Health Care System, Saint Louis, MO, USA
| | - Merab Janelidze
- Department of Clinical Anatomy, Tbilisi State Medical University, 33 V. PshavelaAvenue, 0177 Tbilisi, Georgia
| | - Ann Kakabadze
- Department of Clinical Anatomy, Tbilisi State Medical University, 33 V. PshavelaAvenue, 0177 Tbilisi, Georgia
| | - Yogeshwar Sharma
- Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx 10461, NY, USA.
| | - Sanjeev Gupta
- Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Diabetes Center, The Irwin S. and Sylvia Chanin Institute for Cancer Research, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx 10461, NY, USA.
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24
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Simonetti G, Bruno S, Padella A, Tenti E, Martinelli G. Aneuploidy: Cancer strength or vulnerability? Int J Cancer 2018; 144:8-25. [PMID: 29981145 PMCID: PMC6587540 DOI: 10.1002/ijc.31718] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 06/05/2018] [Accepted: 06/14/2018] [Indexed: 12/12/2022]
Abstract
Aneuploidy is a very rare and tissue‐specific event in normal conditions, occurring in a low number of brain and liver cells. Its frequency increases in age‐related disorders and is one of the hallmarks of cancer. Aneuploidy has been associated with defects in the spindle assembly checkpoint (SAC). However, the relationship between chromosome number alterations, SAC genes and tumor susceptibility remains unclear. Here, we provide a comprehensive review of SAC gene alterations at genomic and transcriptional level across human cancers and discuss the oncogenic and tumor suppressor functions of aneuploidy. SAC genes are rarely mutated but frequently overexpressed, with a negative prognostic impact on different tumor types. Both increased and decreased SAC gene expression show oncogenic potential in mice. SAC gene upregulation may drive aneuploidization and tumorigenesis through mitotic delay, coupled with additional oncogenic functions outside mitosis. The genomic background and environmental conditions influence the fate of aneuploid cells. Aneuploidy reduces cellular fitness. It induces growth and contact inhibition, mitotic and proteotoxic stress, cell senescence and production of reactive oxygen species. However, aneuploidy confers an evolutionary flexibility by favoring genome and chromosome instability (CIN), cellular adaptation, stem cell‐like properties and immune escape. These properties represent the driving force of aneuploid cancers, especially under conditions of stress and pharmacological pressure, and are currently under investigation as potential therapeutic targets. Indeed, promising results have been obtained from synthetic lethal combinations exploiting CIN, mitotic defects, and aneuploidy‐tolerating mechanisms as cancer vulnerability.
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Affiliation(s)
- Giorgia Simonetti
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna and Institute of Hematology "L. e A. Seràgnoli", Bologna, Italy
| | - Samantha Bruno
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna and Institute of Hematology "L. e A. Seràgnoli", Bologna, Italy
| | - Antonella Padella
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna and Institute of Hematology "L. e A. Seràgnoli", Bologna, Italy
| | - Elena Tenti
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna and Institute of Hematology "L. e A. Seràgnoli", Bologna, Italy
| | - Giovanni Martinelli
- Scientific Directorate, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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25
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Okano-Uchida T, Kent LN, Ouseph MM, McCarty B, Frank JJ, Kladney R, Cuitino MC, Thompson JC, Coppola V, Asano M, Leone G. Endoreduplication of the mouse genome in the absence of ORC1. Genes Dev 2018; 32:978-990. [PMID: 29967292 PMCID: PMC6075035 DOI: 10.1101/gad.311910.118] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 05/09/2018] [Indexed: 01/24/2023]
Abstract
In this study, Okano-Uchida et al. describe the physiological role of ORC1 in mice by generating knock-in mice with LoxP sites flanking exons encoding the critical ATPase domain of ORC1. They show that ORC1 ablation in extraembryonic trophoblasts and hepatocytes failed to impede genome endoreduplication and organ development and function and conclude that ORC1 in mice is essential for mitotic cell divisions but dispensable for endoreduplication. The largest subunit of the origin recognition complex (ORC1) is essential for assembly of the prereplicative complex, firing of DNA replication origins, and faithful duplication of the genome. Here, we generated knock-in mice with LoxP sites flanking exons encoding the critical ATPase domain of ORC1. Global or tissue-specific ablation of ORC1 function in mouse embryo fibroblasts and fetal and adult diploid tissues blocked DNA replication, cell lineage expansion, and organ development. Remarkably, ORC1 ablation in extraembryonic trophoblasts and hepatocytes, two polyploid cell types in mice, failed to impede genome endoreduplication and organ development and function. Thus, ORC1 in mice is essential for mitotic cell divisions but dispensable for endoreduplication. We propose that DNA replication of mammalian polyploid genomes uses a distinct ORC1-independent mechanism.
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Affiliation(s)
- Takayuki Okano-Uchida
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA
| | - Lindsey N Kent
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA
| | - Madhu M Ouseph
- Solid Tumor Biology Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.,Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.,Department of Cancer Biology and Genetics, Ohio State University, Columbus, Ohio 43210, USA
| | - Britney McCarty
- Solid Tumor Biology Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.,Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.,Department of Cancer Biology and Genetics, Ohio State University, Columbus, Ohio 43210, USA
| | - Jeffrey J Frank
- Solid Tumor Biology Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.,Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.,Department of Cancer Biology and Genetics, Ohio State University, Columbus, Ohio 43210, USA
| | - Raleigh Kladney
- Solid Tumor Biology Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.,Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.,Department of Cancer Biology and Genetics, Ohio State University, Columbus, Ohio 43210, USA
| | - Maria C Cuitino
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA
| | - John C Thompson
- Solid Tumor Biology Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.,Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.,Department of Cancer Biology and Genetics, Ohio State University, Columbus, Ohio 43210, USA
| | - Vincenzo Coppola
- Solid Tumor Biology Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.,Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.,Department of Cancer Biology and Genetics, Ohio State University, Columbus, Ohio 43210, USA
| | - Maki Asano
- Solid Tumor Biology Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.,Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.,Department of Molecular Cellular and Biochemistry, Ohio State University, Columbus, Ohio 43210, USA
| | - Gustavo Leone
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA
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26
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Abstract
Polyploid cells, which contain multiple copies of the typically diploid genome, are widespread in plants and animals. Polyploidization can be developmentally programmed or stress induced, and arises from either cell-cell fusion or a process known as endoreplication, in which cells replicate their DNA but either fail to complete cytokinesis or to progress through M phase entirely. Polyploidization offers cells several potential fitness benefits, including the ability to increase cell size and biomass production without disrupting cell and tissue structure, and allowing improved cell longevity through higher tolerance to genomic stress and apoptotic signals. Accordingly, recent studies have uncovered crucial roles for polyploidization in compensatory cell growth during tissue regeneration in the heart, liver, epidermis and intestine. Here, we review current knowledge of the molecular pathways that generate polyploidy and discuss how polyploidization is used in tissue repair and regeneration.
