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• W2068511028 abstract "The liver is a central organ for homeostasis with unique regenerative capacities. Mature hepatocytes possess a remarkable capacity to proliferate upon injury, challenging efforts to discern the role of adult liver stem cells in this process. In contrast, stem/progenitor cells in the developing liver have been extensively characterized, and these investigations have informed efforts to produce functional hepatocytes in vitro for cell therapy and drug screening. In this Review, we describe recent advances in the characterization of liver stem cells and discuss evidence supporting and refuting whether self-renewable and bipotential liver stem cells exist in development, homeostasis, regeneration, and disease. The liver is a central organ for homeostasis with unique regenerative capacities. Mature hepatocytes possess a remarkable capacity to proliferate upon injury, challenging efforts to discern the role of adult liver stem cells in this process. In contrast, stem/progenitor cells in the developing liver have been extensively characterized, and these investigations have informed efforts to produce functional hepatocytes in vitro for cell therapy and drug screening. In this Review, we describe recent advances in the characterization of liver stem cells and discuss evidence supporting and refuting whether self-renewable and bipotential liver stem cells exist in development, homeostasis, regeneration, and disease. Stem cells are defined, in general, by their ability to self-renew and differentiate into multiple lineages. Functionally, stem cell activity can be defined by several methods. Clonogenicity and multilineage differentiation in vitro are classical and convenient assays to demonstrate stemness and have been widely used to assess stem cell activity in various tissues. Genetic lineage tracing and long-term label-retaining assays have been used to identify and characterize stem cells in vivo. These assays have allowed extensive characterization of several tissue-specific stem cells, including intestinal stem cells, dermal stem cells, and hair follicle stem cells (Barker et al., 2012Barker N. van Oudenaarden A. Clevers H. Identifying the stem cell of the intestinal crypt: strategies and pitfalls.Cell Stem Cell. 2012; 11: 452-460Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, Blanpain and Fuchs, 2009Blanpain C. Fuchs E. Epidermal homeostasis: a balancing act of stem cells in the skin.Nat. Rev. Mol. Cell Biol. 2009; 10: 207-217Crossref PubMed Scopus (369) Google Scholar, Fuchs, 2009Fuchs E. The tortoise and the hair: slow-cycling cells in the stem cell race.Cell. 2009; 137: 811-819Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar). Alternatively, long-term repopulation upon transplantation of a single sorted cell has been long regarded as the gold standard of stem cell activity in the hematopoietic compartment (Oguro et al., 2013Oguro H. Ding L. Morrison S.J. SLAM family markers resolve functionally distinct subpopulations of hematopoietic stem cells and multipotent progenitors.Cell Stem Cell. 2013; 13: 102-116Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, Smith et al., 1991Smith L.G. Weissman I.L. Heimfeld S. Clonal analysis of hematopoietic stem-cell differentiation in vivo.Proc. Natl. Acad. Sci. USA. 1991; 88: 2788-2792Crossref PubMed Google Scholar). The stem cell for the liver has been defined as the cell that gives rise to both hepatocytes and biliary epithelial cells (cholangiocytes), the two types of liver epithelial cells. Although there are many reports describing liver stem cells, the measures used to define liver stem cells have not necessarily been adequate in many cases. In