1
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Zhu Y, Wunderlich Z, Lander AD. Epithelial cell competition is promoted by signaling from immune cells. Nat Commun 2025; 16:3710. [PMID: 40251197 PMCID: PMC12008283 DOI: 10.1038/s41467-025-59130-5] [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: 06/19/2023] [Accepted: 04/11/2025] [Indexed: 04/20/2025] Open
Abstract
In epithelial tissues, juxtaposition of cells of different phenotypes can trigger cell competition, a process whereby one type of cell drives death and extrusion of another. During growth and homeostasis, cell competition is thought to serve a quality control function, eliminating cells that are "less fit". Tissues may also attack and eliminate newly arising tumor cells, exploiting mechanisms shared with other instances of cell competition, but that differ, reportedly, in the involvement of the immune system. Whereas immune cells have been shown to play a direct role in killing tumor cells, this has not been observed in other cases of cell competition, suggesting that tissues recognize and handle cancer cells differently. Here, we challenge this view, showing that, in the fruit fly Drosophila, innate immune cells play similar roles in cell killing during classical cell competition as in eliminating tumors. These findings suggest that immune suppression of cancer may exploit the same mechanisms as are involved in promoting phenotypic uniformity among epithelial cells.
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Affiliation(s)
- Yilun Zhu
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, 92697, USA
- Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, 92697, USA
| | - Zeba Wunderlich
- Department of Biology, Boston University, Boston, MA, 02215, USA
- Biological Design Center, Boston University, Boston, MA, 02215, USA
| | - Arthur D Lander
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, 92697, USA.
- Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, 92697, USA.
- Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, 92697, USA.
- NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, 92697, USA.
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2
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Bener MB, Slepchenko BM, Inaba M. Asymmetric stem cell division maintains genetic heterogeneity of tissue cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.16.594576. [PMID: 38798517 PMCID: PMC11118488 DOI: 10.1101/2024.05.16.594576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Within a given tissue, the stem cell niche provides the microenvironment for stem cells suitable for their self-renewal. Conceptually, the niche space constrains the size of a stem-cell pool, as the cells sharing the niche compete for its space. It has been suggested that either neutral- or non-neutral-competition of stem cells changes the clone dynamics of stem cells. Theoretically, if the rate of asymmetric division is high, the stem cell competition is limited, thus suppressing clonal expansion. However, the effects of asymmetric division on clone dynamics have never been experimentally tested. Here, using the Drosophila germline stem cell (GSC) system, as a simple model of the in-vivo niche, we examine the effect of division modes (asymmetric or symmetric) on clonal dynamics by combining experimental approaches with mathematical modeling. Our results suggest that the rate of asymmetric division positively correlates with the time a stem cell clone takes to expand. Taken together, our data suggests that asymmetric division is essential for maintaining the genetic variation of stem cells and thus serves as a critical mechanism for safeguarding fertility over the animal age or preventing multiple disorders caused by the clonal expansion of stem cells.
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Affiliation(s)
- Muhammed Burak Bener
- Department of Cell Biology, University of Connecticut School of Medicine, Farmington, CT 06030
| | - Boris M. Slepchenko
- Department of Cell Biology, University of Connecticut School of Medicine, Farmington, CT 06030
- Richard D. Berlin Center for Cell Analysis and Modeling, University of Connecticut School of Medicine, Farmington, CT 06030
| | - Mayu Inaba
- Department of Cell Biology, University of Connecticut School of Medicine, Farmington, CT 06030
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3
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Vonada A, Grompe M. In vivo selection of hepatocytes. Hepatology 2024:01515467-990000000-01066. [PMID: 39787488 DOI: 10.1097/hep.0000000000001143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 09/13/2024] [Indexed: 01/12/2025]
Abstract
The liver is a highly regenerative organ capable of significant proliferation and remodeling during homeostasis and injury responses. Experiments of nature in rare genetic diseases have illustrated that healthy hepatocytes may have a selective advantage, outcompete diseased cells, and result in extensive liver replacement. This observation has given rise to the concept of therapeutic liver repopulation by providing an engineered selective advantage to a subpopulation of beneficial hepatocytes. In vivo selection can greatly enhance the efficiency of both gene and cell transplantation therapies for hepatic diseases. In vivo hepatocyte selection has also enabled the expansion of human hepatocytes in animals, creating novel models of human liver disease and biology. Finally, recent work has shown that somatic mutations produce clonal expansion of injury-resistant hepatocytes in most chronic liver diseases. In this review, we will address the role of hepatocyte selection in disease pathophysiology and therapeutic strategies.
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Affiliation(s)
- Anne Vonada
- Department of Pediatrics, Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, USA
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4
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Chen Y, Yan Y, Tian R, Sheng Z, Li L, Chen J, Liao Y, Wen Y, Lu J, Liu X, Sun W, Wu H, Liao Y, Zhang X, Chen X, An C, Zhao K, Liu W, Gao J, Hay DC, Ouyang H. Chemically programmed metabolism drives a superior cell fitness for cartilage regeneration. SCIENCE ADVANCES 2024; 10:eadp4408. [PMID: 39259800 PMCID: PMC11389791 DOI: 10.1126/sciadv.adp4408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 08/02/2024] [Indexed: 09/13/2024]
Abstract
The rapid advancement of cell therapies underscores the importance of understanding fundamental cellular attributes. Among these, cell fitness-how transplanted cells adapt to new microenvironments and maintain functional stability in vivo-is crucial. This study identifies a chemical compound, FPH2, that enhances the fitness of human chondrocytes and the repair of articular cartilage, which is typically nonregenerative. Through drug screening, FPH2 was shown to broadly improve cell performance, especially in maintaining chondrocyte phenotype and enhancing migration. Single-cell transcriptomics indicated that FPH2 induced a super-fit cell state. The mechanism primarily involves the inhibition of carnitine palmitoyl transferase I and the optimization of metabolic homeostasis. In animal models, FPH2-treated human chondrocytes substantially improved cartilage regeneration, demonstrating well-integrated tissue interfaces in rats. In addition, an acellular FPH2-loaded hydrogel proved effective in preventing the onset of osteoarthritis. This research provides a viable and safe method to enhance chondrocyte fitness, offering insights into the self-regulatory mechanisms of cell fitness.
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Affiliation(s)
- Yishan Chen
- Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, China
| | - Yiyang Yan
- Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, China
| | - Ruonan Tian
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, China
| | - Zixuan Sheng
- Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Liming Li
- Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Jiachen Chen
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yuan Liao
- Center for Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ya Wen
- Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Junting Lu
- Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, China
| | - Xinyu Liu
- Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, China
| | - Wei Sun
- Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, China
| | - Haoyu Wu
- Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Youguo Liao
- Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Xianzhu Zhang
- Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xuri Chen
- Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Chengrui An
- Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Kun Zhao
- Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Wanlu Liu
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, China
| | - Jianqing Gao
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - David C Hay
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, UK
| | - Hongwei Ouyang
- Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, China
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China
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5
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van Luyk ME, Krotenberg Garcia A, Lamprou M, Suijkerbuijk SJE. Cell competition in primary and metastatic colorectal cancer. Oncogenesis 2024; 13:28. [PMID: 39060237 PMCID: PMC11282291 DOI: 10.1038/s41389-024-00530-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 07/05/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024] Open
Abstract
Adult tissues set the scene for a continuous battle between cells, where a comparison of cellular fitness results in the elimination of weaker "loser" cells. This phenomenon, named cell competition, is beneficial for tissue integrity and homeostasis. In fact, cell competition plays a crucial role in tumor suppression, through elimination of early malignant cells, as part of Epithelial Defense Against Cancer. However, it is increasingly apparent that cell competition doubles as a tumor-promoting mechanism. The comparative nature of cell competition means that mutational background, proliferation rate and polarity all factor in to determine the outcome of these processes. In this review, we explore the intricate and context-dependent involvement of cell competition in homeostasis and regeneration, as well as during initiation and progression of primary and metastasized colorectal cancer. We provide a comprehensive overview of molecular and cellular mechanisms governing cell competition and its parallels with regeneration.
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Affiliation(s)
- Merel Elise van Luyk
- Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Ana Krotenberg Garcia
- Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Maria Lamprou
- Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Saskia Jacoba Elisabeth Suijkerbuijk
- Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
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6
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Paul PK, Umarvaish S, Bajaj S, S. RF, Mohan H, Annaert W, Chaudhary V. Maintenance of proteostasis by Drosophila Rer1 is essential for competitive cell survival and Myc-driven overgrowth. PLoS Genet 2024; 20:e1011171. [PMID: 38408084 PMCID: PMC10919865 DOI: 10.1371/journal.pgen.1011171] [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: 05/17/2023] [Revised: 03/07/2024] [Accepted: 02/05/2024] [Indexed: 02/28/2024] Open
Abstract
Defects in protein homeostasis can induce proteotoxic stress, affecting cellular fitness and, consequently, overall tissue health. In various growing tissues, cell competition based mechanisms facilitate detection and elimination of these compromised, often referred to as 'loser', cells by the healthier neighbors. The precise connection between proteotoxic stress and competitive cell survival remains largely elusive. Here, we reveal the function of an endoplasmic reticulum (ER) and Golgi localized protein Rer1 in the regulation of protein homeostasis in the developing Drosophila wing epithelium. Our results show that loss of Rer1 leads to proteotoxic stress and PERK-mediated phosphorylation of eukaryotic initiation factor 2α. Clonal analysis showed that rer1 mutant cells are identified as losers and eliminated through cell competition. Interestingly, we find that Rer1 levels are upregulated upon Myc-overexpression that causes overgrowth, albeit under high proteotoxic stress. Our results suggest that increased levels of Rer1 provide cytoprotection to Myc-overexpressing cells by alleviating the proteotoxic stress and thereby supporting Myc-driven overgrowth. In summary, these observations demonstrate that Rer1 acts as a novel regulator of proteostasis in Drosophila and reveal its role in competitive cell survival.
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Affiliation(s)
- Pranab Kumar Paul
- Cell and developmental signaling laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh, India
| | - Shruti Umarvaish
- Cell and developmental signaling laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh, India
| | - Shivani Bajaj
- Cell and developmental signaling laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh, India
| | - Rishana Farin S.
- Cell and developmental signaling laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh, India
| | - Hrudya Mohan
- Cell and developmental signaling laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh, India
| | - Wim Annaert
- Laboratory for Membrane Trafficking, VIB-Center for Brain and Disease Research, KU Leuven, Leuven, Belgium, and Department of Neurosciences, KU Leuven, Gasthuisberg, Leuven, Belgium
| | - Varun Chaudhary
- Cell and developmental signaling laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh, India
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7
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Yusupova M, Fuchs Y. To not love thy neighbor: mechanisms of cell competition in stem cells and beyond. Cell Death Differ 2023; 30:979-991. [PMID: 36813919 PMCID: PMC10070350 DOI: 10.1038/s41418-023-01114-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 12/28/2022] [Accepted: 01/09/2023] [Indexed: 02/24/2023] Open
Abstract
Cell competition describes the process in which cells of greater fitness are capable of sensing and instructing elimination of lesser fit mutant cells. Since its discovery in Drosophila, cell competition has been established as a critical regulator of organismal development, homeostasis, and disease progression. It is therefore unsurprising that stem cells (SCs), which are central to these processes, harness cell competition to remove aberrant cells and preserve tissue integrity. Here, we describe pioneering studies of cell competition across a variety of cellular contexts and organisms, with the ultimate goal of better understanding competition in mammalian SCs. Furthermore, we explore the modes through which SC competition takes place and how this facilitates normal cellular function or contributes to pathological states. Finally, we discuss how understanding of this critical phenomenon will enable targeting of SC-driven processes, including regeneration and tumor progression.
