Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells.

doi:10.1053/J.GASTRO.2011.06.049

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Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells.

Journal Article•DOI•

Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells.

Rodolphe Carpentier¹, Regina Espanol Suner¹, Noémi Van Hul¹, Janel L. Kopp², Jean Bernard Beaudry¹, Sabine Cordi¹, Aline Antoniou¹, Peggy Raynaud¹, Sébastien Lepreux³, Patrick Jacquemin¹, Isabelle Leclercq¹, Maike Sander², Frédéric P. Lemaigre¹ - Show less +9 more•Institutions (3)

Université catholique de Louvain¹, University of California, San Diego², Université Bordeaux Segalen³

01 Oct 2011-Gastroenterology (Elsevier)-Vol. 141, Iss: 4, pp 1432-1438

TL;DR: It was found that liver homeostasis required a continuous supply of cells from SOX9-expressing progenitors, and cells that express the SRY-related HMG box transcription factor 9 (SOX9) were proposed to continuously supply the liver with hepatic cells.

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About: This article is published in Gastroenterology.The article was published on 2011-10-01 and is currently open access. It has received 245 citations till now. The article focuses on the topics: Canals of Hering & Intrahepatic bile ducts.

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Journal Article•DOI•

Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming.

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Atsushi Miyajima¹, Minoru Tanaka¹, Tohru Itoh¹•Institutions (1)

University of Tokyo¹

01 May 2014-Cell Stem Cell

TL;DR: Evidence supporting and refuting whether self-renewable and bipotential liver stem cells exist in development, homeostasis, regeneration, and disease is discussed.

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452 citations

Journal Article•DOI•

Modeling mouse and human development using organoid cultures.

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Meritxell Huch¹, Bon-Kyoung Koo¹•Institutions (1)

University of Cambridge¹

15 Sep 2015-Development

TL;DR: Recent advances in the generation of pluripotent stem cell- and AdSC-derived organoids are discussed, highlighting their potential for enhancing the understanding of human development and how this new culture system allows disease modeling and gene repair for a personalized regenerative medicine approach.

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Abstract: In vitro three-dimensional (3D) cultures are emerging as novel systems with which to study tissue development, organogenesis and stem cell behavior ex vivo. When grown in a 3D environment, embryonic stem cells (ESCs) self-organize into organoids and acquire the right tissue patterning to develop into several endoderm- and ectoderm-derived tissues, mimicking their in vivo counterparts. Tissue-resident adult stem cells (AdSCs) also form organoids when grown in 3D and can be propagated in vitro for long periods of time. In this Review, we discuss recent advances in the generation of pluripotent stem cell- and AdSC-derived organoids, highlighting their potential for enhancing our understanding of human development. We will also explore how this new culture system allows disease modeling and gene repair for a personalized regenerative medicine approach.

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384 citations

Cites background from "Embryonic ductal plate cells give r..."

...Indeed, extensive lineage tracing approaches indicate that the contribution of progenitor cells to the normal homeostasis is negligible, at least in mouse models (Carpentier et al., 2011; Schaub et al., 2014; Tarlow et al., 2014; Yanger et al., 2014)....
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Journal Article•DOI•

Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer.

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Joan Font-Burgada¹, Shabnam Shalapour¹, Suvasini Ramaswamy², Brian Hsueh³, David Rossell⁴, Atsushi Umemura¹, Koji Taniguchi¹, Hayato Nakagawa¹, Mark A. Valasek¹, Li Ye³, Janel L. Kopp¹, Maike Sander¹, Hannah Carter¹, Karl Deisseroth³, Inder M. Verma², Michael Karin¹ - Show less +12 more•Institutions (4)

University of California, San Diego¹, Salk Institute for Biological Studies², Howard Hughes Medical Institute³, University of Warwick⁴

13 Aug 2015-Cell

TL;DR: A pre-existing population of periportal hepatocytes, located in the portal triads of healthy livers and expressing low amounts of Sox9 and other bile-duct-enriched genes, undergo extensive proliferation and replenish liver mass after chronic hepatocyte-depleting injuries and represent a unique way to restore tissue function and avoid tumorigenesis.

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384 citations

Cites background from "Embryonic ductal plate cells give r..."