this Review, we describe the defining characteristics used to describe liver stem cells and discuss the evidence supporting and refuting whether self-renewable and bipotential liver stem cells exist in development, homeostasis, and regeneration. The liver is a central organ for homeostasis and carries out a wide range of functions, including metabolism, glycogen storage, drug detoxification, production of various serum proteins, and bile secretion. Since liver functions are essential for homeostasis, liver diseases, such as hepatitis, fibrosis, and cirrhosis, often result in morbidity and mortality. The liver is unique in its extraordinary capacity to regenerate from various injuries. Strikingly, the liver’s ability to recover its original mass after surgical removal of a significant portion makes it possible to transplant liver tissue from a living donor. The basic architectural unit of the liver is the liver lobule, which is described in detail in Figure 1. Most of the metabolic and synthetic functions of the liver are carried out by hepatocytes, which account for approximately 60% of total liver cells and 80% of the volume of the organ. Hepatocytes are highly polarized epithelial cells and form cords. Their basolateral surfaces face fenestrated sinusoidal endothelial cells, facilitating the exchange of materials between hepatocytes and blood vessels. Tight junctions formed between hepatocytes create a canaliculus that surrounds each hepatocyte. Bile secreted from mature hepatocytes is exported sequentially through bile canaliculi surrounded by the apical membrane of neighboring hepatocytes, intrahepatic bile ducts, extrahepatic bile ducts, and, finally, the duodenum. The bile duct is formed by a specialized type of epithelial cell called a cholangiocyte. The onset of mouse liver development begins at embryonic day (E) 8.5 from the foregut endoderm, which is derived from medial and lateral domains of developing ventral foregut (Tremblay and Zaret, 2005Tremblay K.D. Zaret K.S. Distinct populations of endoderm cells converge to generate the embryonic liver bud and ventral foregut tissues.Dev. Biol. 2005; 280: 87-99Crossref PubMed Scopus (123) Google Scholar). The commitment of endoderm cells to the liver is dictated by two crucial cytokines: fibroblast growth factor (FGF) from the developing heart (Gualdi et al., 1996Gualdi R. Bossard P. Zheng M. Hamada Y. Coleman J.R. Zaret K.S. Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control.Genes Dev. 1996; 10: 1670-1682Crossref PubMed Google Scholar, Jung et al., 1999Jung J. Zheng M. Goldfarb M. Zaret K.S. Initiation of mammalian liver development from endoderm by fibroblast growth factors.Science. 1999; 284: 1998-2003Crossref PubMed Scopus (462) Google Scholar) and bone morphogenetic protein (BMP) from the septum transversum mesenchyme (STM) (Rossi et al., 2001Rossi J.M. Dunn N.R. Hogan B.L. Zaret K.S. Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm.Genes Dev. 2001; 15: 1998-2009Crossref PubMed Scopus (347) Google Scholar). The foregut endoderm cells destined for hepatic fate begin to express transcription factors Hex and HNF4α as well as the liver-specific genes α-fetoprotein (AFP) and albumin (ALB) and migrate as cords into the surrounding STM. These cells are common progenitor cells, which give rise to both hepatocytes and cholangiocytes, and are called “hepatoblasts” during liver development. Historically, immunohistochemical analysis had been used to characterize hepatoblasts; however, specific cell surface markers for prospective isolation of hepatoblasts were not identified until more recently. Because the fetal liver is a major hematopoietic organ and blood cells occupy the majority of liver cells, a combination