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Affiliation(s)
- Marianna Yusupova
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion Israel Institute of Technology, Haifa, Israel
- Lorry Lokey Interdisciplinary Center for Life Sciences & Engineering, Technion Israel Institute of Technology, Haifa, Israel
| | - Yaron Fuchs
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion Israel Institute of Technology, Haifa, Israel.
- Lorry Lokey Interdisciplinary Center for Life Sciences & Engineering, Technion Israel Institute of Technology, Haifa, Israel.
- Augmanity, Rehovot, Israel.
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8
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Abstract
Organ development and homeostasis involve dynamic interactions between individual cells that collectively regulate tissue architecture and function. To ensure the highest tissue fidelity, equally fit cell populations are continuously renewed by stochastic replacement events, while cells perceived as less fit are actively removed by their fitter counterparts. This renewal is mediated by surveillance mechanisms that are collectively known as cell competition. Recent studies have revealed that cell competition has roles in most, if not all, developing and adult tissues. They have also established that cell competition functions both as a tumour-suppressive mechanism and as a tumour-promoting mechanism, thereby critically influencing cancer initiation and development. This Review discusses the latest insights into the mechanisms of cell competition and its different roles during embryonic development, homeostasis and cancer.
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9
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Abstract
Although differential transcription drives the development of multicellular organisms, the ultimate readout of a protein-coding gene is ribosome-dependent mRNA translation. Ribosomes were once thought of as uniform molecular machines, but emerging evidence indicates that the complexity and diversity of ribosome biogenesis and function should be given a fresh look in the context of development. This Review begins with a discussion of different developmental disorders that have been linked with perturbations in ribosome production and function. We then highlight recent studies that reveal how different cells and tissues exhibit variable levels of ribosome production and protein synthesis, and how changes in protein synthesis capacity can influence specific cell fate decisions. We finish by touching upon ribosome heterogeneity in stress responses and development. These discussions highlight the importance of considering both ribosome levels and functional specialization in the context of development and disease.
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Affiliation(s)
- Chunyang Ni
- Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
| | - Michael Buszczak
- Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
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10
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Ni C, Buszczak M. The homeostatic regulation of ribosome biogenesis. Semin Cell Dev Biol 2023; 136:13-26. [PMID: 35440410 PMCID: PMC9569395 DOI: 10.1016/j.semcdb.2022.03.043] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/30/2022] [Accepted: 03/31/2022] [Indexed: 12/22/2022]
Abstract
The continued integrity of biological systems depends on a balance between interdependent elements at the molecular, cellular, and organismal levels. This is particularly true for the generation of ribosomes, which influence almost every aspect of cell and organismal biology. Ribosome biogenesis (RiBi) is an energetically demanding process that involves all three RNA polymerases, numerous RNA processing factors, chaperones, and the coordinated expression of 79-80 ribosomal proteins (r-proteins). Work over the last several decades has revealed that the dynamic regulation of ribosome production represents a major mechanism by which cells maintain homeostasis in response to changing environmental conditions and acute stress. More recent studies suggest that cells and tissues within multicellular organisms exhibit dramatically different levels of ribosome production and protein synthesis, marked by the differential expression of RiBi factors. Thus, distinct bottlenecks in the RiBi process, downstream of rRNA transcription, may exist within different cell populations of multicellular organisms during development and in adulthood. This review will focus on our current understanding of the mechanisms that link the complex molecular process of ribosome biogenesis with cellular and organismal physiology. We will discuss diverse topics including how different steps in the RiBi process are coordinated with one another, how MYC and mTOR impact RiBi, and how RiBi levels change between stem cells and their differentiated progeny. In turn, we will also review how regulated changes in ribosome production itself can feedback to influence cell fate and function.
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Affiliation(s)
- Chunyang Ni
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA
| | - Michael Buszczak
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
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11
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Shafritz DA, Ebrahimkhani MR, Oertel M. Therapeutic Cell Repopulation of the Liver: From Fetal Rat Cells to Synthetic Human Tissues. Cells 2023; 12:529. [PMID: 36831196 PMCID: PMC9954009 DOI: 10.3390/cells12040529] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/20/2023] [Accepted: 01/26/2023] [Indexed: 02/10/2023] Open
Abstract
Progenitor cells isolated from the fetal liver can provide a unique cell source to generate new healthy tissue mass. Almost 20 years ago, it was demonstrated that rat fetal liver cells repopulate the normal host liver environment via a mechanism akin to cell competition. Activin A, which is produced by hepatocytes, was identified as an important player during cell competition. Because of reduced activin receptor expression, highly proliferative fetal liver stem/progenitor cells are resistant to activin A and therefore exhibit a growth advantage compared to hepatocytes. As a result, transplanted fetal liver cells are capable of repopulating normal livers. Important for cell-based therapies, hepatic stem/progenitor cells containing repopulation potential can be separated from fetal hematopoietic cells using the cell surface marker δ-like 1 (Dlk-1). In livers with advanced fibrosis, fetal epithelial stem/progenitor cells differentiate into functional hepatic cells and out-compete injured endogenous hepatocytes, which cause anti-fibrotic effects. Although fetal liver cells efficiently repopulate the liver, they will likely not be used for human cell transplantation. Thus, utilizing the underlying mechanism of repopulation and developed methods to produce similar growth-advantaged cells in vitro, e.g., human induced pluripotent stem cells (iPSCs), this approach has great potential for developing novel cell-based therapies in patients with liver disease. The present review gives a brief overview of the classic cell transplantation models and various cell sources studied as donor cell candidates. The advantages of fetal liver-derived stem/progenitor cells are discussed, as well as the mechanism of liver repopulation. Moreover, this article reviews the potential of in vitro developed synthetic human fetal livers from iPSCs and their therapeutic benefits.
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Affiliation(s)
- David A. Shafritz
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Mo R. Ebrahimkhani
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15213, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Michael Oertel
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15213, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
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12
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Rahal Z, Sinjab A, Wistuba II, Kadara H. Game of clones: Battles in the field of carcinogenesis. Pharmacol Ther 2022; 237:108251. [PMID: 35850404 PMCID: PMC10249058 DOI: 10.1016/j.pharmthera.2022.108251] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 07/10/2022] [Accepted: 07/12/2022] [Indexed: 11/22/2022]
Abstract
Recent advances in bulk sequencing approaches as well as genomic decoding at the single-cell level have revealed surprisingly high somatic mutational burdens in normal tissues, as well as increased our understanding of the landscape of "field cancerization", that is, molecular and immune alterations in mutagen-exposed normal-appearing tissues that recapitulated those present in tumors. Charting the somatic mutational landscapes in normal tissues can have strong implications on our understanding of how tumors arise from mutagenized epithelium. Making sense of those mutations to understand the progression along the pathologic continuum of normal epithelia, preneoplasias, up to malignant tissues will help pave way for identification of ideal targets that can guide new strategies for preventing or eliminating cancers at their earliest stages of development. In this review, we will provide a brief history of field cancerization and its implications on understanding early stages of cancer pathogenesis and deviation from the pathologically "normal" state. The review will provide an overview of how mutations accumulating in normal tissues can lead to a patchwork of mutated cell clones that compete while maintaining an overall state of functional homeostasis. The review also explores the role of clonal competition in directing the fate of normal tissues and summarizes multiple mechanisms elicited in this phenomenon and which have been linked to cancer development. Finally, we highlight the importance of understanding mutations in normal tissues, as well as clonal competition dynamics (in both the epithelium and the microenvironment) and their significance in exploring new approaches to combatting cancer.
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Affiliation(s)
- Zahraa Rahal
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, USA
| | - Ansam Sinjab
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, USA
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, USA
| | - Humam Kadara
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, USA.
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13
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Feunteun J, Ostyn P, Delaloge S. TUMOR CELL MALIGNANCY: A COMPLEX TRAIT BUILT THROUGH RECIPROCAL INTERACTIONS BETWEEN TUMORS AND TISSUE-BODY SYSTEM. iScience 2022; 25:104217. [PMID: 35494254 PMCID: PMC9044163 DOI: 10.1016/j.isci.2022.104217] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Since the discovery of oncogenes and tumor suppressor genes in the late past century, cancer research has been overwhelmingly focused on the genetics and biology of tumor cells and hence has addressed mostly cell-autonomous processes with emphasis on traditional driver/passenger genetic models. Nevertheless, over that same period, multiple seminal observations have accumulated highlighting the role of non-cell autonomous effectors in tumor growth and metastasis. However, given that cell autonomous and non-autonomous events are observed together at the time of diagnosis, it is in fact impossible to know whether the malignant transformation is initiated by cell autonomous oncogenic events or by non-cell autonomous conditions generated by alterations of the tissue-body ecosystem. This review aims at addressing this issue by taking the option of defining malignancy as a complex genetic trait incorporating genetically determined reciprocal interactions between tumor cells and tissue-body ecosystem.
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Affiliation(s)
- Jean Feunteun
- INSERM U981, Gustave Roussy, Université Paris-Saclay, Villejuif, France
- UMR 9019, Gustave Roussy, Université Paris-Saclay, Villejuif, France
- Corresponding author
| | - Pauline Ostyn
- UMR 9019, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Suzette Delaloge
- Breast Cancer Group, Gustave Roussy, Université Paris-Saclay, Villejuif, France
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14
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Nishina H. Physiological and pathological roles of the Hippo-YAP/TAZ signaling pathway in liver formation, homeostasis and tumorigenesis. Cancer Sci 2022; 113:1900-1908. [PMID: 35349740 PMCID: PMC9207356 DOI: 10.1111/cas.15352] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/22/2022] [Accepted: 03/26/2022] [Indexed: 11/28/2022] Open
Abstract
The liver plays central homeostatic roles in metabolism and detoxification, and has a remarkable capacity to fully recover from injuries caused by the various insults to which it is constantly exposed. To fulfill these functions, the liver must maintain a specific size and so must regulate its cell numbers. It must also remove senescent, transformed, and/or injured cells that impair liver function and can lead to diseases such as cirrhosis and liver cancer. Despite their importance, however, the mechanisms governing liver size control and homeostasis have resisted delineation. The discovery of the Hippo intracellular signaling pathway and its downstream effectors, the transcriptional coactivators Yes‐associated protein (YAP) and transcriptional coactivator with PDZ‐binding motif (TAZ), has provided partial elucidation of these mechanisms. The Hippo‐YAP/TAZ pathway is considered to be a cell’s sensor of its immediate microenvironment and the cells that surround it, in that this pathway responds to changes in elements such as the ECM, cell–cell tension, and cell adhesion. Once triggered, Hippo signaling negatively regulates the binding of YAP/TAZ to transcription factors such as TEAD and Smad, controlling their ability to drive gene expression needed for cellular responses such as proliferation, survival, and stemness. Numerous KO mouse strains lacking YAP/TAZ, as well as transgenic mice showing YAP/TAZ hyperactivation, have been generated, and the effects of these mutations on liver development, size, regeneration, homeostasis, and tumorigenesis have been reported. In this review, I summarize the components and regulation of Hippo‐YAP/TAZ signaling, and discuss this pathway in the context of liver physiology and pathology.