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Affiliation(s)
| | - Bruce A Edgar
- Huntsman Cancer Institute, Salt Lake City, UT 84112, USA
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27
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Willson NL, Forder REA, Tearle R, Williams JL, Hughes RJ, Nattrass GS, Hynd PI. Transcriptional analysis of liver from chickens with fast (meat bird), moderate (F1 layer x meat bird cross) and low (layer bird) growth potential. BMC Genomics 2018; 19:309. [PMID: 29716547 PMCID: PMC5930858 DOI: 10.1186/s12864-018-4723-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 04/24/2018] [Indexed: 01/25/2023] Open
Abstract
Background Divergent selection for meat and egg production in poultry has resulted in strains of birds differing widely in traits related to these products. Modern strains of meat birds can reach live weights of 2 kg in 35 d, while layer strains are now capable of producing more than 300 eggs per annum but grow slowly. In this study, RNA-Seq was used to investigate hepatic gene expression between three groups of birds with large differences in growth potential; meat bird, layer strain as well as an F1 layer x meat bird. The objective was to identify differentially expressed (DE) genes between all three strains to elucidate biological factors underpinning variations in growth performance. Results RNA-Seq analysis was carried out on total RNA extracted from the liver of meat bird (n = 6), F1 layer x meat bird cross (n = 6) and layer strain (n = 6), males. Differential expression of genes were considered significant at P < 0.05, and a false discovery rate of < 0.05, with any fold change considered. In total, 6278 genes were found to be DE with 5832 DE between meat birds and layers (19%), 2935 DE between meat birds and the cross (9.6%) and 493 DE between the cross and layers (1.6%). Comparisons between the three groups identified 155 significant DE genes. Gene ontology (GO) enrichment and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis of the 155 DE genes showed the FoxO signalling pathway was most enriched (P = 0.001), including genes related to cell cycle regulation and insulin signalling. Significant GO terms included ‘positive regulation of glucose import’ and ‘cellular response to oxidative stress’, which is also consistent with FoxOs regulation of glucose metabolism. There were high correlations between FoxO pathway genes and bodyweight, as well as genes related to glycolysis and bodyweight. Conclusions This study revealed large transcriptome differences between meat and layer birds. There was significant evidence implicating the FoxO signalling pathway (via cell cycle regulation and altered metabolism) as an active driver of growth variations in chicken. Functional analysis of the FoxO genes is required to understand how they regulate growth and egg production.
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Affiliation(s)
- Nicky-Lee Willson
- School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, SA, 5371, Australia. .,Poultry CRC, University of New England, PO Box U242, Armidale, NSW, 2351, Australia. .,Institute for Future Farming Systems, Central Queensland University, Rockhampton, QLD, 4702, Australia.
| | - Rebecca E A Forder
- School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, SA, 5371, Australia
| | - Rick Tearle
- Davies Research Centre, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, SA, 5371, Australia
| | - John L Williams
- Davies Research Centre, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, SA, 5371, Australia
| | - Robert J Hughes
- School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, SA, 5371, Australia.,South Australian Research and Development Institute (SARDI), Pig and Poultry Production Institute, Roseworthy, SA, 5371, Australia
| | - Greg S Nattrass
- South Australian Research and Development Institute (SARDI), Livestock and Farming Systems, Roseworthy, SA, 5371, Australia
| | - Philip I Hynd
- School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, SA, 5371, Australia.,Davies Research Centre, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, SA, 5371, Australia
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28
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NFκB activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through TLR4. Sci Rep 2018; 8:6341. [PMID: 29679017 PMCID: PMC5910430 DOI: 10.1038/s41598-018-24444-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 03/21/2018] [Indexed: 01/08/2023] Open
Abstract
We have previously described that the NFκB pathway is upregulated during differentiation of glioblastoma stem-like cells (GSCs) which keeps differentiating GSCs in a proliferative astrocytic precursor state. However, extracellular signals and cellular mediators of this pathway are not clear yet. Here, we show that TLR4 is a key factor to promote NFκB activation in differentiating GSCs. TLR4 is upregulated during differentiation of GSCs and promotes transcriptional activation of NFκB as determined by luciferase-reporter assays and expression of NFκB target genes. Downregulation of TLR4 by shRNAs or blockade with anti-TLR4 specific antibodies drastically inhibited NFκB activity which promoted further differentiation and reduced proliferation of GSCs. We found that hyaluronic acid (HA), a main component of brain extracellular matrix, triggers the TLR4-NFκB pathway in differentiating GSCs. Moreover, HA is synthesized and released by GSCs undergoing differentiation and leads to transcriptional activation of NFκB, which is inhibited following downregulation of TLR4 or blockade of HA synthesis. Thus, we have demonstrated that during the process of differentiation, GSCs upregulate TLR4 and release the TLR4 ligand HA, which activates the TLR4-NFκB signaling pathway. This strategy may efficiently be used by differentiating GSCs to maintain their proliferative potential and consequently their tumorigenic capacity.