of negative selection by CD45 (common leukocyte antigen) and TER119 (erythroid cell antigen) and positive selection by some cell surface markers has been utilized to successfully isolate hepatoblasts. In many cases, the sorted cells from fetal liver were evaluated by the expression of liver-specific genes such as AFP and ALB, clonogenicity and bipotency in vitro, and their ability to repopulate adult liver upon transplantation. Suzuki et al., 2000Suzuki A. Zheng Y. Kondo R. Kusakabe M. Takada Y. Fukao K. Nakauchi H. Taniguchi H. Flow-cytometric separation and enrichment of hepatic progenitor cells in the developing mouse liver.Hepatology. 2000; 32: 1230-1239Crossref PubMed Google Scholar developed a single-cell-based assay called the hepatic colony-forming unit in culture (H-CFU-C) and showed that the CD45– TER119– c-Kit– CD29+ CD49f+ fraction of E13.5 mouse liver contained colony-forming cells with the potential to differentiate into hepatocytic and cholangiocytic lineages. Since then, sorting for c-Kitlow (Minguet et al., 2003Minguet S. Cortegano I. Gonzalo P. Martínez-Marin J.A. de Andrés B. Salas C. Melero D. Gaspar M.L. Marcos M.A. A population of c-Kit(low)(CD45/TER119)- hepatic cell progenitors of 11-day postcoitus mouse embryo liver reconstitutes cell-depleted liver organoids.J. Clin. Invest. 2003; 112: 1152-1163Crossref PubMed Google Scholar), c-Kit– c-Met+ CD49f+/low (Suzuki et al., 2003Suzuki A. Iwama A. Miyashita H. Nakauchi H. Taniguchi H. Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells.Development. 2003; 130: 2513-2524Crossref PubMed Scopus (114) Google Scholar), CD13+ (Kakinuma et al., 2009Kakinuma S. Ohta H. Kamiya A. Yamazaki Y. Oikawa T. Okada K. Nakauchi H. Analyses of cell surface molecules on hepatic stem/progenitor cells in mouse fetal liver.J. Hepatol. 2009; 51: 127-138Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar), or CD13+ c-Kit– CD49f−/low CD133+ (Kamiya et al., 2009Kamiya A. Kakinuma S. Yamazaki Y. Nakauchi H. Enrichment and clonal culture of progenitor cells during mouse postnatal liver development in mice.Gastroenterology. 2009; 137 (e1–e14): 1114-1126Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar) in combination with CD45− and TER119− has been applied to isolate the hepatoblast compartment. Alternatively, positive selection with a single specific marker has also been reported to isolate hepatoblasts. Delta-like 1 homolog (Dlk1), also known as Pref-1, is expressed in liver buds as early as E9.0 in mouse embryo and can also be used to isolate bipotential cells. Dlk1 expression is gradually decreased in the liver by the neonatal stage and becomes undetectable in adult liver. Dlk1+ cells isolated from E14.5 livers form highly proliferative colonies composed of the hepatocyte and cholangiocyte lineages in vitro (Tanimizu et al., 2003Tanimizu N. Nishikawa M. Saito H. Tsujimura T. Miyajima A. Isolation of hepatoblasts based on the expression of Dlk/Pref-1.J. Cell Sci. 2003; 116: 1775-1786Crossref PubMed Scopus (186) Google Scholar). E-cadherin, an epithelial-specific marker, was also utilized to isolate hepatoblasts (Nitou et al., 2002Nitou M. Sugiyama Y. Ishikawa K. Shiojiri N. Purification of fetal mouse hepatoblasts by magnetic beads coated with monoclonal anti-e-cadherin antibodies and their in vitro culture.Exp. Cell Res. 2002; 279: 330-343Crossref PubMed Scopus (63) Google Scholar, Nierhoff et al., 2005Nierhoff D. Ogawa A. Oertel M. Chen Y.Q. Shafritz D.A. Purification and characterization of mouse fetal liver epithelial cells with high in vivo repopulation capacity.Hepatology. 