Overview of Recent Experimental Studies on Liver Stem Cells

Snorri S. Thorgeirsson; Joe W. Grisham

doi:10.1055/s-2004-815559

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2003; 23(4): 303-312
DOI: 10.1055/s-2004-815559

Overview of Recent Experimental Studies on Liver Stem Cells

Snorri S. Thorgeirsson^1,2 , Joe W. Grisham²

¹Chief, Laboratory of Experimental Carcinogenesis National Cancer Institute, National Institutes of Health Bethesda, Maryland
²Laboratory of Experimental Carcinogenesis National Cancer Institute, National Institutes of Health Bethesda, Maryland

Abstract

ABSTRACT

Since our review of the experimental evidence for liver epithelial stem cells in 1997, a large body of new data has been added. The new studies have focused on the analysis of differentiation of candidate liver stem cells when they are transplanted into the liver in vivo and when cultured in vitro under defined conditions. The new studies that we review substantiate the existence of stem cells that can generate new lineages of hepatocytes and cholangiocytes, especially in severely damaged livers. However, the recent studies have introduced new areas of controversy about the essential nature of liver stem cells and about appropriate methods to analyze their properties and functions. Whether the major stem cell for hepatocytes and cholangiocytes is an endodermal epithelial cell that resides in the liver or a mesodermal cell from bone marrow is a current area of controversy. Another controversial topic concerns the appropriateness of cell culture to analyze liver epithelial cells. Both of these situations are addressed, if not yet conclusively solved, by the new data. From our review of recent data, we conclude that the major liver stem cell is an epithelial cell that is a liver resident, and that cell culture is a valuable, even necessary, adjunct for analyzing the properties of liver stem cells and for eventually identifying the molecular mechanisms that regulate their activation, proliferation, and differentiation.