...and tubule formation, suggesting that HybHP and BD may originate from a common embryonic progenitor located at the ductal plate (Carpentier et al., 2011)....
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...See also Figure S7. and tubule formation, suggesting that HybHP and BD may originate from a common embryonic progenitor located at the ductal plate (Carpentier et al., 2011)....
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...…estimated efficiency of 51.4% (Figure 1F; 4,968 YFP+ hepatocytes out of 217,975 hepatocytes, n = 3), mirroring what was observed with the Sox9-GFP transgene (Figures 1A–1C) and inconsistent with the SOX9 expression pattern of wild-type (WT) mice given high tamoxifen doses (Carpentier et al., 2011)....
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...4% (Figure 1F; 4,968 YFP hepatocytes out of 217,975 hepatocytes, n = 3), mirroring what was observed with the Sox9-GFP transgene (Figures 1A–1C) and inconsistent with the SOX9 expression pattern of wild-type (WT) mice given high tamoxifen doses (Carpentier et al., 2011)....
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Journal Article•DOI•

Adult Hepatocytes Are Generated by Self-Duplication Rather than Stem Cell Differentiation

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Kilangsungla Yanger¹, David Knigin², Yiwei Zong¹, Lara R. Maggs¹, Guoqiang Gu³, Haruhiko Akiyama⁴, Eli Pikarsky², Ben Z. Stanger¹ - Show less +4 more•Institutions (4)

University of Pennsylvania¹, Hebrew University of Jerusalem², Vanderbilt University Medical Center³, Gifu University⁴

04 Sep 2014-Cell Stem Cell

TL;DR: It is reported that, contrary to prevailing stem-cell-based models of regeneration, virtually all new hepatocytes come from preexisting hepatocytes.

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360 citations

Cites methods or result from "Embryonic ductal plate cells give r..."

...A choline-deficient diet (MP Biomedicals) supplemented with 0.15% ethionine drinking water (Sigma-Aldrich, E5139) was administered for 2 weeks as described elsewhere (Carpentier et al., 2011), followed by 2 weeks of recovery....
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...Indeed, when we tested the specificity of the same Sox9-CreER strain used by Furuyama and colleagues (Soeda et al., 2010) with a R26YFP reporter, we found that this strain confers substantial hepatocyte labeling (Figure S4)....
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...As a ‘‘terminal’’ biliary marker, Krt19 appears to be an exception to this specificity problem; in contrast to Sox9 and OPN, Krt19 is not expressed by hepatocytes on injury, and hepatocytes become Krt19+ only after prolonged toxin exposure as part of a hepatocyte-to-BEC reprogramming process (Yanger et al., 2013)....
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...Considering that Krt19 staining overlaps completely with staining for these BEC markers (353/353 Sox9+ cells, n = 3; 352/ 352 OPN+ cells, n = 3; and 349/349 HNF1b+ cells, n = 2), these results suggest that tamoxifen treatment of Krt19-CreER/ R26YFP mice results in specific labeling of BECs, including the putative progenitor cells that reside within the Canals of Hering....
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...This analysis showed that colabeling occurred with a similar efficiency to that observed with Krt19, as 39.5% of Sox9+ cells (n = 3), 31.6% of osteopontin+ (Opn+) cells (n = 3), and 40.8% of HNF1b+ cells (n = 3) were labeled (Figure 1C)....
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Journal Article•DOI•

Liver regeneration: biological and pathological mechanisms and implications

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George K. Michalopoulos¹, Bharat Bhushan¹•Institutions (1)

University of Pittsburgh¹

01 Jan 2021-Nature Reviews Gastroenterology & Hepatology

TL;DR: The regenerative mechanisms employed by hepatic cells after liver injury as well as the experimental models used to investigate these mechanisms are described and the clinical implications are discussed.

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Abstract: The liver is the only solid organ that uses regenerative mechanisms to ensure that the liver-to-bodyweight ratio is always at 100% of what is required for body homeostasis. Other solid organs (such as the lungs, kidneys and pancreas) adjust to tissue loss but do not return to 100% of normal. The current state of knowledge of the regenerative pathways that underlie this ‘hepatostat’ will be presented in this Review. Liver regeneration from acute injury is always beneficial and has been extensively studied. Experimental models that involve partial hepatectomy or chemical injury have revealed extracellular and intracellular signalling pathways that are used to return the liver to equivalent size and weight to those prior to injury. On the other hand, chronic loss of hepatocytes, which can occur in chronic liver disease of any aetiology, often has adverse consequences, including fibrosis, cirrhosis and liver neoplasia. The regenerative activities of hepatocytes and cholangiocytes are typically characterized by phenotypic fidelity. However, when regeneration of one of the two cell types fails, hepatocytes and cholangiocytes function as facultative stem cells and transdifferentiate into each other to restore normal liver structure. Liver recolonization models have demonstrated that hepatocytes have an unlimited regenerative capacity. However, in normal liver, cell turnover is very slow. All zones of the resting liver lobules have been equally implicated in the maintenance of hepatocyte and cholangiocyte populations in normal liver. The liver has a broad range of regenerative capacities. In this Review, Michalopoulos and Bhushan describe the regenerative mechanisms employed by hepatic cells after liver injury as well as the experimental models used to investigate these mechanisms and discuss the clinical implications.