2005; 42: 130-139Crossref PubMed Scopus (72) Google Scholar). E12.5 liver epithelial cells were shown to specifically express E-cadherin, Dlk1, and Liv2, a unique marker for epithelial cells in the E9.5–E12.5 fetal liver (Watanabe et al., 2002Watanabe T. Nakagawa K. Ohata S. Kitagawa D. Nishitai G. Seo J. Tanemura S. Shimizu N. Kishimoto H. Wada T. et al.SEK1/MKK4-mediated SAPK/JNK signaling participates in embryonic hepatoblast proliferation via a pathway different from NF-kappaB-induced anti-apoptosis.Dev. Biol. 2002; 250: 332-347Crossref PubMed Google Scholar), and sorted E-cadherin+ cells repopulated the liver after transplantation. Nierhoff et al., 2007Nierhoff D. Levoci L. Schulte S. Goeser T. Rogler L.E. Shafritz D.A. New cell surface markers for murine fetal hepatic stem cells identified through high density complementary DNA microarrays.Hepatology. 2007; 46: 535-547Crossref PubMed Scopus (24) Google Scholar also identified additional markers, CD24a and Neighbor of Punc E11 (Nope), to isolate hepatoblasts by comparing the gene expression profiles of purified E13.5 E-cadherin+ liver cells and adult liver. Epithelial cell adhesion molecule (EpCAM) was expressed in HNF4α+ hepatoblasts of liver buds as early as E9.5 in mice. The EpCAM+ Dlk1+ cell population sorted from E11.5 liver contained in vitro colony-forming cells, indicating that hepatoblasts are present in this population at this early stage of liver development (Tanaka et al., 2009Tanaka M. Okabe M. Suzuki K. Kamiya Y. Tsukahara Y. Saito S. Miyajima A. Mouse hepatoblasts at distinct developmental stages are characterized by expression of EpCAM and DLK1: drastic change of EpCAM expression during liver development.Mech. Dev. 2009; 126: 665-676Crossref PubMed Scopus (36) Google Scholar) (Figure 2). However, clonogenic mouse hepatic cells were found in EpCAM– Dlk1+ cells at E13.5, suggesting that hepatoblasts likely change their characteristics during the course of liver development. Alternatively, fate mapping by dye labeling revealed that there are distinct endodermal regions that give rise to hepatoblasts (Tremblay and Zaret, 2005Tremblay K.D. Zaret K.S. Distinct populations of endoderm cells converge to generate the embryonic liver bud and ventral foregut tissues.Dev. Biol. 2005; 280: 87-99Crossref PubMed Scopus (123) Google Scholar), thus it might be possible that regionally distinct hepatoblast descendants could have different properties. Gadue et al., 2009Gadue P. Gouon-Evans V. Cheng X. Wandzioch E. Zaret K.S. Grompe M. Streeter P.R. Keller G.M. Generation of monoclonal antibodies specific for cell surface molecules expressed on early mouse endoderm.Stem Cells. 2009; 27: 2103-2113Crossref PubMed Scopus (20) Google Scholar generated two monoclonal antibodies, ENDM1 and ENDM2, that show remarkable specificity for mouse foregut ventral endoderm. Interestingly, the endoderm population recognized by those antibodies has the potential to generate cells of the hepatic lineage, although these markers are downregulated by specification to the hepatic fate. These antibodies may be useful to further study the characteristics of endoderm progenitor cells (Xu et al., 2011Xu C.R. Cole P.A. Meyers D.J. Kormish J. Dent S. Zaret K.S. Chromatin “prepattern” and histone modifiers in a fate choice for liver and pancreas.Science. 2011; 332: 963-966Crossref PubMed Scopus (64) Google Scholar). The expression profile of representative cell surface markers during liver development is illustrated in Figure 2, and the characterization of hepatoblasts by prospective isolation is summarized in Table 1.Table 1Identification of Hepatoblasts by Cell Sorting Using Cell Surface MarkersSpeciesDevelopmental Stage Used for AssaysUsed Markers for Cell SortingAfp or Alb ExpressionClonogenicityBipotency in Clonogenic AnalysisRepopulating Activity In VivoReferencesMouseE13.5CD45−/TER119–/c-Kit–/CD29+/CD49f+++++(Suzuki et al., 2000Suzuki A. Zheng Y. Kondo R. Kusakabe M. Takada Y. Fukao K. Nakauchi H. Taniguchi H. Flow-cytometric separation and enrichment of hepatic progenitor cells in the developing mouse liver.Hepatology. 