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Affiliation(s)
- Hiroshi Nishina
- Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
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15
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Tumorigenesis and cell competition in Drosophila in the absence of polyhomeotic function. Proc Natl Acad Sci U S A 2021; 118:2110062118. [PMID: 34702735 DOI: 10.1073/pnas.2110062118] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2021] [Indexed: 12/12/2022] Open
Abstract
Cell competition is a homeostatic process that eliminates by apoptosis unfit or undesirable cells from animal tissues, including tumor cells that appear during the life of the organism. In Drosophila there is evidence that many types of oncogenic cells are eliminated by cell competition. One exception is cells mutant for polyhomeotic (ph), a member of the Polycomb family of genes; most of the isolated mutant ph clones survive and develop tumorous overgrowths in imaginal discs. To characterize the tumorigenic effect of the lack of ph, we first studied the growth of different regions of the wing disc deficient in ph activity and found that the effect is restricted to the proximal appendage. Moreover, we found that ph-deficient tissue is partially refractory to apoptosis. Second, we analyzed the behavior of clones lacking ph function and found that many suffer cell competition but are not completely eliminated. Unexpectedly, we found that nonmutant cells also undergo cell competition when surrounded by ph-deficient cells, indicating that within the same tissue cell competition may operate in opposite directions. We suggest two reasons for the incompleteness of cell competition in ph mutant cells: 1) These cells are partially refractory to apoptosis, and 2) the loss of ph function alters the identity of imaginal cells and subsequently their cell affinities. It compromises the winner/loser interaction, a prerequisite for cell competition.
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16
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Ogasawara H, Inagaki A, Fathi I, Imura T, Yamana H, Saitoh Y, Matsumura M, Fukuoka K, Miyagi S, Nakamura Y, Ohashi K, Unno M, Kamei T, Goto M. Preferable Transplant Site for Hepatocyte Transplantation in a Rat Model. Cell Transplant 2021; 30:9636897211040012. [PMID: 34525872 PMCID: PMC8450989 DOI: 10.1177/09636897211040012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Intraportal injection is regarded as the current standard procedure of hepatocyte transplantation (HTx). In islet transplantation, which shares many aspects with HTx, recent studies have clarified that instant blood-mediated inflammatory reaction (IBMIR), characterized by strong innate immune responses, can cause poor engraftment, so other transplant sites to avoid such a reaction have been established. Although IBMIR was reported to occur in HTx, few reports have evaluated alternative transplant sites for HTx. In this study, we sought to determine the optimum transplant site for HTx. Rat hepatocytes (1.0 × 107) were transplanted at the 9 transplant sites (intraportal (IPO), intrasplenic (IS), liver parenchyma, subcutaneous, intraperitoneal, renal subcapsular, muscle, inguinal subcutaneous white adipose tissue, and omentum) of analbuminemic rats. The serum albumin levels, immunohistochemical staining (albumin, TUNEL, and BrdU), and in vivo imaging of the grafts were evaluated. The serum albumin levels of the IPO group were significantly higher than those of the other groups (p < .0001). The BrdU-positive hepatocyte ratio of liver in the IS group (0.9% ± 0.2%) was comparable to that of the IPO group (0.9% ± 0.3%) and tended to be higher than that of the spleen in the IS group (0.5% ± 0.1%, p = .16). Considering the in vivo imaging evaluation and the influence of splenectomy, the graft function in the IS group may be almost entirely achieved by hepatocytes that have migrated to the liver. The present study clearly showed that the intraportal injection procedure is more efficient than other procedures for performing HTx
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Affiliation(s)
- Hiroyuki Ogasawara
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akiko Inagaki
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Ibrahim Fathi
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takehiro Imura
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroki Yamana
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshikatsu Saitoh
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Muneyuki Matsumura
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kengo Fukuoka
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shigehito Miyagi
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuhiro Nakamura
- Division of Pathology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Kazuo Ohashi
- Laboratory of Drug Development and Science, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masafumi Goto
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.,Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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17
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Aging and Cancer: The Waning of Community Bonds. Cells 2021; 10:cells10092269. [PMID: 34571918 PMCID: PMC8468626 DOI: 10.3390/cells10092269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 08/25/2021] [Accepted: 08/27/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer often arises in the context of an altered tissue landscape. We argue that a major contribution of aging towards increasing the risk of neoplastic disease is conveyed through effects on the microenvironment. It is now firmly established that aged tissues are prone to develop clones of altered cells, most of which are compatible with a normal histological appearance. Such increased clonogenic potential results in part from a generalized decrease in proliferative fitness, favoring the emergence of more competitive variant clones. However, specific cellular genotypes can emerge with reduced cooperative and integrative capacity, leading to disruption of tissue architecture and paving the way towards progression to overt neoplastic phenotypes.
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18
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Parker TM, Gupta K, Palma AM, Yekelchyk M, Fisher PB, Grossman SR, Won KJ, Madan E, Moreno E, Gogna R. Cell competition in intratumoral and tumor microenvironment interactions. EMBO J 2021; 40:e107271. [PMID: 34368984 DOI: 10.15252/embj.2020107271] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 06/14/2021] [Accepted: 06/16/2021] [Indexed: 12/18/2022] Open
Abstract
Tumors are complex cellular and acellular environments within which cancer clones are under continuous selection pressures. Cancer cells are in a permanent mode of interaction and competition with each other as well as with the immediate microenvironment. In the course of these competitive interactions, cells share information regarding their general state of fitness, with less-fit cells being typically eliminated via apoptosis at the hands of those cells with greater cellular fitness. Competitive interactions involving exchange of cell fitness information have implications for tumor growth, metastasis, and therapy outcomes. Recent research has highlighted sophisticated pathways such as Flower, Hippo, Myc, and p53 signaling, which are employed by cancer cells and the surrounding microenvironment cells to achieve their evolutionary goals by means of cell competition mechanisms. In this review, we discuss these recent findings and explain their importance and role in evolution, growth, and treatment of cancer. We further consider potential physiological conditions, such as hypoxia and chemotherapy, that can function as selective pressures under which cell competition mechanisms may evolve differently or synergistically to confer oncogenic advantages to cancer.
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Affiliation(s)
- Taylor M Parker
- Department of Biochemistry, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Kartik Gupta
- Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | | | - Michail Yekelchyk
- Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Paul B Fisher
- Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.,VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Steven R Grossman
- Department of Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Kyoung Jae Won
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen North, Denmark.,Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, University of Copenhagen, Copenhagen North, Denmark
| | - Esha Madan
- Champalimaud Centre for the Unknown, Lisbon, Portugal
| | | | - Rajan Gogna
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen North, Denmark.,Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, University of Copenhagen, Copenhagen North, Denmark
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19
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Ramos CV, Martins VC. Cell competition in hematopoietic cells: Quality control in homeostasis and its role in leukemia. Dev Biol 2021; 475:1-9. [DOI: 10.1016/j.ydbio.2021.02.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/19/2021] [Accepted: 02/23/2021] [Indexed: 12/24/2022]
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20
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Javary J, Allain N, Ezzoukhry Z, Di Tommaso S, Dupuy JW, Costet P, Dugot-Senant N, Saltel F, Moreau V, Dubus P, Benhamouche-Trouillet S. Reptin/RUVBL2 is required for hepatocyte proliferation in vivo, liver regeneration and homeostasis. Liver Int 2021; 41:1423-1429. [PMID: 33792165 DOI: 10.1111/liv.14886] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 03/13/2021] [Accepted: 03/26/2021] [Indexed: 12/31/2022]
Abstract
Previous studies have shown that Reptin is overexpressed in hepatocellular carcinoma and that it is necessary for in vitro proliferation and cell survival. However, its pathophysiological role in vivo remains unknown. We aimed to study the role of Reptin in hepatocyte proliferation after regeneration using a liver Reptin knock-out model (ReptinLKO ). Interestingly, hepatocyte proliferation is strongly impaired in ReptinLKO mice 36 h after partial hepatectomy, associated with a decrease of cyclin-A expression and mTORC1 and MAPK signalling, leading to an impaired liver regeneration. Moreover, in the ReptinLKO model, we have observed a progressive loss of Reptin invalidation associated with an atypical liver regeneration. Hypertrophic and proliferative hepatocytes gradually replace ReptinKO hypotrophic hepatocytes. To conclude, our results show that Reptin is required for hepatocyte proliferation in vivo and liver regeneration and that it plays a crucial role in hepatocyte survival and liver homeostasis.
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Affiliation(s)
- Joaquim Javary
- INSERM, UMR1053, Bordeaux, France.,BaRITOn (Bordeaux Research in Translational Oncology), Université de Bordeaux, Bordeaux, France
| | - Nathalie Allain
- INSERM, UMR1053, Bordeaux, France.,BaRITOn (Bordeaux Research in Translational Oncology), Université de Bordeaux, Bordeaux, France
| | - Zakaria Ezzoukhry
- INSERM, UMR1053, Bordeaux, France.,BaRITOn (Bordeaux Research in Translational Oncology), Université de Bordeaux, Bordeaux, France
| | - Sylvaine Di Tommaso
- INSERM, UMR1053, Bordeaux, France.,BaRITOn (Bordeaux Research in Translational Oncology), Université de Bordeaux, Bordeaux, France.,Oncoprot TBM Core US005, Bordeaux, France
| | | | - Pierre Costet
- CRYME Centre BROCA Nouvelle Aquitaine (CBNA), Université de Bordeaux service commun des animaleries - Bordeaux, Bordeaux, France
| | | | - Frédéric Saltel
- INSERM, UMR1053, Bordeaux, France.,BaRITOn (Bordeaux Research in Translational Oncology), Université de Bordeaux, Bordeaux, France
| | - Violaine Moreau
- INSERM, UMR1053, Bordeaux, France.,BaRITOn (Bordeaux Research in Translational Oncology), Université de Bordeaux, Bordeaux, France
| | - Pierre Dubus
- INSERM, UMR1053, Bordeaux, France.,BaRITOn (Bordeaux Research in Translational Oncology), Université de Bordeaux, Bordeaux, France.,CHU de Bordeaux, Bordeaux, France
| | - Samira Benhamouche-Trouillet
- INSERM, UMR1053, Bordeaux, France.,BaRITOn (Bordeaux Research in Translational Oncology), Université de Bordeaux, Bordeaux, France
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21
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Morata G. Cell competition: A historical perspective. Dev Biol 2021; 476:33-40. [PMID: 33775694 DOI: 10.1016/j.ydbio.2021.02.012] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 02/16/2021] [Accepted: 02/23/2021] [Indexed: 12/21/2022]
Abstract
Cell competition is a homeostatic process designed to remove from animal tissues viable cells that are unfit, abnormal or malignant and that may compromise the general fitness or the viability of the organism. Originally discovered in Drosophila in the mid-seventies of last century, there is strong evidence that it also occurs in other metazoans, where cell competition appears to play a similar surveillance role. In this review I summarize the field of cell competition, with special emphasis in the history of the phenomenon within the general frame of Developmental Biology in the second half of the XX century, pointing out the key observations and the evolution of ideas that have led to the current understanding.
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Affiliation(s)
- Ginés Morata
- Centro de Biología Molecular CSIC-UAM, Madrid, Spain.