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29
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Viswanathan P, Sharma Y, Gupta P, Gupta S. Replicative stress and alterations in cell cycle checkpoint controls following acetaminophen hepatotoxicity restrict liver regeneration. Cell Prolif 2018; 51:e12445. [PMID: 29504225 DOI: 10.1111/cpr.12445] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 01/16/2018] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVES Acetaminophen hepatotoxicity is a leading cause of hepatic failure with impairments in liver regeneration producing significant mortality. Multiple intracellular events, including oxidative stress, mitochondrial damage, inflammation, etc., signify acetaminophen toxicity, although how these may alter cell cycle controls has been unknown and was studied for its significance in liver regeneration. MATERIALS AND METHODS Assays were performed in HuH-7 human hepatocellular carcinoma cells, primary human hepatocytes and tissue samples from people with acetaminophen-induced acute liver failure. Cellular oxidative stress, DNA damage and cell proliferation events were investigated by mitochondrial membrane potential assays, flow cytometry, fluorescence staining, comet assays and spotted arrays for protein expression after acetaminophen exposures. RESULTS In experimental groups with acetaminophen toxicity, impaired mitochondrial viability and substantial DNA damage were observed with rapid loss of cells in S and G2/M and cell cycle restrictions or even exit in the remainder. This resulted from altered expression of the DNA damage regulator, ATM and downstream transducers, which imposed G1/S checkpoint arrest, delayed entry into S and restricted G2 transit. Tissues from people with acute liver failure confirmed hepatic DNA damage and cell cycle-related lesions, including restrictions of hepatocytes in aneuploid states. Remarkably, treatment of cells with a cytoprotective cytokine reversed acetaminophen-induced restrictions to restore cycling. CONCLUSIONS Cell cycle lesions following mitochondrial and DNA damage led to failure of hepatic regeneration in acetaminophen toxicity but their reversibility offers molecular targets for treating acute liver failure.
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Affiliation(s)
- Preeti Viswanathan
- Division of Pediatric Gastroenterology and Hepatology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Yogeshwar Sharma
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Priya Gupta
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Sanjeev Gupta
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.,Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.,Marion Bessin Liver Research Center, Diabetes Center, Irwin S. and Sylvia Chanin Institute for Cancer Research, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY, USA
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30
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Lizier M, Castelli A, Montagna C, Lucchini F, Vezzoni P, Faggioli F. Cell fusion in the liver, revisited. World J Hepatol 2018; 10:213-221. [PMID: 29527257 PMCID: PMC5838440 DOI: 10.4254/wjh.v10.i2.213] [Citation(s) in RCA: 12] [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: 11/21/2017] [Revised: 12/28/2017] [Accepted: 02/06/2018] [Indexed: 02/06/2023] Open
Abstract
There is wide agreement that cell fusion is a physiological process in cells in mammalian bone, muscle and placenta. In other organs, such as the cerebellum, cell fusion is controversial. The liver contains a considerable number of polyploid cells: They are commonly believed to originate by genome endoreplication, although the contribution of cell fusion to polyploidization has not been excluded. Here, we address the topic of cell fusion in the liver from a historical point of view. We discuss experimental evidence clearly supporting the hypothesis that cell fusion occurs in the liver, specifically when bone marrow cells were injected into mice and shown to rescue genetic hepatic degenerative defects. Those experiments-carried out in the latter half of the last century-were initially interpreted to show “transdifferentiation”, but are now believed to demonstrate fusion between donor macrophages and host hepatocytes, raising the possibility that physiologically polyploid cells, such as hepatocytes, could originate, at least partially, through homotypic cell fusion. In support of the homotypic cell fusion hypothesis, we present new data generated using a chimera-based model, a much simpler model than those previously used. Cell fusion as a road to polyploidization in the liver has not been extensively investigated, and its contribution to a variety of conditions, such as viral infections, carcinogenesis and aging, remains unclear.
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Affiliation(s)
- Michela Lizier
- Istituto di Ricerca Genetica e Biomedica, CNR, Milan 20138, Italy
- Human Genome Laboratory, Humanitas Clinical and Research Center, IRCCS, Milan 20089, Italy
| | - Alessandra Castelli
- Istituto di Ricerca Genetica e Biomedica, CNR, Milan 20138, Italy
- Human Genome Laboratory, Humanitas Clinical and Research Center, IRCCS, Milan 20089, Italy
| | - Cristina Montagna
- Department of Genetics and Pathology Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, United States
| | - Franco Lucchini
- Centro Ricerche Biotecnologiche, Università Cattolica del Sacro Cuore, Cremona 26100, Italy
| | - Paolo Vezzoni
- Istituto di Ricerca Genetica e Biomedica, CNR, Milan 20138, Italy
- Human Genome Laboratory, Humanitas Clinical and Research Center, IRCCS, Milan 20089, Italy
| | - Francesca Faggioli
- Istituto di Ricerca Genetica e Biomedica, CNR, Milan 20138, Italy
- Human Genome Laboratory, Humanitas Clinical and Research Center, IRCCS, Milan 20089, Italy
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31
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Yoon YJ, Suh MJ, Lee HY, Lee HJ, Choi EH, Moon IS, Song K. Anti-tumor effects of cold atmospheric pressure plasma on vestibular schwannoma demonstrate its feasibility as an intra-operative adjuvant treatment. Free Radic Biol Med 2018; 115:43-56. [PMID: 29138018 DOI: 10.1016/j.freeradbiomed.2017.11.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 11/07/2017] [Accepted: 11/10/2017] [Indexed: 12/12/2022]
Abstract
Vestibular schwannoma (VS), although a benign intracranial tumor, causes morbidities by brainstem compression. Since chemotherapy is not very effective in most Nf2-negative schwannomas, surgical removal or radiation therapy is required. However, depending on the size and site of the tumor, these approaches may cause loss of auditory or vestibular functions, and severely decrease the post-surgical wellbeing. Here, we examined the feasibility of cold atmospheric pressure plasma (CAP) as an intra-operative adjuvant treatment for VS after surgery. Cell death was efficiently induced in both human HEI-193 and mouse SC4 VS cell lines upon exposure to CAP for seven minutes. Interestingly, both apoptosis and necroptosis were simultaneously induced by CAP treatment, and cell death was not completely inhibited by pan-caspase and receptor-interacting serine/threonine-protein kinase 1 (RIK1) inhibitors. Upon CAP exposure, cell death phenotype was similarly observed in patient-derived primary VS cells and tumor mass. In addition, CAP exposure after the surgical removal of primary tumor efficiently inhibited tumor recurrence in SC4-grafted mouse models. Collectively, these results strongly suggest that CAP should be developed as an efficient adjuvant treatment for VS after surgery to eliminate the possible remnant tumor cells, and to minimize the surgical area in the brain for post-surgical wellbeing.
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Affiliation(s)
- Yeo Jun Yoon
- Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Michelle J Suh
- Department of Otorhinolaryngology, College of Medicine, Yonsei University, Seoul 03722, Korea
| | - Hyun Young Lee
- Department of Electrical Engineering, Pusan National University, Pusan 46269, Korea
| | - Hae June Lee
- Department of Electrical Engineering, Pusan National University, Pusan 46269, Korea
| | - Eun Ha Choi
- Plasma Bioscience Research Center and Department of Electrical and Biological Physics, Kwangwoon University, Seoul 01897, Korea
| | - In Seok Moon
- Department of Otorhinolaryngology, College of Medicine, Yonsei University, Seoul 03722, Korea.
| | - Kiwon Song
- Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul 03722, Korea.