2000; 32: 1230-1239Crossref PubMed Google Scholar)E12.5E-cad++NThepatocyticNT(Nitou et al., 2002Nitou M. Sugiyama Y. Ishikawa K. Shiojiri N. Purification of fetal mouse hepatoblasts by magnetic beads coated with monoclonal anti-e-cadherin antibodies and their in vitro culture.Exp. Cell Res. 2002; 279: 330-343Crossref PubMed Scopus (63) Google Scholar)E11CD45–/TER119–/c-Kitlow+++chimeric fetal liver organoids(Minguet et al., 2003Minguet S. Cortegano I. Gonzalo P. Martínez-Marin J.A. de Andrés B. Salas C. Melero D. Gaspar M.L. Marcos M.A. A population of c-Kit(low)(CD45/TER119)- hepatic cell progenitors of 11-day postcoitus mouse embryo liver reconstitutes cell-depleted liver organoids.J. Clin. Invest. 2003; 112: 1152-1163Crossref PubMed Google Scholar)E14.5Dlk1+++++(Tanimizu et al., 2003Tanimizu N. Nishikawa M. Saito H. Tsujimura T. Miyajima A. Isolation of hepatoblasts based on the expression of Dlk/Pref-1.J. Cell Sci. 2003; 116: 1775-1786Crossref PubMed Scopus (186) Google Scholar)E13.5CD45–/TER119–/c-Kit–/c-Met+/CD49f+/low+++NT(Suzuki et al., 2003Suzuki A. Iwama A. Miyashita H. Nakauchi H. Taniguchi H. Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells.Development. 2003; 130: 2513-2524Crossref PubMed Scopus (114) Google Scholar)E12.5E-cad+, Liv2+++NT+(Nierhoff et al., 2005Nierhoff D. Ogawa A. Oertel M. Chen Y.Q. Shafritz D.A. Purification and characterization of mouse fetal liver epithelial cells with high in vivo repopulation capacity.Hepatology. 2005; 42: 130-139Crossref PubMed Scopus (72) Google Scholar)E13.5Nope+, CD24a++NTNTNT(Nierhoff et al., 2007Nierhoff D. Levoci L. Schulte S. Goeser T. Rogler L.E. Shafritz D.A. New cell surface markers for murine fetal hepatic stem cells identified through high density complementary DNA microarrays.Hepatology. 2007; 46: 535-547Crossref PubMed Scopus (24) Google Scholar)E11.5Epcam+/Dlk1+++NTNT(Tanaka et al., 2009Tanaka M. Okabe M. Suzuki K. Kamiya Y. Tsukahara Y. Saito S. Miyajima A. Mouse hepatoblasts at distinct developmental stages are characterized by expression of EpCAM and DLK1: drastic change of EpCAM expression during liver development.Mech. Dev. 2009; 126: 665-676Crossref PubMed Scopus (36) Google Scholar)E13.5CD45–/TER119–/CD13+++++(Kakinuma et al., 2009Kakinuma S. Ohta H. Kamiya A. Yamazaki Y. Oikawa T. Okada K. Nakauchi H. Analyses of cell surface molecules on hepatic stem/progenitor cells in mouse fetal liver.J. Hepatol. 2009; 51: 127-138Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar)E13.5CD45−/TER119−/c-Kit−/CD13+/CD49f−/low/CD133++++NT(Kamiya et al., 2009Kamiya A. Kakinuma S. Yamazaki Y. Nakauchi H. Enrichment and clonal culture of progenitor cells during mouse postnatal liver development in mice.Gastroenterology. 2009; 137 (e1–e14): 1114-1126Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar)RatE13RT1Al−OX18low/ICAM-1++++NT(Kubota and Reid, 2000Kubota H. Reid L.M. Clonogenic hepatoblasts, common precursors for hepatocytic and biliary lineages, are lacking classical major histocompatibility complex class I antigen.Proc. Natl. Acad. Sci. USA. 2000; 97: 12132-12137Crossref PubMed Scopus (158) Google Scholar)E16–E18(OX43/OX44)–/Thy-1++NTNTNT(Fiegel et al., 2003Fiegel H.C. Kluth J. Lioznov M.V. Holzhüter S. Fehse B. Zander A.R. Kluth D. Hepatic lineages isolated from developing rat liver show different ways of maturation.Biochem. Biophys. Res. Commun. 