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22
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Cell competition-induced apical elimination of transformed cells, EDAC, orchestrates the cellular homeostasis. Dev Biol 2021; 476:112-116. [PMID: 33774012 DOI: 10.1016/j.ydbio.2021.03.015] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/05/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023]
Abstract
Newly emerging transformed cells are often eliminated from the epithelium via cell competition with the surrounding normal cells. A number of recent studies using mammalian cell competition systems have demonstrated that cells with various types of oncogenic insults are extruded from the tissue in a cell death-dependent or -independent manner. Cell competition-mediated elimination of transformed cells, called EDAC (epithelial defense against cancer), represents an intrinsic anti-tumor activity within the epithelial cell society to reduce the risk of oncogenesis. Here we delineate roles and molecular mechanisms of this homeostatic process, especially focusing on mammalian models.
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23
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Marques-Reis M, Moreno E. Role of cell competition in ageing. Dev Biol 2021; 476:79-87. [PMID: 33753080 DOI: 10.1016/j.ydbio.2021.03.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 02/25/2021] [Accepted: 03/16/2021] [Indexed: 11/30/2022]
Abstract
Recent advances in rapid medical detection and diagnostic technology have extended both human health and life expectancy. However, ageing remains one of the critical risk factors in contributing to major incapacitating and fatal conditions, including cancer and neurodegeneration. Therefore, it is vital to study how ageing attributes to (or participates in) endangering human health via infliction of age-related diseases and what must be done to tackle this intractable process. This review encompasses the most recent literature elaborating the role of cell competition (CC) during ageing. CC is a process that occurs between two heterogeneous populations, where the cells with higher fitness levels have a competitive advantage over the neighbouring cells that have comparatively lower fitness levels. This interaction results in the selection of the fit cells, within a population, and elimination of the viable yet suboptimal cells. Therefore, it is tempting to speculate that, if this quality control mechanism works efficiently throughout life, can it ultimately lead to a healthier ageing and extended lifespan. Furthermore, the review aims to collate all the important state of the art publications that provides evidence of the relevance of CC in dietary restriction, stem cell dynamics, and cell senescence, thus, prompting us to advocate its contribution and in exploring new avenues and opportunities in fighting age-related conditions.
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Affiliation(s)
- Mariana Marques-Reis
- Cell Fitness Laboratory, Champalimaud Centre for the Unknown, Av. Brasília, 1400-038, Lisbon, Portugal
| | - Eduardo Moreno
- Cell Fitness Laboratory, Champalimaud Centre for the Unknown, Av. Brasília, 1400-038, Lisbon, Portugal.
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24
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Esteban-Martínez L, Torres M. Metabolic regulation of cell competition. Dev Biol 2021; 475:30-36. [PMID: 33652024 DOI: 10.1016/j.ydbio.2021.02.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/15/2021] [Accepted: 02/23/2021] [Indexed: 02/04/2023]
Abstract
Cell Competition is a selective process by which viable cells are eliminated from developing or adult tissues by interactions with their neighbors. In many cases, the eliminated cells (losers) display reduced fitness, yet they would be able to sustain tissue growth or maintenance in a homotypic environment, and are only eliminated when confronted with surrounding wild type cells (winners). In addition, cells with oncogenic mutations that do not show reduced fitness can also be eliminated from tissues when surrounded by wild type cells. Depending on the context, transformed cells can also become supercompetitors and eliminate surrounding wild type cells, thereby promoting tumor formation. Several factors have been shown to play essential roles in Cell Competition, including genes relevant in developmental growth, tumor formation and epithelial apico-basal polarity. Recent discoveries, however, suggest that energy metabolism plays a central role in very different models of cell competition. Here we review the involvement of mitochondrial dynamics and metabolism, autophagy and nutritional status in cell competition and discuss the possible implications of this emerging field.
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Affiliation(s)
- Lorena Esteban-Martínez
- Cardiovascular Development Program. Centro Nacional de Investigaciones Cardiovasculares (CNIC). Melchor Fernández Almagro 3, Madrid, 28029, Spain
| | - Miguel Torres
- Cardiovascular Development Program. Centro Nacional de Investigaciones Cardiovasculares (CNIC). Melchor Fernández Almagro 3, Madrid, 28029, Spain.
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25
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Marongiu F, Laconi E. Cell competition in liver carcinogenesis. World J Hepatol 2020; 12:475-484. [PMID: 32952874 PMCID: PMC7475782 DOI: 10.4254/wjh.v12.i8.475] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 06/22/2020] [Accepted: 07/26/2020] [Indexed: 02/06/2023] Open
Abstract
Cell competition is now a well-established quality control strategy to optimize cell and tissue fitness in multicellular organisms. While pursuing this goal, it is also effective in selecting against altered/defective cells with putative (pre)-neoplastic potential, thereby edging the risk of cancer development. The flip side of the coin is that the molecular machinery driving cell competition can also be co-opted by neoplastic cell populations to expand unchecked, outside the boundaries of tissue homeostatic control. This review will focus on information that begins to emerge regarding the role of cell competition in liver physiology and pathology. Liver repopulation by normal transplanted hepatocytes is an interesting field of investigation in this regard. The biological coordinates of this process share many features suggesting that cell competition is a driving force for the clearance of endogenous damaged hepatocytes by normal donor-derived cells, as previously proposed. Intriguing analogies between liver repopulation and carcinogenesis will be briefly discussed and the potential dual role of cell competition, as a barrier or a spur to neoplastic development, will be considered. Cell competition is in essence a cooperative strategy organized at tissue level. One facet of such cooperative attitude is expressed in the elimination of altered cells which may represent a threat to the organismal community. On the other hand, the society of cells can be disrupted by the emergence of selfish clones, exploiting the molecular bar codes of cell competition, thereby paving their way to uncontrolled growth.
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Affiliation(s)
- Fabio Marongiu
- Department of Biomedical Sciences, Unit of Experimental Medicine, University of Cagliari, Cagliari 09124, Italy
| | - Ezio Laconi
- Department of Biomedical Sciences, Unit of Experimental Medicine, University of Cagliari, Cagliari 09124, Italy
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26
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Abstract
The growth and survival of cells within tissues can be affected by 'cell competition' between different cell clones. This phenomenon was initially recognized between wild-type cells and cells with mutations in ribosomal protein (Rp) genes in Drosophila melanogaster. However, competition also affects D. melanogaster cells with mutations in epithelial polarity genes, and wild-type cells exposed to 'super-competitor' cells with mutation in the Salvador-Warts-Hippo tumour suppressor pathway or expressing elevated levels of Myc. More recently, cell competition and super-competition were recognized in mammalian development, organ homeostasis and cancer. Genetic and cell biological studies have revealed that mechanisms underlying cell competition include the molecular recognition of 'different' cells, signalling imbalances between distinct cell populations and the mechanical consequences of differential growth rates; these mechanisms may also involve innate immune proteins, p53 and changes in translation.
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27
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Qiu R, Murata S, Oshiro K, Hatada Y, Taniguchi H. Transplantation of fetal liver tissue coated by ultra-purified alginate gel over liver improves hepatic function in the cirrhosis rat model. Sci Rep 2020; 10:8231. [PMID: 32427847 PMCID: PMC7237464 DOI: 10.1038/s41598-020-65069-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 04/28/2020] [Indexed: 02/06/2023] Open
Abstract
In this study, we used a new coating agent, that is, ultra-purified alginate gel (UPAL), for fetal liver tissue transplantation. This study aims to compare the effect of UPAL with the effect of other coating agents on improving the effect of fetal liver tissue transplantation in a liver cirrhosis rat model. Prior to the transplantation of wild-type ED14 fetal liver tissues, various coating agents were separately applied on the liver surface of rats with cirrhosis. Then, we compared the engraftment area, engraftment rate and liver function level of these rats. As a result, coating the liver surface of a cirrhosis rat with UPAL obtained the best effect in terms of engraftment area and engraftment rate of the transplanted liver tissue and in the recovery of liver function compared with control group. Therefore, UPAL coating may serve as a novel strategy for liver organoid transplantation.
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Affiliation(s)
- Rong Qiu
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9, Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Soichiro Murata
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9, Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan.
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, the Institute of Medical Science, the University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
| | - Katsutomo Oshiro
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9, Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Yumi Hatada
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9, Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Hideki Taniguchi
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9, Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan.
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, the Institute of Medical Science, the University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
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28
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Messina A, Luce E, Hussein M, Dubart-Kupperschmitt A. Pluripotent-Stem-Cell-Derived Hepatic Cells: Hepatocytes and Organoids for Liver Therapy and Regeneration. Cells 2020; 9:cells9020420. [PMID: 32059501 PMCID: PMC7072243 DOI: 10.3390/cells9020420] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 02/04/2020] [Accepted: 02/10/2020] [Indexed: 12/19/2022] Open
Abstract
The liver is a very complex organ that ensures numerous functions; it is thus susceptible to multiple types of damage and dysfunction. Since 1983, orthotopic liver transplantation (OLT) has been considered the only medical solution available to patients when most of their liver function is lost. Unfortunately, the number of patients waiting for OLT is worryingly increasing, and extracorporeal liver support devices are not yet able to counteract the problem. In this review, the current and expected methodologies in liver regeneration are briefly analyzed. In particular, human pluripotent stem cells (hPSCs) as a source of hepatic cells for liver therapy and regeneration are discussed. Principles of hPSC differentiation into hepatocytes are explored, along with the current limitations that have led to the development of 3D culture systems and organoid production. Expected applications of these organoids are discussed with particular attention paid to bio artificial liver (BAL) devices and liver bio-fabrication.
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Affiliation(s)
- Antonietta Messina
- INSERM unité mixte de recherche (UMR_S) 1193, F-94800 Villejuif, France; (A.M.)
- UMR_S 1193, Université Paris-Sud/Paris-Saclay, F-94800 Villejuif, France
- Département Hospitalo-Universitaire (DHU) Hépatinov, F-94800 Villejuif, France
| | - Eléanor Luce
- INSERM unité mixte de recherche (UMR_S) 1193, F-94800 Villejuif, France; (A.M.)
- UMR_S 1193, Université Paris-Sud/Paris-Saclay, F-94800 Villejuif, France
- Département Hospitalo-Universitaire (DHU) Hépatinov, F-94800 Villejuif, France
| | - Marwa Hussein
- INSERM unité mixte de recherche (UMR_S) 1193, F-94800 Villejuif, France; (A.M.)
- UMR_S 1193, Université Paris-Sud/Paris-Saclay, F-94800 Villejuif, France
- Département Hospitalo-Universitaire (DHU) Hépatinov, F-94800 Villejuif, France
| | - Anne Dubart-Kupperschmitt
- INSERM unité mixte de recherche (UMR_S) 1193, F-94800 Villejuif, France; (A.M.)