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32
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Apte U, Bhushan B, Dadhania V. Hepatic Defenses Against Toxicity: Liver Regeneration and Tissue Repair. COMPREHENSIVE TOXICOLOGY 2018:368-396. [DOI: 10.1016/b978-0-12-801238-3.64918-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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33
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Wang MJ, Chen F, Lau JTY, Hu YP. Hepatocyte polyploidization and its association with pathophysiological processes. Cell Death Dis 2017; 8:e2805. [PMID: 28518148 PMCID: PMC5520697 DOI: 10.1038/cddis.2017.167] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 03/01/2017] [Accepted: 03/14/2017] [Indexed: 12/14/2022]
Abstract
A characteristic cellular feature of the mammalian liver is the progressive polyploidization of the hepatocytes, where individual cells acquire more than two sets of chromosomes. Polyploidization results from cytokinesis failure that takes place progressively during the course of postnatal development. The proportion of polyploidy also increases with the aging process or with cellular stress such as surgical resection, toxic stimulation, metabolic overload, or oxidative damage, to involve as much as 90% of the hepatocytes in mice and 40% in humans. Hepatocyte polyploidization is generally considered an indicator of terminal differentiation and cellular senescence, and related to the dysfunction of insulin and p53/p21 signaling pathways. Interestingly, the high prevalence of hepatocyte polyploidization in the aged mouse liver can be reversed when the senescent hepatocytes are serially transplanted into young mouse livers. Here we review the current knowledge on the mechanism of hepatocytes polyploidization during postnatal growth, aging, and liver diseases. The biologic significance of polyploidization in senescent reversal, within the context of new ways to think of liver aging and liver diseases is considered.
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Affiliation(s)
- Min-Jun Wang
- Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
| | - Fei Chen
- Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
| | - Joseph T Y Lau
- Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Yi-Ping Hu
- Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
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34
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Khalil A, Parker M, Mpanga R, Cevik SE, Thorburn C, Suvorov A. Developmental Exposure to 2,2',4,4'-Tetrabromodiphenyl Ether Induces Long-Lasting Changes in Liver Metabolism in Male Mice. J Endocr Soc 2017; 1:323-344. [PMID: 29264491 PMCID: PMC5686773 DOI: 10.1210/js.2016-1011] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 03/09/2017] [Indexed: 12/11/2022] Open
Abstract
Polybrominated diphenyl ethers (PBDEs) were used as flame-retardant additives in a wide range of polymers. The generations born when environmental concentrations of PBDEs reached their maximum account in the United States for one-fifth of the total population. We hypothesized that exposure to PBDEs during sensitive developmental windows might result in long-lasting changes in liver metabolism. The present study was based on experiments with CD-1 mice and human hepatocellular carcinoma cells (human hepatoma cell line, HepG2). Pregnant mice were exposed to 0.2 mg/kg 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) from gestation day 8 until postnatal day 21. The metabolic health-related outcomes were analyzed on postnatal day 21 and postnatal week 20 in male offspring. Several groups of metabolic genes, including ribosomal and mitochondrial genes, were significantly upregulated in the liver at both points. Genes regulated via mechanistic target of rapamycin (mTOR) pathway, the gatekeeper of metabolic homeostasis, were whether up- or downregulated at both measurement points. On postnatal day 21, but not week 20, both mTOR complexes in the liver were activated, as measured by phosphorylation of their targets. mTOR complexes were also activated by BDE-47 in HepG2 cells in vitro. The following changes were observed at week 20: a decreased number of polyploid hepatocytes, suppressed cytoplasmic S6K1, twofold greater blood insulin-like growth factor-1 and triglycerides, and 2.5-fold lower expression of fatty acid uptake membrane receptor CD36 in liver tissue. Thus, perinatal exposure to environmentally relevant doses of BDE-47 in laboratory mice results in long-lasting changes in liver physiology. Our evidence suggests involvement of the mTOR pathway in the observed metabolic programming of the liver.
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Affiliation(s)
- Ahmed Khalil
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003
- Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications, Alexandria 21934, Egypt
| | - Mikhail Parker
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003
| | - Richard Mpanga
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003
| | - Sebnem E. Cevik
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003
| | - Cassandra Thorburn
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003
| | - Alexander Suvorov
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003
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35
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Tormos AM, Rius-Pérez S, Jorques M, Rada P, Ramirez L, Valverde ÁM, Nebreda ÁR, Sastre J, Taléns-Visconti R. p38α regulates actin cytoskeleton and cytokinesis in hepatocytes during development and aging. PLoS One 2017; 12:e0171738. [PMID: 28166285 PMCID: PMC5293263 DOI: 10.1371/journal.pone.0171738] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 01/25/2017] [Indexed: 12/02/2022] Open
Abstract
Background Hepatocyte poliploidization is an age-dependent process, being cytokinesis failure the main mechanism of polyploid hepatocyte formation. Our aim was to study the role of p38α MAPK in the regulation of actin cytoskeleton and cytokinesis in hepatocytes during development and aging. Methods Wild type and p38α liver-specific knock out mice at different ages (after weaning, adults and old) were used. Results We show that p38α MAPK deficiency induces actin disassembly upon aging and also cytokinesis failure leading to enhanced binucleation. Although the steady state levels of cyclin D1 in wild type and p38α knock out old livers remained unaffected, cyclin B1- a marker for G2/M transition- was significantly overexpressed in p38α knock out mice. Our findings suggest that hepatocytes do enter into S phase but they do not complete cell division upon p38α deficiency leading to cytokinesis failure and binucleation. Moreover, old liver-specific p38α MAPK knock out mice exhibited reduced F-actin polymerization and a dramatic loss of actin cytoskeleton. This was associated with abnormal hyperactivation of RhoA and Cdc42 GTPases. Long-term p38α deficiency drives to inactivation of HSP27, which seems to account for the impairment in actin cytoskeleton as Hsp27-silencing decreased the number and length of actin filaments in isolated hepatocytes. Conclusions p38α MAPK is essential for actin dynamics with age in hepatocytes.