2003; 305: 46-53Crossref PubMed Scopus (20) Google Scholar)E14Dlk-1++NT++(Oertel et al., 2008Oertel M. Menthena A. Chen Y.Q. Teisner B. Jensen C.H. Shafritz D.A. Purification of fetal liver stem/progenitor cells containing all the repopulation potential for normal adult rat liver.Gastroenterology. 2008; 134: 823-832Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar)Human18–22 week gestation ageEpCAM+++++ (NOD/SCID mice)(Schmelzer et al., 2007Schmelzer E. Zhang L. Bruce A. Wauthier E. Ludlow J. Yao H.L. Moss N. Melhem A. McClelland R. Turner W. et al.Human hepatic stem cells from fetal and postnatal donors.J. Exp. Med. 2007; 204: 1973-1987Crossref PubMed Scopus (260) Google Scholar)NT, not tested. Open table in a new tab NT, not tested. Engraftment of in vitro expanded hepatoblasts in adult mouse liver injury models can be used to demonstrate some aspects of stem cell activity. However, unlike long-term repopulation of a single sorted hematopoietic stem cell, which demonstrates self-renewal and multidifferentiation potential in mice, engraftment of hepatoblasts requires a large number of cells, with more than 5 × 104 cells needed to engraft a single mouse or rat (Kakinuma et al., 2009Kakinuma S. Ohta H. Kamiya A. Yamazaki Y. Oikawa T. Okada K. Nakauchi H. Analyses of cell surface molecules on hepatic stem/progenitor cells in mouse fetal liver.J. Hepatol. 2009; 51: 127-138Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, Nierhoff et al., 2005Nierhoff D. Ogawa A. Oertel M. Chen Y.Q. Shafritz D.A. Purification and characterization of mouse fetal liver epithelial cells with high in vivo repopulation capacity.Hepatology. 2005; 42: 130-139Crossref PubMed Scopus (72) Google Scholar, Oertel et al., 2008Oertel M. Menthena A. Chen Y.Q. Teisner B. Jensen C.H. Shafritz D.A. Purification of fetal liver stem/progenitor cells containing all the repopulation potential for normal adult rat liver.Gastroenterology. 2008; 134: 823-832Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, Suzuki et al., 2000Suzuki A. Zheng Y. Kondo R. Kusakabe M. Takada Y. Fukao K. Nakauchi H. Taniguchi H. Flow-cytometric separation and enrichment of hepatic progenitor cells in the developing mouse liver.Hepatology. 2000; 32: 1230-1239Crossref PubMed Google Scholar, Tanimizu et al., 2003Tanimizu N. Nishikawa M. Saito H. Tsujimura T. Miyajima A. Isolation of hepatoblasts based on the expression of Dlk/Pref-1.J. Cell Sci. 2003; 116: 1775-1786Crossref PubMed Scopus (186) Google Scholar). In addition, engraftment of transplanted hepatoblasts to bile ducts has not necessarily been convincingly demonstrated, most likely because of the lack of an appropriate bile duct injury model to assess engraftment. Thus, transplantation studies using hepatoblasts do not provide sufficient evidence to fulfill the stringent criteria of “stemness” that is used for other stem cell types, such as hematopoietic stem cells. Several reports using culture systems have demonstrated the presence of a potential liver “stem cell” in the fetal liver, which has the capacity for unlimited proliferation and multilineage differentiation. Dlk1+ cells in mouse fetal liver contain clonogenic cells named “HPPL” that continuously proliferate on laminin-coated plates and differentiate to both hepatocytes and cholangiocytes under differentiation conditions (Tanimizu et al., 2004Tanimizu N. Saito H. Mostov K. Miyajima A. Long-term culture of hepatic progenitors derived from mouse Dlk+ hepatoblasts.J. Cell Sci. 2004; 117: 6425-6434Crossref PubMed Scopus (44) Google Scholar). Similar bipotential cell lines exhibiting the properties of liver stem cells were also obtained after a long latency period in culture of fetal liver cells, though their specific cellular origin was unknown (Strick-Marchand and Weiss, 2002Strick-Marchand H. Weiss M.C. Inducible differentiation and morphogenesis of bipotential liver cell lines from wild-type mouse embryos.Hepatology. 