- UMR_S 1193, Université Paris-Sud/Paris-Saclay, F-94800 Villejuif, France
- Département Hospitalo-Universitaire (DHU) Hépatinov, F-94800 Villejuif, France
- Correspondence: ; Tel.: +33-145595138
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29
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Ko S, Russell JO, Molina LM, Monga SP. Liver Progenitors and Adult Cell Plasticity in Hepatic Injury and Repair: Knowns and Unknowns. ANNUAL REVIEW OF PATHOLOGY 2020; 15:23-50. [PMID: 31399003 PMCID: PMC7212705 DOI: 10.1146/annurev-pathmechdis-012419-032824] [Citation(s) in RCA: 111] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The liver is a complex organ performing numerous vital physiological functions. For that reason, it possesses immense regenerative potential. The capacity for repair is largely attributable to the ability of its differentiated epithelial cells, hepatocytes and biliary epithelial cells, to proliferate after injury. However, in cases of extreme acute injury or prolonged chronic insult, the liver may fail to regenerate or do so suboptimally. This often results in life-threatening end-stage liver disease for which liver transplantation is the only effective treatment. In many forms of liver injury, bipotent liver progenitor cells are theorized to be activated as an additional tier of liver repair. However, the existence, origin, fate, activation, and contribution to regeneration of liver progenitor cells is hotly debated, especially since hepatocytes and biliary epithelial cells themselves may serve as facultative stem cells for one another during severe liver injury. Here, we discuss the evidence both supporting and refuting the existence of liver progenitor cells in a variety of experimental models. We also debate the validity of developing therapies harnessing the capabilities of these cells as potential treatments for patients with severe and chronic liver diseases.
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Affiliation(s)
- Sungjin Ko
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
| | - Jacquelyn O Russell
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
| | - Laura M Molina
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
| | - Satdarshan P Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
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30
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Tsuchida T, Murata S, Matsuki K, Mori A, Matsuo M, Mikami S, Okamoto S, Ueno Y, Tadokoro T, Zheng YW, Taniguchi H. The Regenerative Effect of Portal Vein Injection of Liver Organoids by Retrorsine/Partial Hepatectomy in Rats. Int J Mol Sci 2019; 21:178. [PMID: 31887985 PMCID: PMC6981799 DOI: 10.3390/ijms21010178] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 12/18/2019] [Accepted: 12/23/2019] [Indexed: 12/15/2022] Open
Abstract
In this study, we reveal that liver organoid transplantation through the portal vein is a safe and effective method for the treatment of chronic liver damage. The liver organoids significantly reconstituted the hepatocytes; hence, the liver was significantly enlarged in this group, compared to the monolayer cell transplantation group in the retrorsine/partial hepatectomy (RS/PH) model. In the liver organoid transplantation group, the bile ducts were located in the donor area and connected to the recipient bile ducts. Thus, the rate of bile reconstruction in the liver was significantly higher compared to that in the monolayer group. By transplanting liver organoids, we saw a level of 70% replacement of the damaged liver. Consequently, in the transplantation group, diminished ductular reaction and a decrease of placental glutathione S-transferase (GST-p) precancerous lesions were observed. After trans-portal injection, the human induced pluripotent stem cell (hiPSC)-derived liver organoids revealed no translocation outside the liver; in contrast, the monolayer cells had spread to the lungs. The hiPSC-derived liver organoids were attached to the liver in the immunodeficient RS/PH rats. This study clearly demonstrates that liver organoid transplantation through the portal vein is a safe and effective method for the treatment of chronic liver damage in rats.
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Affiliation(s)
- Tomonori Tsuchida
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.T.); (K.M.); (A.M.); (M.M.); (S.M.); (S.O.); (Y.U.); (T.T.); (Y.-W.Z.)
| | - Soichiro Murata
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.T.); (K.M.); (A.M.); (M.M.); (S.M.); (S.O.); (Y.U.); (T.T.); (Y.-W.Z.)
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
| | - Koichiro Matsuki
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.T.); (K.M.); (A.M.); (M.M.); (S.M.); (S.O.); (Y.U.); (T.T.); (Y.-W.Z.)
| | - Akihiro Mori
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.T.); (K.M.); (A.M.); (M.M.); (S.M.); (S.O.); (Y.U.); (T.T.); (Y.-W.Z.)
| | - Megumi Matsuo
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.T.); (K.M.); (A.M.); (M.M.); (S.M.); (S.O.); (Y.U.); (T.T.); (Y.-W.Z.)
| | - Satoshi Mikami
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.T.); (K.M.); (A.M.); (M.M.); (S.M.); (S.O.); (Y.U.); (T.T.); (Y.-W.Z.)
| | - Satoshi Okamoto
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.T.); (K.M.); (A.M.); (M.M.); (S.M.); (S.O.); (Y.U.); (T.T.); (Y.-W.Z.)
| | - Yasuharu Ueno
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.T.); (K.M.); (A.M.); (M.M.); (S.M.); (S.O.); (Y.U.); (T.T.); (Y.-W.Z.)
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
| | - Tomomi Tadokoro
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.T.); (K.M.); (A.M.); (M.M.); (S.M.); (S.O.); (Y.U.); (T.T.); (Y.-W.Z.)
| | - Yun-Wen Zheng
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.T.); (K.M.); (A.M.); (M.M.); (S.M.); (S.O.); (Y.U.); (T.T.); (Y.-W.Z.)
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
- Department of Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Hideki Taniguchi
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.T.); (K.M.); (A.M.); (M.M.); (S.M.); (S.O.); (Y.U.); (T.T.); (Y.-W.Z.)
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
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31
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Pathological features of vessel co-option versus sprouting angiogenesis. Angiogenesis 2019; 23:43-54. [DOI: 10.1007/s10456-019-09690-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 10/05/2019] [Indexed: 12/19/2022]
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32
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Yasen A, Tuxun T, Apaer S, Li W, Maimaitinijiati Y, Wang H, Aisan M, Aji T, Shao Y, Hao W. Fetal liver stem cell transplantation for liver diseases. Regen Med 2019; 14:703-714. [PMID: 31393226 DOI: 10.2217/rme-2018-0160] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Stem cell transplantation exhibited a promising lifesaving therapy for various end-stage liver diseases and could serve as a salvaging bridge until curative methods can be performed. In past decades, mature hepatocytes, liver progenitor cells, mesenchymal stem cells and induced pluripotent stem cells have been practiced in above settings. However, long-term survival rates and continuous proliferation ability of these cells in vivo are unsatisfactory, whereas, fetal liver stem cells (FLSCs), given their unique superiority, may be the best candidate for stem cell transplantation technique. Recent studies have revealed that FLSCs could be used as an attractive genetic therapy or regenerative treatments for inherited metabolic or other hepatic disorders. In this study, we reviewed current status and advancements of FLSCs-based treatment.
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Affiliation(s)
- Aimaiti Yasen
- Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,State Key Laboratory on Pathogenesis, Prevention & Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, 393 Xin Yi Road, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,Department of Liver & Laparoscopic Surgery, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Tuerhongjiang Tuxun
- Department of Liver & Laparoscopic Surgery, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Shadike Apaer
- State Key Laboratory on Pathogenesis, Prevention & Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, 393 Xin Yi Road, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,Department of Liver & Laparoscopic Surgery, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Wending Li
- Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,State Key Laboratory on Pathogenesis, Prevention & Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, 393 Xin Yi Road, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,Department of Liver & Laparoscopic Surgery, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Yusufukadier Maimaitinijiati
- Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,State Key Laboratory on Pathogenesis, Prevention & Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, 393 Xin Yi Road, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Hui Wang
- State Key Laboratory on Pathogenesis, Prevention & Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, 393 Xin Yi Road, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Meiheriayi Aisan
- Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Tuerganaili Aji
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Yingmei Shao
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Wen Hao
- State Key Laboratory on Pathogenesis, Prevention & Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, 393 Xin Yi Road, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
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33
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Yovchev MI, Lee EJ, Rodriguez‐Silva W, Locker J, Oertel M. Biliary Obstruction Promotes Multilineage Differentiation of Hepatic Stem Cells. Hepatol Commun 2019; 3:1137-1150. [PMID: 31388633 PMCID: PMC6672331 DOI: 10.1002/hep4.1367] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 04/23/2019] [Indexed: 12/17/2022] Open
Abstract
Because of their high regenerative potential, stem cells are an ideal resource for development of therapies that replace injured tissue mass and restore function in patients with end-stage liver diseases. Using a rat model of bile duct ligation (BDL) and biliary fibrosis, we investigated cell engraftment, liver repopulation, and ectopic tissue formation after intrasplenic transplantation of epithelial stem/progenitor cells. Fetal liver cells were infused into the spleens of Fisher 344 rats with progressing biliary fibrosis induced by common BDL or rats without BDL. Cell delivery was well tolerated. After migration to the liver, donor-derived stem/progenitor cells engrafted, differentiated into hepatocytes and cholangiocytes, and formed large cell clusters at 2 months in BDL rats but not controls. Substantial numbers of donor cells were also detected at the splenic injection site where they generated hepatic and nonhepatic tissue. Transplanted cells differentiated into phenotypes other than hepato/cholangiocytic cells only in rats that underwent BDL. Quantitative reverse-transcription polymerase chain reaction analyses demonstrated marked up-regulation of tissue-specific genes of nonhepatic endodermal lineages (e.g., caudal type homeobox 2 [Cdx2], pancreatic and duodenal homeobox 1 [Pdx1], keratin 13 [CK-13]), confirmed by immunohistochemistry. Conclusion: BDL and its induced fibrosis promote liver repopulation by ectopically transplanted fetal liver-derived cells. These cell fractions contain multipotent stem cells that colonize the spleen of BDL rats and differentiate into multiple gastrointestinal tissues, including liver, pancreas, intestine, and esophagus. The splenic microenvironment, therefore, represents an ideal niche to assess the differentiation of these stem cells, while BDL provides a stimulus that induces their differentiation.
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Affiliation(s)
- Mladen I. Yovchev
- Department of Pathology, Division of Experimental PathologyUniversity of PittsburghPittsburghPA
| | - Edward J. Lee
- Department of Pathology, Division of Experimental PathologyUniversity of PittsburghPittsburghPA
| | | | - Joseph Locker
- Department of Pathology, Division of Experimental PathologyUniversity of PittsburghPittsburghPA
- Pittsburgh Liver Research CenterUniversity of PittsburghPittsburghPA
| | - Michael Oertel
- Department of Pathology, Division of Experimental PathologyUniversity of PittsburghPittsburghPA
- Pittsburgh Liver Research CenterUniversity of PittsburghPittsburghPA
- McGowan Institute for Regenerative MedicineUniversity of PittsburghPittsburghPA
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Abstract
All solid tumours require a vascular supply in order to progress. Although the ability to induce angiogenesis (new blood vessel growth) has long been regarded as essential to this purpose, thus far, anti-angiogenic therapies have shown only modest efficacy in patients. Importantly, overshadowed by the literature on tumour angiogenesis is a long-standing, but continually emerging, body of research indicating that tumours can grow instead by hijacking pre-existing blood vessels of the surrounding nonmalignant tissue. This process, termed vessel co-option, is a frequently overlooked mechanism of tumour vascularization that can influence disease progression, metastasis and response to treatment. In this Review, we describe the evidence that tumours located at numerous anatomical sites can exploit vessel co-option. We also discuss the proposed molecular mechanisms involved and the multifaceted implications of vessel co-option for patient outcomes.