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Affiliation(s)
- Ana M. Tormos
- Department of Physiology, University of Valencia. Burjassot, Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, University of Valencia. Burjassot, Valencia, Spain
| | - María Jorques
- Department of Physiology, University of Valencia. Burjassot, Valencia, Spain
| | - Patricia Rada
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, Madrid, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), ISCIII, Madrid, Spain
| | - Lorena Ramirez
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Ángela M. Valverde
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, Madrid, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), ISCIII, Madrid, Spain
| | - Ángel R. Nebreda
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Juan Sastre
- Department of Physiology, University of Valencia. Burjassot, Valencia, Spain
| | - Raquel Taléns-Visconti
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia. Burjassot, Valencia, Spain
- * E-mail:
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36
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Reid LM. Stem/progenitor cells and reprogramming (plasticity) mechanisms in liver, biliary tree, and pancreas. Hepatology 2016; 64:4-7. [PMID: 27102721 DOI: 10.1002/hep.28606] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 04/15/2016] [Indexed: 12/12/2022]
Affiliation(s)
- Lola M Reid
- Department of Cell Biology and Physiology Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, NC
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37
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Marcos R, Lopes C, Malhão F, Correia-Gomes C, Fonseca S, Lima M, Gebhardt R, Rocha E. Stereological assessment of sexual dimorphism in the rat liver reveals differences in hepatocytes and Kupffer cells but not hepatic stellate cells. J Anat 2016; 228:996-1005. [PMID: 26892301 DOI: 10.1111/joa.12448] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/05/2016] [Indexed: 12/11/2022] Open
Abstract
There is long-standing evidence that male and female rat livers differ in enzyme activity. More recently, differences in gene expression profiling have also been found to exist; however, it is still unclear whether there is morphological expression of male/female differences in the normal liver. Such differences could help to explain features seen at the pathological level, such as the greater regenerative potential generally attributed to the female liver. In this paper, hepatocytes (HEP), Kupffer cells (KC) and hepatic stellate cells (HSC) of male and female rats were examined to investigate hypothesised differences in number, volume and spatial co-localisation of these cell types. Immunohistochemistry and design-based stereology were used to estimate total numbers, numbers per gram and mean cell volumes. The position of HSC within lobules (periportal vs. centrilobular) and their spatial proximity to KC was also assessed. In addition, flow cytometry was used to investigate the liver ploidy. In the case of HEP and KC, differences in the measured cell parameters were observed between male and female specimens; however, no such differences were detected for HSC. Female samples contained a higher number of HEP per gram, with more binucleate cells. The HEP nuclei were smaller in females, which was coincident with more abundant diploid particles in these animals. The female liver also had a greater number of KC per gram, with a lower percentage of KC in the vicinity of HSC compared with males. In this study, we document hitherto unknown morphological sexual dimorphism in the rat liver, namely in HEP and KC. These differences may account for the higher regenerative potential of the female liver and lend weight to the argument for considering the rat liver as a sexually dimorphic organ.
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Affiliation(s)
- Ricardo Marcos
- Laboratory of Histology and Embryology, Department of Microscopy, ICBAS - Institute of Biomedical Sciences Abel Salazar, U.Porto - University of Porto, Porto, Portugal.,Histomorphology, Physiopathology and Applied Toxicology Group, CIIMAR - Interdisciplinary Centre of Marine and Environmental Research, U.Porto - University of Porto, Porto, Portugal
| | - Célia Lopes
- Laboratory of Histology and Embryology, Department of Microscopy, ICBAS - Institute of Biomedical Sciences Abel Salazar, U.Porto - University of Porto, Porto, Portugal.,Histomorphology, Physiopathology and Applied Toxicology Group, CIIMAR - Interdisciplinary Centre of Marine and Environmental Research, U.Porto - University of Porto, Porto, Portugal
| | - Fernanda Malhão
- Laboratory of Histology and Embryology, Department of Microscopy, ICBAS - Institute of Biomedical Sciences Abel Salazar, U.Porto - University of Porto, Porto, Portugal.,Histomorphology, Physiopathology and Applied Toxicology Group, CIIMAR - Interdisciplinary Centre of Marine and Environmental Research, U.Porto - University of Porto, Porto, Portugal
| | - Carla Correia-Gomes
- Scotland's Rural College, Epidemiology Research Unit - Future Farming Systems Group, Inverness, UK
| | - Sónia Fonseca
- Laboratory of Cytometry, Department of Hematology, UMIB - Unit for Multidisciplinary Research in Biomedicine, CHP - Centro Hospitalar do Porto, ICBAS - Institute of Biomedical Sciences Abel Salazar, HSA - Hospital de Santo António, U.Porto - University of Porto, Porto, Portugal
| | - Margarida Lima
- Laboratory of Cytometry, Department of Hematology, UMIB - Unit for Multidisciplinary Research in Biomedicine, CHP - Centro Hospitalar do Porto, ICBAS - Institute of Biomedical Sciences Abel Salazar, HSA - Hospital de Santo António, U.Porto - University of Porto, Porto, Portugal
| | - Rolf Gebhardt
- Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - Eduardo Rocha
- Laboratory of Histology and Embryology, Department of Microscopy, ICBAS - Institute of Biomedical Sciences Abel Salazar, U.Porto - University of Porto, Porto, Portugal.,Histomorphology, Physiopathology and Applied Toxicology Group, CIIMAR - Interdisciplinary Centre of Marine and Environmental Research, U.Porto - University of Porto, Porto, Portugal
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38
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Huntington JT, Tang X, Kent LN, Schmidt CR, Leone G. The Spectrum of E2F in Liver Disease--Mediated Regulation in Biology and Cancer. J Cell Physiol 2016; 231:1438-49. [PMID: 26566968 DOI: 10.1002/jcp.25242] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 11/03/2015] [Indexed: 12/11/2022]
Abstract
Uncoordinated cell growth is one of the fundamental concepts in carcinogenesis and occurs secondary to dysregulation of the cell cycle. The E2Fs are a large family of transcription factors and are key regulators of the cell cycle. The activation of E2Fs is intimately regulated by retinoblastoma 1 (RB1). The RB pathway has been implicated in almost every human malignancy. Recently there have been exciting developments in the E2F field using animal models to better understand the role of E2Fs in vivo. Genetic mouse models have proven essential in implicating E2Fs in hepatocellular carcinoma (HCC) and liver disease. In this review, the general structure and function of E2Fs as well as the role for E2Fs in the development of HCC and liver disease is evaluated. Specifically, what is known about E2Fs in human disease is explored in depth, and future directions are discussed.