2002; 36: 794-804Crossref PubMed Google Scholar, Tsuchiya et al., 2005Tsuchiya A. Heike T. Fujino H. Shiota M. Umeda K. Yoshimoto M. Matsuda Y. Ichida T. Aoyagi Y. Nakahata T. Long-term extensive expansion of mouse hepatic stem/progenitor cells in a novel serum-free culture system.Gastroenterology. 2005; 128: 2089-2104Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). One of the cell lines, referred to as BMEL (Strick-Marchand and Weiss, 2002Strick-Marchand H. Weiss M.C. Inducible differentiation and morphogenesis of bipotential liver cell lines from wild-type mouse embryos.Hepatology. 2002; 36: 794-804Crossref PubMed Google Scholar), expresses hepatocytic transcription factors such as HNF1α, HNF4α, and GATA4, but not ALB. Because BMEL cell lines can be generated reproducibly, the bipotential progenitors provide a useful experimental model to study the mechanism of differentiation. Dan et al., 2006Dan Y.Y. Riehle K.J. Lazaro C. Teoh N. Haque J. Campbell J.S. Fausto N. Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages.Proc. Natl. Acad. Sci. USA. 2006; 103: 9912-9917Crossref PubMed Scopus (186) Google Scholar established cells similar to those mouse cells—multipotent progenitor cells from human fetal liver cells in long-term culture named “hFLMPCs,” which exhibited capacities of self-renewal, multipotent differentiation, and repopulation in a mouse liver injury model. Intriguingly, the hFLMPCs expressed several stem-cell-related markers, such as CD90, c-Kit, CD44h, and EpCAM, but neither AFP nor ALB. Schmelzer et al., 2007Schmelzer E. Zhang L. Bruce A. Wauthier E. Ludlow J. Yao H.L. Moss N. Melhem A. McClelland R. Turner W. et al.Human hepatic stem cells from fetal and postnatal donors.J. Exp. Med. 2007; 204: 1973-1987Crossref PubMed Scopus (260) Google Scholar reported that EpCAM+ cells isolated from human fetal liver contained multipotent precursors of hepatoblasts, which expressed stem cell markers and could be expanded in culture. The cultured EpCAM+ cells, which they called hepatic stem cells (hHpSCs), expressed ALB weakly, but no AFP. Transplantation of freshly isolated EpCAM+ cells or hHpSCs expanded in culture into NOD/SCID mice resulted in mature liver tissue expressing human-specific proteins. Recently, Goldman et al., 2013Goldman O. Han S. Sourrisseau M. Dziedzic N. Hamou W. Corneo B. D’Souza S. Sato T. Kotton D.N. Bissig K.D. et al.KDR identifies a conserved human and murine hepatic progenitor and instructs early liver development.Cell Stem Cell. 2013; 12: 748-760Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar reported that mouse and human fetal liver cells distinct from endothelial cells expressed KDR, also known as VEGFR2/Flk1, and expressed low levels of ALB. A lineage-tracing experiment using the Kdr-Cre mouse revealed that KDR+ cells were present in the endoderm in E8.0 embryos prior to hepatic specification and that the labeled hepatic progenitor gave rise to hepatocytes and cholangiocytes, suggesting that KDR+ ALB− AFP− hepatic progenitors are a precursor of hepatoblasts (Figure 2). Ultimately, the absence of liver-specific ALB or AFP in “fetal liver-derived stem-like cells” expanded in vitro suggests that fetal liver stem cells may be present as hepatoblast precursors, such as foregut endoderm stem cells, rather than hepatoblasts in vivo. In other words, if the liver stem cell were defined as a persistently self-renewable cell, most hepatoblasts would be unlikely to fall into this category. Because liver development from foregut endoderm is a continuous process, it seems likely that the cell surface characteristics of hepatoblasts change over time. Whether or