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Affiliation(s)
- Elizabeth A Kuczynski
- Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada.
| | - Peter B Vermeulen
- HistoGeneX, Antwerp, Belgium
- Translational Cancer Research Unit, GZA Hospitals St Augustinus, University of Antwerp, Wilrijk-Antwerp, Belgium
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Francesco Pezzella
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Robert S Kerbel
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Andrew R Reynolds
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
- Oncology Translational Medicine Unit, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
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35
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Bowling S, Lawlor K, Rodríguez TA. Cell competition: the winners and losers of fitness selection. Development 2019; 146:146/13/dev167486. [PMID: 31278123 DOI: 10.1242/dev.167486] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The process of cell competition results in the 'elimination of cells that are viable but less fit than surrounding cells'. Given the highly heterogeneous nature of our tissues, it seems increasingly likely that cells are engaged in a 'survival of the fittest' battle throughout life. The process has a myriad of positive roles in the organism: it selects against mutant cells in developing tissues, prevents the propagation of oncogenic cells and eliminates damaged cells during ageing. However, 'super-fit' cancer cells can exploit cell competition mechanisms to expand and spread. Here, we review the regulation, roles and risks of cell competition in organism development, ageing and disease.
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Affiliation(s)
- Sarah Bowling
- National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
| | - Katerina Lawlor
- National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
| | - Tristan A Rodríguez
- National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
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36
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Coelho DS, Moreno E. Emerging links between cell competition and Alzheimer's disease. J Cell Sci 2019; 132:132/13/jcs231258. [PMID: 31263078 DOI: 10.1242/jcs.231258] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Alzheimer's disease (AD) causes a progressive loss of memory and other cognitive functions, which inexorably debilitates patients. There is still no cure for AD and effective treatments to delay or revert AD are urgently needed. On a molecular level, the excessive accumulation of amyloid-β (Aβ) peptides triggers a complex cascade of pathological events underlying neuronal death, whose details are not yet completely understood. Our laboratory recently discovered that cell competition may play a protective role against AD by eliminating less fit neurons from the brain of Aβ-transgenic flies. Loss of Aβ-damaged neurons through fitness comparison with healthy counterparts is beneficial for the organism, delaying cognitive decline and motor disability. In this Review, we introduce the molecular mechanisms of cell competition, including seminal works on the field and latest advances regarding genetic triggers and effectors of cell elimination. We then describe the biological relevance of competition in the nervous system and discuss how competitive interactions between neurons may arise and be exacerbated in the context of AD. Selection of neurons through fitness comparison is a promising, but still emerging, research field that may open new avenues for the treatment of neurological disorders.
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Affiliation(s)
- Dina S Coelho
- Cell Fitness Laboratory, Champalimaud Centre for the Unknown, Av. Brasília., 1400-038 Lisbon, Portugal
| | - Eduardo Moreno
- Cell Fitness Laboratory, Champalimaud Centre for the Unknown, Av. Brasília., 1400-038 Lisbon, Portugal
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37
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Chen J, Yang T, Song S, Liu Q, Sun Y, Zhao L, Fu Z, Wang MJ, Hu YP, Chen F. Senescence suppressed proliferation of host hepatocytes is precondition for liver repopulation. Biochem Biophys Res Commun 2019; 516:591-598. [PMID: 31239154 DOI: 10.1016/j.bbrc.2019.06.103] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 06/18/2019] [Indexed: 01/18/2023]
Abstract
In the fumarylacetoacetate hydrolase deficient (Fah-/-) mouse, massive liver repopulation can be easily obtained after transplanted hepatocytes. Understanding the mechanisms of complete liver repopulation in Fah-/- mice will be useful for future clinical application. Here, we found that the endogenous hepatocytes in liver of Fah-/- mice undertook senescence during the time of tyrosinemia symptoms. Increase of senescent hepatocytes in Fah-/- mice provided proliferative advantage to the transplanted hepatocytes. Importantly, senescent hepatocytes upregulated the expression of extracellular matrix enzyme, contributing to degradation of extracellular matrix components and weakness of cell adhesion and connection. The liver exhibiting a loose architecture provided the space for the engraftment and expansion of transplanted hepatocytes. These findings underscore the underlying mechanisms of completed liver repopulation in Fah-/- mice. Senescence followed by loose hepatic parenchyma is a preconditioning for liver repopulation, which would be a promising strategy to achieve therapeutic liver repopulation in clinical settings.
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Affiliation(s)
- Jiajia Chen
- Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai, 200433, PR China
| | - Tao Yang
- Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai, 200433, PR China
| | - Shaohua Song
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200433, PR China
| | - Qinggui Liu
- Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai, 200433, PR China
| | - Yu Sun
- Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai, 200433, PR China
| | - Linghao Zhao
- Estern Hepatobilliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, PR China
| | - Zhiren Fu
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200433, PR China
| | - Min-Jun Wang
- Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai, 200433, PR China
| | - Yi-Ping Hu
- Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai, 200433, PR China.
| | - Fei Chen
- Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai, 200433, PR China.
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38
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Paglia S, Sollazzo M, Di Giacomo S, Strocchi S, Grifoni D. Exploring MYC relevance to cancer biology from the perspective of cell competition. Semin Cancer Biol 2019; 63:49-59. [PMID: 31102666 DOI: 10.1016/j.semcancer.2019.05.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 05/08/2019] [Accepted: 05/14/2019] [Indexed: 12/13/2022]
Abstract
Cancer has long been regarded and treated as a foreign body appearing by mistake inside a living organism. However, now we know that cancer cells communicate with neighbours, thereby creating modified environments able to support their unusual need for nutrients and space. Understanding the molecular basis of these bi-directional interactions is thus mandatory to approach the complex nature of cancer. Since their discovery, MYC proteins have been showing to regulate a steadily increasing number of processes impacting cell fitness, and are consistently found upregulated in almost all human tumours. Of interest, MYC takes part in cell competition, an evolutionarily conserved fitness comparison strategy aimed at detecting weakened cells, which are then committed to death, removed from the tissue and replaced by fitter neighbours. During physiological development, MYC-mediated cell competition is engaged to eliminate cells with suboptimal MYC levels, so as to guarantee selective growth of the fittest and proper homeostasis, while transformed cells expressing high levels of MYC coopt cell competition to subvert tissue constraints, ultimately disrupting homeostasis. Therefore, the interplay between cells with different MYC levels may result in opposite functional outcomes, depending on the nature of the players. In the present review, we describe the most recent findings on the role of MYC-mediated cell competition in different contexts, with a special emphasis on its impact on cancer initiation and progression. We also discuss the relevance of competition-associated cell death to cancer disease.
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Affiliation(s)
- Simona Paglia
- CanceЯEvolutionLab, University of Bologna, Department of Pharmacy and Biotechnology, Via Selmi 3, 40126, Bologna, Italy.
| | - Manuela Sollazzo
- CanceЯEvolutionLab, University of Bologna, Department of Pharmacy and Biotechnology, Via Selmi 3, 40126, Bologna, Italy.
| | - Simone Di Giacomo
- CanceЯEvolutionLab, University of Bologna, Department of Pharmacy and Biotechnology, Via Selmi 3, 40126, Bologna, Italy.
| | - Silvia Strocchi
- CanceЯEvolutionLab, University of Bologna, Department of Pharmacy and Biotechnology, Via Selmi 3, 40126, Bologna, Italy.
| | - Daniela Grifoni
- CanceЯEvolutionLab, University of Bologna, Department of Pharmacy and Biotechnology, Via Selmi 3, 40126, Bologna, Italy.
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Fahey-Lozano N, La Marca JE, Portela M, Richardson HE. Drosophila Models of Cell Polarity and Cell Competition in Tumourigenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1167:37-64. [PMID: 31520348 DOI: 10.1007/978-3-030-23629-8_3] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Cell competition is an important surveillance mechanism that measures relative fitness between cells in a tissue during development, homeostasis, and disease. Specifically, cells that are "less fit" (losers) are actively eliminated by relatively "more fit" (winners) neighbours, despite the less fit cells otherwise being able to survive in a genetically uniform tissue. Originally described in the epithelial tissues of Drosophila larval imaginal discs, cell competition has since been shown to occur in other epithelial and non-epithelial Drosophila tissues, as well as in mammalian model systems. Many genes and signalling pathways have been identified as playing conserved roles in the mechanisms of cell competition. Among them are genes required for the establishment and maintenance of apico-basal cell polarity: the Crumbs/Stardust/Patj (Crb/Sdt/Patj), Bazooka/Par-6/atypical Protein Kinase C (Baz/Par-6/aPKC), and Scribbled/Discs large 1/Lethal (2) giant larvae (Scrib/Dlg1/L(2)gl) modules. In this chapter, we describe the concepts and mechanisms of cell competition, with emphasis on the relationship between cell polarity proteins and cell competition, particularly the Scrib/Dlg1/L(2)gl module, since this is the best described module in this emerging field.
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Affiliation(s)
- Natasha Fahey-Lozano
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
| | - John E La Marca
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
| | - Marta Portela
- Department of Molecular, Cellular and Developmental Neurobiology, Cajal Institute (CSIC), Madrid, Spain
| | - Helena E Richardson
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia.
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40
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Sollazzo M, Genchi C, Paglia S, Di Giacomo S, Pession A, de Biase D, Grifoni D. High MYC Levels Favour Multifocal Carcinogenesis. Front Genet 2018; 9:612. [PMID: 30619451 PMCID: PMC6297171 DOI: 10.3389/fgene.2018.00612] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Accepted: 11/20/2018] [Indexed: 02/05/2023] Open
Abstract
The term "field cancerisation" describes the formation of tissue sub-areas highly susceptible to multifocal tumourigenesis. In the earlier stages of cancer, cells may indeed display a series of molecular alterations that allow them to proliferate faster, eventually occupying discrete tissue regions with irrelevant morphological anomalies. This behaviour recalls cell competition, a process based on a reciprocal fitness comparison: when cells with a growth advantage arise in a tissue, they are able to commit wild-type neighbours to death and to proliferate at their expense. It is known that cells expressing high MYC levels behave as super-competitors, able to kill and replace less performant adjacent cells; given MYC upregulation in most human cancers, MYC-mediated cell competition is likely to pioneer field cancerisation. Here we show that MYC overexpression in a sub-territory of the larval wing epithelium of Drosophila is sufficient to trigger a number of cellular responses specific to mammalian pre-malignant tissues. Moreover, following induction of different second mutations, high MYC-expressing epithelia were found to be susceptible to multifocal growth, a hallmark of mammalian pre-cancerous fields. In summary, our study identified an early molecular alteration implicated in field cancerisation and established a genetically amenable model which may help study the molecular basis of early carcinogenesis.
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Affiliation(s)
| | | | | | | | | | | | - Daniela Grifoni
- Cancer Evolution Laboratory, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
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41
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Barahman M, Asp P, Roy-Chowdhury N, Kinkhabwala M, Roy-Chowdhury J, Kabarriti R, Guha C. Hepatocyte Transplantation: Quo Vadis? Int J Radiat Oncol Biol Phys 2018; 103:922-934. [PMID: 30503786 DOI: 10.1016/j.ijrobp.2018.11.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 10/10/2018] [Accepted: 11/10/2018] [Indexed: 12/21/2022]
Abstract
Orthotopic liver transplantation (OLT) has been effective in managing end-stage liver disease since the advent of cyclosporine immunosuppression therapy in 1980. The major limitations of OLT are organ supply, monetary cost, and the burden of lifelong immunosuppression. Hepatocyte transplantation, as a substitute for OLT, has been an exciting topic of investigation for several decades. HT is potentially minimally invasive and can serve as a vehicle for delivery of personalized medicine through autologous cell transplant after modification ex vivo. However, 3 major hurdles have prevented large-scale clinical application: (1) availability of transplantable cells; (2) safe and efficient ex vivo gene therapy methods; and (3) engraftment and repopulation efficiency. This review will discuss new sources for transplantable liver cells obtained by lineage reprogramming, clinically acceptable methods of genetic manipulation, and the development of hepatic irradiation-based preparative regimens for enhancing engraftment and repopulation of transplanted hepatocytes. We will also review the results of the first 3 patients with genetic liver disorders who underwent preparative hepatic irradiation before hepatocyte transplantation.