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Affiliation(s)
- Justin T Huntington
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Xing Tang
- Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, Columbus, Ohio.,Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio.,Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Lindsey N Kent
- Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, Columbus, Ohio.,Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio.,Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Carl R Schmidt
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Gustavo Leone
- Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, Columbus, Ohio.,Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio.,Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
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39
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Kim SH, Jeon Y, Kim HS, Lee JK, Lim HJ, Kang D, Cho H, Park CK, Lee H, Lee CW. Hepatocyte homeostasis for chromosome ploidization and liver function is regulated by Ssu72 protein phosphatase. Hepatology 2016; 63:247-59. [PMID: 26458163 DOI: 10.1002/hep.28281] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 10/07/2015] [Indexed: 12/27/2022]
Abstract
UNLABELLED Hepatocyte chromosome polyploidization is an important feature of liver development and seems to be required for response to liver stress and injury signals. However, the question of how polyploidization can be tightly regulated in liver growth remains to be answered. Using a conditional knockout mouse model, liver-specific depletion of Ssu72 protein phosphatase was found to result in impairment in regulation of polyploidization. Interestingly, the aberrant polyploidization in Ssu72-depleted mice was associated with impaired liver damage response and increased markers of liver injury and seemed to mimic the phenotypic features of liver diseases such as fibrosis, steatosis, and steatohepatitis. In addition, depletion of Ssu72 caused deregulation of cell cycle progression by overriding the restriction point of the cell cycle and aberrantly promoting DNA endoreplication through G2 /M arrest. CONCLUSION Ssu72 plays a substantial role in the maintenance of hepatic chromosome homeostasis and would allow monitoring of liver function.
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Affiliation(s)
- Se-Hyuk Kim
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Yoon Jeon
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.,Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center, Goyang, Korea
| | - Hyun-Soo Kim
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Jin-Kwan Lee
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea
| | - Han Jeong Lim
- Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center, Goyang, Korea
| | - Donglim Kang
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Hyeseong Cho
- Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea
| | - Cheol-Keun Park
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ho Lee
- Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center, Goyang, Korea
| | - Chang-Woo Lee
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea
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40
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Yant L, Bomblies K. Genome management and mismanagement--cell-level opportunities and challenges of whole-genome duplication. Genes Dev 2015; 29:2405-19. [PMID: 26637526 PMCID: PMC4691946 DOI: 10.1101/gad.271072.115] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Whole-genome duplication (WGD) doubles the DNA content in the nucleus and leads to polyploidy. In whole-organism polyploids, WGD has been implicated in adaptability and the evolution of increased genome complexity, but polyploidy can also arise in somatic cells of otherwise diploid plants and animals, where it plays important roles in development and likely environmental responses. As with whole organisms, WGD can also promote adaptability and diversity in proliferating cell lineages, although whether WGD is beneficial is clearly context-dependent. WGD is also sometimes associated with aging and disease and may be a facilitator of dangerous genetic and karyotypic diversity in tumorigenesis. Scaling changes can affect cell physiology, but problems associated with WGD in large part seem to arise from problems with chromosome segregation in polyploid cells. Here we discuss both the adaptive potential and problems associated with WGD, focusing primarily on cellular effects. We see value in recognizing polyploidy as a key player in generating diversity in development and cell lineage evolution, with intriguing parallels across kingdoms.
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Affiliation(s)
- Levi Yant
- John Innes Centre, Colney, Norwich NR4 7UH, United Kingdom
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41
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Tormos AM, Taléns-Visconti R, Sastre J. Regulation of cytokinesis and its clinical significance. Crit Rev Clin Lab Sci 2015; 52:159-67. [DOI: 10.3109/10408363.2015.1012191] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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42
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Trakala M, Rodríguez-Acebes S, Maroto M, Symonds CE, Santamaría D, Ortega S, Barbacid M, Méndez J, Malumbres M. Functional reprogramming of polyploidization in megakaryocytes. Dev Cell 2015; 32:155-67. [PMID: 25625205 DOI: 10.1016/j.devcel.2014.12.015] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 10/31/2014] [Accepted: 12/17/2014] [Indexed: 12/30/2022]
Abstract
Polyploidization is a natural process that frequently accompanies differentiation; its deregulation is linked to genomic instability and cancer. Despite its relevance, why cells select different polyploidization mechanisms is unknown. Here we report a systematic genetic analysis of endomitosis, a process in which megakaryocytes become polyploid by entering mitosis but aborting anaphase. Whereas ablation of the APC/C cofactor Cdc20 results in mitotic arrest and severe thrombocytopenia, lack of the kinases Aurora-B, Cdk1, or Cdk2 does not affect megakaryocyte polyploidization or platelet levels. Ablation of Cdk1 forces a switch to endocycles without mitosis, whereas polyploidization in the absence of Cdk1 and Cdk2 occurs in the presence of aberrant re-replication events. Importantly, ablation of these kinases rescues the defects in Cdc20 null megakaryocytes. These findings suggest that endomitosis can be functionally replaced by alternative polyploidization mechanisms in vivo and provide the cellular basis for therapeutic approaches aimed to discriminate mitotic and polyploid cells.
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Affiliation(s)
- Marianna Trakala
- Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
| | | | - María Maroto
- Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
| | | | | | | | | | - Juan Méndez
- DNA Replication Group, CNIO, 28029 Madrid, Spain
| | - Marcos Malumbres
- Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
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43
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Tanaka H, Goto H, Inoko A, Makihara H, Enomoto A, Horimoto K, Matsuyama M, Kurita K, Izawa I, Inagaki M. Cytokinetic Failure-induced Tetraploidy Develops into Aneuploidy, Triggering Skin Aging in Phosphovimentin-deficient Mice. J Biol Chem 2015; 290:12984-98. [PMID: 25847236 PMCID: PMC4505553 DOI: 10.1074/jbc.m114.633891] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Indexed: 01/16/2023] Open
Abstract
Tetraploidy, a state in which cells have doubled chromosomal sets, is observed in ∼20% of solid tumors and is considered to frequently precede aneuploidy in carcinogenesis. Tetraploidy is also detected during terminal differentiation and represents a hallmark of aging. Most tetraploid cultured cells are arrested by p53 stabilization. However, the fate of tetraploid cells in vivo remains largely unknown. Here, we analyze the ability to repair wounds in the skin of phosphovimentin-deficient (VIMSA/SA) mice. Early into wound healing, subcutaneous fibroblasts failed to undergo cytokinesis, resulting in binucleate tetraploidy. Accordingly, the mRNA level of p21 (a p53-responsive gene) was elevated in a VIMSA/SA-specific manner. Disappearance of tetraploidy coincided with an increase in aneuploidy. Thereafter, senescence-related markers were significantly elevated in VIMSA/SA mice. Because our tetraploidy-prone mouse model also exhibited subcutaneous fat loss at the age of 14 months, another premature aging phenotype, our data suggest that following cytokinetic failure, a subset of tetraploid cells enters a new cell cycle and develops into aneuploid cells in vivo, which promote premature aging.