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331 citations

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References

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Open Access

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Journal Article•DOI•

Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus

[...]

Shankar Srinivas¹, Tomoko Watanabe¹, Chyuan-Sheng Lin¹, Chris M William², Yasuto Tanabe², Thomas M. Jessell², Frank Costantini¹ - Show less +3 more•Institutions (2)

Columbia University¹, Howard Hughes Medical Institute²

27 Mar 2001-BMC Developmental Biology

TL;DR: In contrast to existing lacZ reporter lines, where lacZ expression cannot easily be detected in living tissue, the EYFP and ECFP reporter strains are useful for monitoring the expression of Cre and tracing the lineage of these cells and their descendants in cultured embryos or organs.

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Abstract: Background Several Cre reporter strains of mice have been described, in which a lacZ gene is turned on in cells expressing Cre recombinase, as well as their daughter cells, following Cre-mediated excision of a loxP-flanked transcriptional "stop" sequence. These mice are useful for cell lineage tracing experiments as well as for monitoring the expression of Cre transgenes. The green fluorescent protein (GFP) and variants such as EYFP and ECFP offer an advantage over lacZ as a reporter, in that they can be easily visualized without recourse to the vital substrates required to visualize β-gal in living tissue.

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2,941 citations

Journal Article•DOI•

Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine

[...]

Kenichiro Furuyama¹, Yoshiya Kawaguchi¹, Haruhiko Akiyama¹, Masashi Horiguchi¹, S. Kodama¹, T. Kuhara¹, Shinichi Hosokawa¹, Ashraf Elbahrawy¹, Tsunemitsu Soeda¹, Masayuki Koizumi¹, Toshihiko Masui¹, Michiya Kawaguchi¹, Kyoichi Takaori¹, Ryuichiro Doi¹, Eiichiro Nishi¹, Ryosuke Kakinoki¹, Jian Min Deng², Richard R. Behringer, Takashi Nakamura¹, Shinji Uemoto¹ - Show less +16 more•Institutions (2)

Kyoto University¹, University of Texas MD Anderson Cancer Center²

01 Jan 2011-Nature Genetics

TL;DR: It is shown that Sox9 is expressed throughout the biliary and pancreatic ductal epithelia, which are connected to the intestinal stem-cell zone, which suggests interdependence between the structure and homeostasis of endodermal organs, with Sox9 expression being linked to progenitor status.

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Abstract: The liver and exocrine pancreas share a common structure, with functioning units (hepatic plates and pancreatic acini) connected to the ductal tree. Here we show that Sox9 is expressed throughout the biliary and pancreatic ductal epithelia, which are connected to the intestinal stem-cell zone. Cre-based lineage tracing showed that adult intestinal cells, hepatocytes and pancreatic acinar cells are supplied physiologically from Sox9-expressing progenitors. Combination of lineage analysis and hepatic injury experiments showed involvement of Sox9-positive precursors in liver regeneration. Embryonic pancreatic Sox9-expressing cells differentiate into all types of mature cells, but their capacity for endocrine differentiation diminishes shortly after birth, when endocrine cells detach from the epithelial lining of the ducts and form the islets of Langerhans. We observed a developmental switch in the hepatic progenitor cell type from Sox9-negative to Sox9-positive progenitors as the biliary tree develops. These results suggest interdependence between the structure and homeostasis of endodermal organs, with Sox9 expression being linked to progenitor status.

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772 citations

Journal Article•DOI•

Organogenesis and development of the liver.

[...]

Karim Si-Tayeb¹, Frédéric P. Lemaigre², Stephen A. Duncan¹, Stephen A. Duncan²•Institutions (2)

Medical College of Wisconsin¹, Université catholique de Louvain²

16 Feb 2010-Developmental Cell

TL;DR: The basic molecular mechanisms that control the formation of the liver as an organ are reviewed.