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Affiliation(s)
- Mark Barahman
- Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Patrik Asp
- Department of Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Namita Roy-Chowdhury
- Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Milan Kinkhabwala
- Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Jayanta Roy-Chowdhury
- Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; Department of Genetics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Rafi Kabarriti
- Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Chandan Guha
- Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; Department of Urology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.
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van Dam PJ, Daelemans S, Ross E, Waumans Y, Van Laere S, Latacz E, Van Steen R, De Pooter C, Kockx M, Dirix L, Vermeulen PB. Histopathological growth patterns as a candidate biomarker for immunomodulatory therapy. Semin Cancer Biol 2018; 52:86-93. [PMID: 29355613 DOI: 10.1016/j.semcancer.2018.01.009] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 01/15/2018] [Accepted: 01/16/2018] [Indexed: 12/17/2022]
Abstract
The encroachment of a growing tumor upon the cells and structures of surrounding normal tissue results in a series of histopathological growth patterns (HGPs). These morphological changes can be assessed in hematoxylin-and-eosin (H&E) stained tissue sections from primary and metastatic tumors and have been characterized in a range of tissue types including liver, lung, lymph node and skin. HGPs in different tissues share certain general characteristics like the extent of angiogenesis, but also appropriate tissue-specific mechanisms which ultimately determine differences in the biology of HGP subtypes. For instance, in the well-characterized HGPs of liver metastases, the two main subtypes, replacement and desmoplastic, recapitulate two responses of the normal liver to injury: regeneration and fibrosis. HGP subtypes have distinct cytokine profiles and differing levels of lymphocytic infiltration which suggests that they are indicative of immune status in the tumor microenvironment. HGPs predict response to bevacizumab and are associated with overall survival (OS) after surgery for liver metastases in colorectal cancer (CRC). In addition, HGPs can change over time in response to therapy. With standard scoring methods being developed, HGPs represent an easily accessible, dynamic biomarker to consider when determining strategies for treatment using anti-VEGF and immunomodulatory drugs.
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Affiliation(s)
- Pieter-Jan van Dam
- Translational Cancer Research Unit (CORE), Gasthuiszusters Antwerpen Hospitals, University of Antwerp, Wilrijk, Antwerp, Belgium; HistoGeneX NV, Wilrijk, Antwerp, Belgium
| | | | | | | | - Steven Van Laere
- Translational Cancer Research Unit (CORE), Gasthuiszusters Antwerpen Hospitals, University of Antwerp, Wilrijk, Antwerp, Belgium
| | - Emily Latacz
- Translational Cancer Research Unit (CORE), Gasthuiszusters Antwerpen Hospitals, University of Antwerp, Wilrijk, Antwerp, Belgium
| | - Roanne Van Steen
- Translational Cancer Research Unit (CORE), Gasthuiszusters Antwerpen Hospitals, University of Antwerp, Wilrijk, Antwerp, Belgium
| | - Christel De Pooter
- Translational Cancer Research Unit (CORE), Gasthuiszusters Antwerpen Hospitals, University of Antwerp, Wilrijk, Antwerp, Belgium
| | - Mark Kockx
- HistoGeneX NV, Wilrijk, Antwerp, Belgium
| | - Luc Dirix
- Translational Cancer Research Unit (CORE), Gasthuiszusters Antwerpen Hospitals, University of Antwerp, Wilrijk, Antwerp, Belgium
| | - Peter B Vermeulen
- Translational Cancer Research Unit (CORE), Gasthuiszusters Antwerpen Hospitals, University of Antwerp, Wilrijk, Antwerp, Belgium; HistoGeneX NV, Wilrijk, Antwerp, Belgium.
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43
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Insulin-like growth factor 2 is a key mitogen driving liver repopulation in mice. Cell Death Dis 2018; 9:26. [PMID: 29348399 PMCID: PMC5833551 DOI: 10.1038/s41419-017-0186-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 11/02/2017] [Accepted: 11/27/2017] [Indexed: 12/22/2022]
Abstract
Hepatocyte transplantation holds great promise as an alternative to orthotopic organ transplantation in the treatment of liver diseases. However, obtaining clinically meaningful levels of liver repopulation has not been achieved because the mechanisms regulating hepatocyte proliferation in recipient livers have not yet been well characterized. In the mouse model of Hereditary Tyrosinemia Type I, the fumarylacetoacetate hydrolase-deficient (Fah−/−) mouse, we found gradually increasing expression level of insulin-like growth factor 2 (IGF2) in the hepatocytes of host livers. Similarly, high levels of IGF2 were found in the livers of patients with deficient FAH activity. Recombinant IGF2 directly promotes proliferation of primary hepatocytes in vitro. Inhibition on IGF2 expression through the interruption of PI3K/Akt and MAPK pathways significantly reduced the level of liver repopulation in Fah−/− mice. Interestingly, treatment with IGF2 before hepatocyte transplantation generally improved the amount of liver repopulation seen in various mice models of liver injury. Altogether, these findings underscore the underlying mechanisms of therapeutic liver repopulation in Fah−/− mice, and indicate that IGF2 is a potential hepatocyte mitogen for liver cell transplantation therapies.
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44
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Kon S. Physiological and pathological relevance of cell competition in fly to mammals. Dev Growth Differ 2017; 60:14-20. [PMID: 29250773 DOI: 10.1111/dgd.12415] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 10/24/2017] [Accepted: 10/30/2017] [Indexed: 12/20/2022]
Abstract
In multicellular organisms, incidentally emerging suboptimal cells are removed to maintain homeostasis of tissues. The unfavorable cells are excluded by a process termed cell competition whereby the resident normal cells actively eliminate the unfit cells of the identical lineage. Although the phenomenon of cell competition was originally discovered in Drosophila, a number of recent studies have provided implications of cell competition in tissue regeneration, development and oncogenesis in mammals. Here the roles of cell competition in fly to mammals are discussed.
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Affiliation(s)
- Shunsuke Kon
- Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University Graduate School of Chemical Sciences and Engineering, Sapporo, 060-0815, Japan
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45
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van Dam PJ, van der Stok EP, Teuwen LA, Van den Eynden GG, Illemann M, Frentzas S, Majeed AW, Eefsen RL, Coebergh van den Braak RRJ, Lazaris A, Fernandez MC, Galjart B, Laerum OD, Rayes R, Grünhagen DJ, Van de paer M, Sucaet Y, Mudhar HS, Schvimer M, Nyström H, Kockx M, Bird NC, Vidal-Vanaclocha F, Metrakos P, Simoneau E, Verhoef C, Dirix LY, Van Laere S, Gao ZH, Brodt P, Reynolds AR, Vermeulen PB. International consensus guidelines for scoring the histopathological growth patterns of liver metastasis. Br J Cancer 2017; 117:1427-1441. [PMID: 28982110 PMCID: PMC5680474 DOI: 10.1038/bjc.2017.334] [Citation(s) in RCA: 167] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 06/12/2017] [Accepted: 08/30/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs. METHODS Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined. RESULTS Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006). CONCLUSIONS The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.
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Affiliation(s)
- Pieter-Jan van Dam
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
| | - Eric P van der Stok
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Laure-Anne Teuwen
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
| | - Gert G Van den Eynden
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
| | - Martin Illemann
- The Finsen Laboratory, Rigshospitalet/BRIC, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sophia Frentzas
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Ali W Majeed
- Hepatobiliary Surgery, Sheffield Teaching Hospitals, Sheffield, UK
| | - Rikke L Eefsen
- Department of Oncology, Naestved Hospital, Naestved, Denmark
| | | | - Anthoula Lazaris
- Department of Surgery, Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC, Canada
| | - Maria Celia Fernandez
- Departments of Surgery, Oncology and Medicine, McGill University and the McGill University Health Center Research Institute, Cancer Research Program, Montreal, QC, Canada
| | - Boris Galjart
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Ole Didrik Laerum
- The Finsen Laboratory and Department of Radiation Biology, Copenhagen University Hospital, University of Copenhagen, Denmark
| | - Roni Rayes
- Departments of Surgery, Oncology and Medicine, McGill University and the McGill University Health Center Research Institute, Cancer Research Program, Montreal, QC, Canada
| | - Dirk J Grünhagen
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Michelle Van de paer
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
- HistoGeneX, Sint-Bavostraat 78-80, Antwerp 2610, Belgium
| | - Yves Sucaet
- Department of Pathology, Faculty of Medicine, Vrije Universiteit Brussel, Brussels, Belgium
- Pathomation, Berchem, Belgium
| | | | - Michael Schvimer
- Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel
| | - Hanna Nyström
- Department of Surgery, Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden
| | - Mark Kockx
- HistoGeneX, Sint-Bavostraat 78-80, Antwerp 2610, Belgium
| | - Nigel C Bird
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | | | - Peter Metrakos
- Department of Surgery, Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC, Canada
| | - Eve Simoneau
- Department of Surgery, Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC, Canada
| | - Cornelis Verhoef
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Luc Y Dirix
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
| | - Steven Van Laere
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
| | - Zu-hua Gao
- Department of Pathology and Oncology, McGill University, Montreal, QC, Canada
| | - Pnina Brodt
- Departments of Surgery, Oncology and Medicine, McGill University and the McGill University Health Center Research Institute, Cancer Research Program, Montreal, QC, Canada
| | - Andrew R Reynolds
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
- Early Clinical Development, Innovative Medicines and Early Development, AstraZeneca, Cambridge, UK
| | - Peter B Vermeulen
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
- HistoGeneX, Sint-Bavostraat 78-80, Antwerp 2610, Belgium
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Haridoss S, Yovchev MI, Schweizer H, Megherhi S, Beecher M, Locker J, Oertel M. Activin A is a prominent autocrine regulator of hepatocyte growth arrest. Hepatol Commun 2017; 1:852-870. [PMID: 29404498 PMCID: PMC5721463 DOI: 10.1002/hep4.1106] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 08/28/2017] [Accepted: 08/31/2017] [Indexed: 02/06/2023] Open
Abstract
Activin A, a multifunctional cytokine, plays an important role in hepatocyte growth suppression and is involved in liver size control. The present study was aimed to determine the cell location of activin A in the normal rat liver microenvironment and the contribution of activin A signaling to the hepatocyte phenotype to obtain insight into molecular mechanisms. Immunohistochemical and in situ hybridization analyses identified hepatocytes as the major activin A‐positive cell population in normal liver and identified mast cells as an additional activin A source. To investigate paracrine and autocrine activin A‐stimulated effects, hepatocytes were cocultured with engineered activin A‐secreting cell lines (RF1, TL8) or transduced with an adeno‐associated virus vector encoding activin βA, which led to strikingly altered expression of cell cycle‐related genes (Ki‐67, E2F transcription factor 1 [E2F1], minichromosome maintenance complex component 2 [Mcm2], forkhead box M1 [FoxM1]) and senescence‐related genes (cyclin‐dependent kinase inhibitor 2B [p15INK4b/CDKN2B], differentiated embryo‐chondrocyte expressed gene 1 [DEC1]) and reduced proliferation and induction of senescence. Microarray analyses identified 453 differentially expressed genes, many of which were not yet recognized as activin A downstream targets (e.g., ADAM metallopeptidase domain 12 [Adam12], semaphorin 7A [Sema7a], LIM and cysteine‐rich domains‐1 [Lmcd1], DAB2, clathrin adaptor protein [Dab2]). Among the main activin A‐mediated molecular/cellular functions are cellular growth/proliferation and movement, molecular transport, and metabolic processes containing highly down‐regulated genes, such as cytochrome P450, subfamily 2, polypeptide 11 (Cyp2C11), sulfotransferase family 1A, member 1 (Sult1a1), glycine‐N‐acyltransferase (Glyat), and bile acid‐CoA:amino acid N‐acyltransferase (Baat). Moreover, Ingenuity Pathway Analyses identified particular gene networks regulated by hepatocyte nuclear factor (HNF)‐4α and peroxisome proliferator‐activated receptor gamma (PPARγ) as key targets of activin A signaling. Conclusion: Our in vitro models demonstrated that activin A‐stimulated growth inhibition and cellular senescence is mediated through p15INK4b/CDKN2B and is associated with up‐ and down‐regulation of numerous target genes involved in multiple biological processes performed by hepatocytes, suggesting that activin A fulfills a critical role in normal liver function. (Hepatology Communications 2017;1:852‐870)