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Affiliation(s)
- Hiroki Tanaka
- From the Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681
| | - Hidemasa Goto
- From the Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681, the Departments of Cellular Oncology and
| | - Akihito Inoko
- From the Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681
| | - Hiroyuki Makihara
- From the Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681, the Department of Oral and Maxillofacial Surgery, School of Dentistry, Aichi Gakuin University, Nagoya 466-8550, and
| | - Atsushi Enomoto
- Pathology, Nagoya University Graduate School of Medicine, Nagoya 466-8550
| | - Katsuhisa Horimoto
- the Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan
| | - Makoto Matsuyama
- From the Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681
| | - Kenichi Kurita
- the Department of Oral and Maxillofacial Surgery, School of Dentistry, Aichi Gakuin University, Nagoya 466-8550, and
| | - Ichiro Izawa
- From the Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681
| | - Masaki Inagaki
- From the Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681, the Departments of Cellular Oncology and
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44
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Tormos AM, Taléns-Visconti R, Bonora-Centelles A, Pérez S, Sastre J. Oxidative stress triggers cytokinesis failure in hepatocytes upon isolation. Free Radic Res 2015; 49:927-34. [PMID: 25744598 DOI: 10.3109/10715762.2015.1016019] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Primary hepatocytes are highly differentiated cells and proliferatively quiescent. However, the stress produced during liver digestion seems to activate cell cycle entry by proliferative/dedifferentiation programs that still remain unclear. The aim of this work was to assess whether the oxidative stress associated with hepatocyte isolation affects cell cycle and particularly cytokinesis, the final step of mitosis. Hepatocytes were isolated from C57BL/6 mice by collagenase perfusion in the absence and presence of N-acetyl cysteine (NAC). Polyploidy, cell cycle, and reactive oxygen species (ROS) were studied by flow cytometry (DNA, phospho-histone 3, and CellROX(®) Deep Red) and Western blotting (cyclins B1 and D1, and proliferating cell nuclear antigen). mRNA expression of cyclins A1, B1, B2, D1, and F by reverse transcription (RT)-PCR was also assessed. Glutathione levels were measured by mass spectrometry. Here we show that hepatocyte isolation enhanced cell cycle entry, increased hepatocyte binucleation, and caused marked glutathione oxidation. Addition of 5 mM NAC to the hepatocyte isolation media prevented glutathione depletion, partially blocked ROS production and cell cycle entry of hepatocytes, and avoided the blockade of mitosis progression, abrogating defective cytokinesis and diminishing the formation of binucleated hepatocytes during isolation. Therefore, addition of NAC to the isolation media decreased the generation of polyploid hepatocytes confirming that oxidative stress occurs during hepatocyte isolation and it is responsible, at least in part, for cytokinesis failure and hepatocyte binucleation.
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Affiliation(s)
- A M Tormos
- Department of Physiology, University of Valencia , Burjassot, Valencia , Spain
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45
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Piano A, Titorenko VI. The Intricate Interplay between Mechanisms Underlying Aging and Cancer. Aging Dis 2015; 6:56-75. [PMID: 25657853 PMCID: PMC4306474 DOI: 10.14336/ad.2014.0209] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 01/30/2014] [Accepted: 02/09/2014] [Indexed: 12/15/2022] Open
Abstract
Age is the major risk factor in the incidence of cancer, a hyperplastic disease associated with aging. Here, we discuss the complex interplay between mechanisms underlying aging and cancer as a reciprocal relationship. This relationship progresses with organismal age, follows the history of cell proliferation and senescence, is driven by common or antagonistic causes underlying aging and cancer in an age-dependent fashion, and is maintained via age-related convergent and divergent mechanisms. We summarize our knowledge of these mechanisms, outline the most important unanswered questions and suggest directions for future research.
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Affiliation(s)
- Amanda Piano
- Department of Biology, Concordia University, Montreal, Quebec, Canada
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46
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Bannert K, Kuhla A, Abshagen K, Vollmar B. Anti-apoptotic therapeutic approaches in liver diseases: do they really make sense? Apoptosis 2015; 19:1243-53. [PMID: 24872082 DOI: 10.1007/s10495-014-1004-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A variety of data suggesting apoptotic cell death as a key feature of liver injury stimulated researchers to investigate the therapeutic potential of anti-apoptotic strategies in experimental models. However, the overestimated role of apoptotic cell death in liver injury has tempered the clinical translation of the protection afforded by anti-apoptotic regimes in experimental models. Thus, the hope for apoptosis modulation as potential treatment strategy for injured liver in humans could not be confirmed. Herein, we evaluated the degree of apoptosis in different hepatic stress models which are relevant for the human pathophysiology. Using morphological criteria of apoptosis, caspase-3 activation as well as TUNEL assay in combination with a positive control of apoptosis in liver injury, we quantified apoptotic cell death discriminating between parenchymal and non-parenchymal cells and confirmed these results by cleaved caspase-3 and PARP-1 protein expression. Discussing our findings and relating them to the existing literature on the potential role of apoptotic cell death, we strongly recommend reconsidering anti-apoptotic strategies to ameliorate liver injury efficiently.