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683 citations

Journal Article•DOI•

Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers.

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Tania Roskams¹, Neil D. Theise², Charles Balabaud³, Govind Bhagat⁴, Prithi S. Bhathal⁵, Paulette Bioulac-Sage³, Elizabeth M. Brunt⁶, James M. Crawford⁷, Heather A. Crosby⁸, Valeer Desmet¹, Milton J. Finegold⁹, Stephen A. Geller¹⁰, Annette S. H. Gouw¹¹, Prodromos Hytiroglou, A. S. Knisely¹², Masamichi Kojiro¹³, Jay H. Lefkowitch⁴, Yasuni Nakanuma¹⁴, John K. Olynyk¹⁵, Young Nyun Park¹⁶, Bernard Portmann¹², Romil Saxena¹⁷, Peter J. Scheuer¹⁸, Alastair J. Strain⁸, Swan N. Thung¹⁹, Ian R. Wanless²⁰, A. Brian West²¹ - Show less +23 more•Institutions (21)

Katholieke Universiteit Leuven¹, Beth Israel Medical Center², French Institute of Health and Medical Research³, Columbia University⁴, University of Melbourne⁵, Saint Louis University⁶, University of Florida⁷, University of Birmingham⁸, Boston Children's Hospital⁹, Cedars-Sinai Medical Center¹⁰, University of Groningen¹¹, University of Cambridge¹², Kurume University¹³, Kanazawa University¹⁴, University of Western Australia¹⁵, Yonsei University¹⁶, Indiana University¹⁷, Royal Free Hospital¹⁸, Icahn School of Medicine at Mount Sinai¹⁹, Toronto General Hospital²⁰, New York University²¹

01 Jun 2004-Hepatology

TL;DR: This international group of liver pathologists and hepatologists seeks to arrive at a consensus on nomenclature for normal human livers and human reactive lesions that can facilitate more rapid advancement of the field.

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642 citations

Journal Article•DOI•

Human hepatic stem cells from fetal and postnatal donors

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Eva Schmelzer¹, Lili Zhang, Andrew Bruce², Eliane Wauthier, John W. Ludlow², Hsin-lei Yao, Nicholas G. Moss, Alaa Melhem, Randall McClelland, William S. Turner, Michael Kulik², Sonya Sherwood², Tommi Tallheden, Nancy Cheng, Mark E. Furth³, Lola M. Reid¹ - Show less +12 more•Institutions (3)

University of North Carolina at Chapel Hill¹, Durham University², Wake Forest Baptist Medical Center³

06 Aug 2007-Journal of Experimental Medicine

TL;DR: The self-renewal capacity of hHpSCs is indicated by phenotypic stability after expansion for >150 population doublings in a serum-free, defined medium and with a doubling time of ∼36 h, and they are candidates for liver cell therapies.

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Abstract: Human hepatic stem cells (hHpSCs), which are pluripotent precursors of hepatoblasts and thence of hepatocytic and biliary epithelia, are located in ductal plates in fetal livers and in Canals of Hering in adult livers. They can be isolated by immunoselection for epithelial cell adhesion molecule–positive (EpCAM+) cells, and they constitute ∼0.5–2.5% of liver parenchyma of all donor ages. The self-renewal capacity of hHpSCs is indicated by phenotypic stability after expansion for >150 population doublings in a serum-free, defined medium and with a doubling time of ∼36 h. Survival and proliferation of hHpSCs require paracrine signaling by hepatic stellate cells and/or angioblasts that coisolate with them. The hHpSCs are ∼9 μm in diameter, express cytokeratins 8, 18, and 19, CD133/1, telomerase, CD44H, claudin 3, and albumin (weakly). They are negative for α-fetoprotein (AFP), intercellular adhesion molecule (ICAM) 1, and for markers of adult liver cells (cytochrome P450s), hemopoietic cells (CD45), and mesenchymal cells (vascular endothelial growth factor receptor and desmin). If transferred to STO feeders, hHpSCs give rise to hepatoblasts, which are recognizable by cordlike colony morphology and up-regulation of AFP, P4503A7, and ICAM1. Transplantation of freshly isolated EpCAM+ cells or of hHpSCs expanded in culture into NOD/SCID mice results in mature liver tissue expressing human-specific proteins. The hHpSCs are candidates for liver cell therapies.

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573 citations