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Affiliation(s)
| | | | | | | | - Maria Beecher
- Department of Pathology University of Pittsburgh Pittsburgh PA
| | - Joseph Locker
- Department of Pathology University of Pittsburgh Pittsburgh PA.,Pittsburgh Liver Research Center University of Pittsburgh Pittsburgh PA
| | - Michael Oertel
- Department of Pathology University of Pittsburgh Pittsburgh PA.,Pittsburgh Liver Research Center University of Pittsburgh Pittsburgh PA.,McGowan Institute for Regenerative Medicine University of Pittsburgh Pittsburgh PA
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47
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Abstract
BACKGROUND The limited availability of donor organs has led to a search for alternatives to liver transplantation to restore liver function and bridge patients to transplantation. We have shown that the proliferation of late gestation (embryonic day 19) fetal rat hepatocytes is mitogen-independent and that mechanisms regulating mRNA translation, cell cycle progression, and gene expression differ from those of adult rat hepatocytes. In the present study, we investigated whether E19 fetal hepatocytes can engraft and repopulate an injured adult liver. METHODS Fetal hepatocytes were isolated using a monoclonal antibody against a hepatic surface protein, leucine amino peptidase (LAP). LAP+ and LAP- fractions were analyzed by immunofluorescence and microarray. Immunopurified E19 liver cells from DPPIV+ rats were transplanted via splenic injection into partial hepatectomized DPPIV- rats that had been pretreated with mitomycin C. RESULTS More than a third of LAP+ fetal hepatocytes expressed ductal markers. Transcriptomic analysis revealed that these dual-expressing cells represent a population of less well-differentiated hepatocytes. Upon transplantation, LAP+ late gestation fetal hepatocytes formed hepatic, endothelial, and ductal colonies within 1 month. By 10 months, colonies derived from LAP+ cells increased so that up to 35% of the liver was repopulated by donor-derived cells. CONCLUSIONS Late gestation fetal hepatocytes, despite being far along in the differentiation process, possess the capacity for extensive liver repopulation. This is likely related to the unexpected presence of a significant proportion of hepatocyte marker-positive cells maintaining a less well-differentiated phenotype.
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48
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Irudayaswamy A, Muthiah M, Zhou L, Hung H, Jumat NHB, Haque J, Teoh N, Farrell G, Riehle KJ, Lin JS, Su LL, Chan JK, Choolani M, Wong PC, Wee A, Lim SG, Campbell J, Fausto N, Dan YY. Long-Term Fate of Human Fetal Liver Progenitor Cells Transplanted in Injured Mouse Livers. Stem Cells 2017; 36:103-113. [PMID: 28960647 DOI: 10.1002/stem.2710] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 08/25/2017] [Accepted: 09/13/2017] [Indexed: 12/15/2022]
Abstract
Liver progenitor cells have the potential to repair and regenerate a diseased liver. The success of any translational efforts, however, hinges on thorough understanding of the fate of these cells after transplant, especially in terms of long-term safety and efficacy. Here, we report transplantation of a liver progenitor population isolated from human fetal livers into immune-permissive mice with follow-up up to 36 weeks after transplant. We found that human progenitor cells engraft and differentiate into functional human hepatocytes in the mouse, producing albumin, alpha-1-antitrypsin, and glycogen. They create tight junctions with mouse hepatocytes, with no evidence of cell fusion. Interestingly, they also differentiate into functional endothelial cell and bile duct cells. Transplantation of progenitor cells abrogated carbon tetrachloride-induced fibrosis in recipient mice, with downregulation of procollagen and anti-smooth muscle actin. Paradoxically, the degree of engraftment of human hepatocytes correlated negatively with the anti-fibrotic effect. Progenitor cell expansion was most prominent in cirrhotic animals, and correlated with transcript levels of pro-fibrotic genes. Animals that had resolution of fibrosis had quiescent native progenitor cells in their livers. No evidence of neoplasia was observed, even up to 9 months after transplantation. Human fetal liver progenitor cells successfully attenuate liver fibrosis in mice. They are activated in the setting of liver injury, but become quiescent when injury resolves, mimicking the behavior of de novo progenitor cells. Our data suggest that liver progenitor cells transplanted into injured livers maintain a functional role in the repair and regeneration of the liver. Stem Cells 2018;36:103-113.
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Affiliation(s)
| | - Mark Muthiah
- Department of Medicine, National University Singapore, Singapore.,Division of Gastroenterology and Hepatology, National University Hospital. National University Health System, Singapore
| | - Lei Zhou
- Department of Medicine, National University Singapore, Singapore
| | - Hau Hung
- Department of Medicine, National University Singapore, Singapore
| | | | - Jamil Haque
- Department of Pathology, University of Washington, Seattle, Washington, USA
| | - Narcissus Teoh
- Department of Medicine, Australian National University, Canberra, Australia
| | - Geoffrey Farrell
- Department of Medicine, Australian National University, Canberra, Australia
| | - Kimberly J Riehle
- Department of Pathology, University of Washington, Seattle, Washington, USA.,Department of Surgery, University of Washington, Seattle, Washington, USA
| | - Jaymie Siqi Lin
- Department of Medicine, National University Singapore, Singapore
| | - Lin Lin Su
- Department of Obstetrics and Gynecology, National University Singapore, Singapore
| | - Jerry Ky Chan
- Department of Obstetrics and Gynecology, National University Singapore, Singapore.,Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore
| | - Mahesh Choolani
- Department of Obstetrics and Gynecology, National University Singapore, Singapore
| | - Peng Cheang Wong
- Department of Obstetrics and Gynecology, National University Singapore, Singapore
| | - Aileen Wee
- Department of Pathology, National University Singapore, Singapore
| | - Seng Gee Lim
- Department of Medicine, National University Singapore, Singapore.,Division of Gastroenterology and Hepatology, National University Hospital. National University Health System, Singapore
| | - Jean Campbell
- Clinical Research Divison, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Nelson Fausto
- Department of Pathology, University of Washington, Seattle, Washington, USA
| | - Yock Young Dan
- Department of Medicine, National University Singapore, Singapore.,Division of Gastroenterology and Hepatology, National University Hospital. National University Health System, Singapore.,Cancer Science Institute, National University Singapore, Singapore.,Genome Institute Singapore, ASTAR, Singapore
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49
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Zhong HH, Hu SJ, Yu B, Jiang SS, Zhang J, Luo D, Yang MW, Su WY, Shao YL, Deng HL, Hong FF, Yang SL. Apoptosis in the aging liver. Oncotarget 2017; 8:102640-102652. [PMID: 29254277 PMCID: PMC5731987 DOI: 10.18632/oncotarget.21123] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 08/15/2017] [Indexed: 12/11/2022] Open
Abstract
Various changes in the liver during aging can reduce hepatic function and promote liver injury. Aging is associated with high morbidity and a poor prognosis in patients with various liver diseases, including nonalcoholic fatty liver disease, hepatitis C and liver cancer, as well as with surgeries such as partial hepatectomy and liver transplantation. In addition, apoptosis increases with liver aging. Because apoptosis is involved in regeneration, fibrosis and cancer prevention during liver aging, and restoration of the appropriate level of apoptosis can alleviate the adverse effects of liver aging, it is important to understand the mechanisms underlying this process. Herein, we elaborate on the causes of apoptosis during liver aging, with a focus on oxidative stress, genomic instability, lipotoxicity, endoplasmic reticulum stress, dysregulation of nutrient sensing, and liver stem/progenitor cell activity.
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Affiliation(s)
- Hua-Hua Zhong
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Shao-Jie Hu
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Bo Yu
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Sha-Sha Jiang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Jin Zhang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Dan Luo
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Mei-Wen Yang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Wan-Ying Su
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Ya-Lan Shao
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Hao-Lin Deng
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Fen-Fang Hong
- Department of Experimental Teaching Center, Nanchang University, Nanchang 330031, China
| | - Shu-Long Yang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
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50
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Kucinski I, Dinan M, Kolahgar G, Piddini E. Chronic activation of JNK JAK/STAT and oxidative stress signalling causes the loser cell status. Nat Commun 2017; 8:136. [PMID: 28743877 PMCID: PMC5526992 DOI: 10.1038/s41467-017-00145-y] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 06/02/2017] [Indexed: 01/27/2023] Open
Abstract
Cell competition is a form of cell interaction that causes the elimination of less fit cells, or losers, by wild-type (WT) cells, influencing overall tissue health. Several mutations can cause cells to become losers; however, it is not known how. Here we show that Drosophila wing disc cells carrying functionally unrelated loser mutations (Minute and mahjong) display the common activation of multiple stress signalling pathways before cell competition and find that these pathways collectively account for the loser status. We find that JNK signalling inhibits the growth of losers, while JAK/STAT signalling promotes competition-induced winner cell proliferation. Furthermore, we show that losers display oxidative stress response activation and, strikingly, that activation of this pathway alone, by Nrf2 overexpression, is sufficient to prime cells for their elimination by WT neighbours. Since oxidative stress and Nrf2 are linked to several diseases, cell competition may occur in a number of pathological conditions.Cell competition causes the removal of less fit cells ('losers') but why some gene mutations turn cells into losers is unclear. Here, the authors show that Drosophila wing disc cells carrying some loser mutations activate Nrf2 and JNK signalling, which contribute to the loser status.
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Affiliation(s)
- Iwo Kucinski
- The Wellcome Trust/Cancer Research UK Gurdon Institute and Zoology Department, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK
- Wellcome Trust and MRC Cambridge Stem Cell Institute, Department of Haematology and Cambridge Institute of Medical Research, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK
| | - Michael Dinan
- The Wellcome Trust/Cancer Research UK Gurdon Institute and Zoology Department, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK
| | - Golnar Kolahgar
- The Wellcome Trust/Cancer Research UK Gurdon Institute and Zoology Department, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK
| | - Eugenia Piddini
- The Wellcome Trust/Cancer Research UK Gurdon Institute and Zoology Department, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
- School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, BS8 1TD, UK.
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