not fetal liver cells with self-renewal capacity persist throughout an individual’s life span remains an open question. Proliferation and differentiation of hepatoblasts are supported and coordinated by various cell types in the liver during embryogenesis. Here, we focus on the cell-to-cell interactions relevant to the growth and differentiation of hepatoblasts into hepatocytes (Figure 2). At the earliest stage of liver development, hepatoblasts emerge from foregut endoderm and proliferate to form the liver bud in a process that requires Flk1+ endothelial cells in STM (Matsumoto et al., 2001Matsumoto K. Yoshitomi H. Rossant J. Zaret K.S. Liver organogenesis promoted by endothelial cells prior to vascular function.Science. 2001; 294: 559-563Crossref PubMed Scopus (443) Google Scholar). At later stages, mesothelial cells (MCs), which form the mesothelium that covers the parenchyma and prevents adhesion with other tissues, express high levels of various growth factors for hepatocytes such as HGF, Midkine, and Pleiotrophin (Onitsuka et al., 2010Onitsuka I. Tanaka M. Miyajima A. Characterization and functional analyses of hepatic mesothelial cells in mouse liver development.Gastroenterology. 2010; 138 (e1–e6): 1525-1535Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). Fetal MCs enhance proliferation of Dlk1+ hepatoblasts/immature hepatocytes in a coculture system. Wilms tumor 1 (WT1) is a transcription factor essential for development of MCs and the lack of WT1 impairs liver growth (Ijpenberg et al., 2007Ijpenberg A. Pérez-Pomares J.M. Guadix J.A. Carmona R. Portillo-Sánchez V. Macías D. Hohenstein P. Miles C.M. Hastie N.D. Muñoz-Chápuli R. Wt1 and retinoic acid signaling are essential for stellate cell development and liver morphogenesis.Dev. Biol. 2007; 312: 157-170Crossref PubMed Scopus (51) Google Scholar). Together, these results indicate that immature MCs contribute to hepatoblast proliferation. By contrast, Thy1+ mesenchymal cells in the murine fetal liver promote the maturation of CD49f+ hepatic progenitor cells by direct cell-to-cell contact in a coculture system (Hoppo et al., 2004Hoppo T. Fujii H. Hirose T. Yasuchika K. Azuma H. Baba S. Naito M. Machimoto T. Ikai I. Thy1-positive mesenchymal cells promote the maturation of CD49f-positive hepatic progenitor cells in the mouse fetal liver.Hepatology. 2004; 39: 1362-1370Crossref PubMed Scopus (51) Google Scholar). Interestingly, human embryonic stem cell (ESC)-derived KDR+ AFP− hepatic progenitors were shown to promote the maturation of KDR− AFP+ hepatic cells in vitro, suggesting the possibility that a small population of hepatoblasts itself provides a niche for hepatic maturation (Goldman et al., 2013Goldman O. Han S. Sourrisseau M. Dziedzic N. Hamou W. Corneo B. D’Souza S. Sato T. Kotton D.N. Bissig K.D. et al.KDR identifies a conserved human and murine hepatic progenitor and instructs early liver development.Cell Stem Cell. 2013; 12: 748-760Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar). Hematopoietic cells start to colonize the liver in midgestation, and the fetal liver serves as the major hematopoietic tissue until the perinatal stage when hematopoiesis shifts to the bone marrow. Hepatoblasts/immature hepatocytes are closely associated with hematopoietic precurs" @default.
• W2068511028 created "2016-06-24" @default.
• W2068511028 creator A5016969792 @default.
• W2068511028 creator A5069121285 @default.
• W2068511028 creator A5074011702 @default.
• W2068511028 date "2014-05-01" @default.
• W2068511028 modified "2023-10-16" @default.
• W2068511028 title "Stem/Progenitor Cells in Liver Development, Homeostasis, Regeneration, and Reprogramming" @default.
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