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Affiliation(s)
- Karen Bannert
- Institute for Experimental Surgery, Rostock University Medical School, Schillingallee 69 a, 18057, Rostock, Germany
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47
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Gentric G, Maillet V, Paradis V, Couton D, L'Hermitte A, Panasyuk G, Fromenty B, Celton-Morizur S, Desdouets C. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease. J Clin Invest 2015; 125:981-92. [PMID: 25621497 DOI: 10.1172/jci73957] [Citation(s) in RCA: 180] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 12/15/2014] [Indexed: 12/13/2022] Open
Abstract
Polyploidization is one of the most dramatic changes that can occur in the genome. In the liver, physiological polyploidization events occur during both liver development and throughout adult life. Here, we determined that a pathological polyploidization takes place in nonalcoholic fatty liver disease (NAFLD), a widespread hepatic metabolic disorder that is believed to be a risk factor for hepatocellular carcinoma (HCC). In murine models of NAFLD, the parenchyma of fatty livers displayed alterations of the polyploidization process, including the presence of a large proportion of highly polyploid mononuclear cells, which are rarely observed in normal hepatic parenchyma. Biopsies from patients with nonalcoholic steatohepatitis (NASH) revealed the presence of alterations in hepatocyte ploidy compared with tissue from control individuals. Hepatocytes from NAFLD mice revealed that progression through the S/G2 phases of the cell cycle was inefficient. This alteration was associated with activation of a G2/M DNA damage checkpoint, which prevented activation of the cyclin B1/CDK1 complex. Furthermore, we determined that oxidative stress promotes the appearance of highly polyploid cells, and antioxidant-treated NAFLD hepatocytes resumed normal cell division and returned to a physiological state of polyploidy. Collectively, these findings indicate that oxidative stress promotes pathological polyploidization and suggest that this is an early event in NAFLD that may contribute to HCC development.
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48
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Kapoor S, Berishvili E, Bandi S, Gupta S. Ischemic preconditioning affects long-term cell fate through DNA damage-related molecular signaling and altered proliferation. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 184:2779-2790. [PMID: 25128377 PMCID: PMC4188865 DOI: 10.1016/j.ajpath.2014.07.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 06/11/2014] [Accepted: 06/17/2014] [Indexed: 12/16/2022]
Abstract
Despite the potential of ischemic preconditioning for organ protection, long-term effects in terms of molecular processes and cell fates are ill defined. We determined consequences of hepatic ischemic preconditioning in rats, including cell transplantation assays. Ischemic preconditioning induced persistent alterations; for example, after 5 days liver histology was normal, but γ-glutamyl transpeptidase expression was observed, with altered antioxidant enzyme content, lipid peroxidation, and oxidative DNA adducts. Nonetheless, ischemic preconditioning partially protected from toxic liver injury. Similarly, primary hepatocytes from donor livers preconditioned with ischemia exhibited undesirably altered antioxidant enzyme content and lipid peroxidation, but better withstood insults. However, donor hepatocytes from livers preconditioned with ischemia did not engraft better than hepatocytes from control livers. Moreover, proliferation of hepatocytes from donor livers preconditioned with ischemia decreased under liver repopulation conditions. Hepatocytes from donor livers preconditioned with ischemia showed oxidative DNA damage with expression of genes involved in MAPK signaling that impose G1/S and G2/M checkpoint restrictions, including p38 MAPK-regulated or ERK-1/2-regulated cell-cycle genes such as FOS, MAPK8, MYC, various cyclins, CDKN2A, CDKN2B, TP53, and RB1. Thus, although ischemic preconditioning allowed hepatocytes to better withstand secondary insults, accompanying DNA damage and molecular events simultaneously impaired their proliferation capacity over the long term. Mitigation of ischemic preconditioning-induced DNA damage and deleterious molecular perturbations holds promise for advancing clinical applications.
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Affiliation(s)
- Sorabh Kapoor
- Department of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York
| | - Ekaterine Berishvili
- Department of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York
| | - Sriram Bandi
- Department of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York; Department of Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York
| | - Sanjeev Gupta
- Department of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York; Department of Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York; Department of Diabetes Center, Albert Einstein College of Medicine, Bronx, New York; Department of Cancer Center, Albert Einstein College of Medicine, Bronx, New York; Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York; Institute for Clinical and Translational Research, Albert Einstein College of Medicine, Bronx, New York.
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49
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Dolka I, Giżejewska A, Giżejewski Z, Kluciński W, Kołodziejska J. Histological Evaluation of Selected Organs of the Eurasian Beavers(Castor fiber)Inhabiting Poland. Anat Histol Embryol 2014; 44:378-90. [DOI: 10.1111/ahe.12150] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2013] [Accepted: 08/14/2014] [Indexed: 12/22/2022]
Affiliation(s)
- I. Dolka
- Department of Pathology and Veterinary Diagnostics; Faculty of Veterinary Medicine; Warsaw University of Life Sciences (WULS-SGGW); Nowoursynowska 159c 02-776 Warsaw Poland
| | - A. Giżejewska
- Department of Pharmacology and Toxicology; Faculty of Veterinary Medicine; University of Warmia and Mazury in Olsztyn; Oczapowskiego 2 10-719 Olsztyn Poland
| | - Z. Giżejewski
- Institute of Animal Reproduction and Food Research; Polish Academy of Sciences; Tuwima 10 10-747 Olsztyn Poland
| | - W. Kluciński
- Department of Pathology and Veterinary Diagnostics; Faculty of Veterinary Medicine; Warsaw University of Life Sciences (WULS-SGGW); Nowoursynowska 159c 02-776 Warsaw Poland
| | - J. Kołodziejska
- Department of Pathology and Veterinary Diagnostics; Faculty of Veterinary Medicine; Warsaw University of Life Sciences (WULS-SGGW); Nowoursynowska 159c 02-776 Warsaw Poland
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Varetti G, Pellman D, Gordon DJ. Aurea mediocritas: the importance of a balanced genome. Cold Spring Harb Perspect Biol 2014; 6:a015842. [PMID: 25237130 DOI: 10.1101/cshperspect.a015842] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Aneuploidy, defined as an abnormal number of chromosomes, is a hallmark of cancer. Paradoxically, aneuploidy generally has a negative impact on cell growth and fitness in nontransformed cells. In this work, we review recent progress in identifying how aneuploidy leads to genomic and chromosomal instability, how cells can adapt to the deleterious effects of aneuploidy, and how aneuploidy contributes to tumorigenesis in different genetic contexts. Finally, we also discuss how aneuploidy might be a target for anticancer therapies.
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Affiliation(s)
- Gianluca Varetti
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115
| | - David Pellman
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789
| | - David J Gordon
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115
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