KEYWORDS

Liver stem cells - hepatocytes - cholangiocytes

Full Text

References

REFERENCES

1 Grisham J W, Thorgeirsson S S. Liver stem cells. In: Potten CS, ed. Stem Cells New York: Academic Press 1997: 234-282
2 Blau H M, Brazelton T R, Weimann J M. The evolving concept of a stem cell: entity or function?. Cell . 2001; 105 829-841
3 Loeffler M, Roeder I. Tissue stem cells: definition, plasticity, heterogeneity, self-organization and models-a conceptual approach. Cells Tissues Organs . 2002; 171 8-26
4 Rhim J A, Sandgren E P, Degen J L. et al . Replacement of diseased mouse liver by hepatic cell transplantation. Science . 1994; 263 1149-1152
5 Overturf K, Al-Dhalimy M, Ou C N. et al . Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes. Am J Pathol . 1997; 151 1273-1280
6 Dabeva M D, Petkov P M, Sandhu J. et al . Proliferation and differentiation of fetal liver epithelial progenitor cells after transplantation into adult rat liver. Am J Pathol . 2000; 156 2017-2031
7 Sandhu J S, Petkov P M, Dabeva M D, Shafritz D A. Stem cell properties and repopulation of the rat liver by fetal liver epithelial progenitor cells. Am J Pathol . 2001; 159 1323-1334
8 Lilja H, Arkadopoulos N, Blanc P. et al . Fetal rat hepatocytes: isolation characterization, and transplantation into the Nagase analbuminemic rat. Transplantation . 1997; 64 1240-1248
9 Cantz T, Zuckerman D M, Burda M R. et al . Quantitative gene expression analysis reveals transition of fetal liver progenitor cells to mature hepatocytes after transplantation in uPA/RAG-2 mice. Am J Pathol . 2003; 162 37-45
10 Suzuki A, Zheng Y, Kondo R. et al . Flow-cytometric separation and enrichment of hepatic progenitor cells in the developing mouse liver. Hepatology . 2000; 32 1230-1239
11 Suzuki A, Zheng Y W, Kaneko S. et al . Clonal identification and characterization of self-renewing pluripotent stem cells in the developing liver. J Cell Biol . 2002; 156 173-184
12 Allain J E, Dagher I, Mahieu-Caputo O. et al . Immortalization of a primate bipotent epithelial liver stem cell. Proc Natl Acad Sci USA . 2002; 99 3639-3644
13 Malhi H, Irani A N, Gagandeep S, Gupta S. Isolation of human progenitor liver epithelial cells with extensive replication capacity and differentiation into mature hepatocytes. J Cell Sci . 2002; 115 2679-2688
14 Coleman W B, McCullough K D, Esch G L. et al . Evaluation of the differentiation potential of WB-F344 rat liver epithelial stem-like cells in vivo. Differentiation into hepatocytes following transplantation into dipeptidylpeptidase-IV-deficient rat liver. Am J Pathol . 1997; 151 353-359
15 Coleman W B, Butz G M, Howell J A, Grisham J W. Transplantation of rat liver epithelial stem-like cells. In: Gupta S, Jansen PLM, Klempnauer J, Manns MP, eds. Hepatocyte Transplantation Dordrecht, The Netherlands: Kluwer 2002 : 38-50
16 Chapman L, Coleman W B, Hixson D. Integration, survival, and differentiation of liver epithelial cells in hepatic and pancreatic ducts (abstract). FASEB J . 1999; 13 A160
17 Ott M, Rajvanshi P, Sokhi R P. et al . Differentiation-specific regulation of transgene expression in a diploid epithelial cell line derived from the normal F344 rat liver. J Pathol . 1999; 187 365-373
18 Malouf N N, Coleman W B, Grisham J W. et al . Adult-derived stem cells from the liver become myocytes in the heart in vivo. Am J Pathol . 2001; 158 1929-1935
19 Malouf N N, Coleman W B, Grisham J W. et al . Stem cells derived from cloned adult liver engraft and differentiate in the heart in a niche-specific fashion (abstract). Circulation . 2001; 104(suppl) II-129
20 Kirby S L, Bentley S, Fry J. et al . Hematopoietic cell transdifferentiation of cloned adult liver-derived stem cells (abstract). Mol Biol Cell . 2002; 13(suppl) 121a
21 Dabeva M D, Hwang S G, Vasa S RG. et al . Differentiation of pancreatic epithelial progenitor cells into hepatocytes following transplantation into rat liver. Proc Natl Acad Sci USA . 1997; 94 7356-7361
22 Wang X, Foster M, Al-Dhalimy M. et al . The origin and liver repopulating capacity of murine oval cells. Proc Natl Acad Sci USA . 2003; 100 (suppl 1) 11881-11888
23 Yasui O, Miura N, Terada K. et al . Isolation of oval cells from Long-Evans Cinnamon rats and their transformation into hepatocytes in vivo in the rat liver. Hepatology . 1997; 25 329-334
24 Gordon G J, Coleman W B, Hixson D C, Grisham J W. Liver regeneration in rats with retrorsine-induced hepatocellular injury proceeds through a novel cellular response. Am J Pathol . 2000; 156 607-619
25 Gordon G J, Coleman W B, Grisham J W. Temporal analysis of hepatocyte differentiation by small hepatocyte-like progenitor cells during liver regeneration in retrorsine-exposed rats. Am J Pathol . 2000; 157 771-786
26 Gordon G J, Butz G M, Grisham J W, Coleman W B. Isolation, short-term culture, and transplantation of small hepatocyte-like progenitor cells from retorsine-exposed rats. Transplantation . 2002; 73 1236-1243
27 Wang X, Al-Dhalimy M, Legasse E. et al . Liver repopulation and correction of metabolic liver disease by transplanted adult mouse pancreatic cells. Am J Pathol . 2001; 158 571-579
28 Petersen B E, Bowen W L, Patrene K D. et al . Bone marrow as a potential source of hepatic oval cells. Science . 1999; 284 1168-1170
29 Thiese N D, Badve S, Saxena R. et al . Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology . 2000; 31 235-240
30 Lagasse E, Connors H, Al-Dhalimy M. et al . Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med . 2000; 6 1229-1234
31 Wang X, Willenbring H, Akkari Y. et al . Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature . 2003; 422 897-901
32 Vassilopoulos G, Wang P R, Russell D W. Transplanted bone marrow regenerates liver by cell fusion. Nature . 2003; 422 901-904
33 Avital I, Inderbitzin D, Aoki T. et al . Isolation, characterization, and transplantation of bone marrow-derived hepatocyte stem cells. Biochem Biophys Res Commun . 2001; 288 156-164
34 Wang X, Ge S, McNamara G. et al . Albumin-expressing hepatocyte-like cells develop in the livers of immune-deficient mice that received transplants of highly purified human hematopoietic stem cells. Blood . 2003; 101 4201-4208
35 Danet G H, Luongo J L, Butler G. et al . C1qR^p defines a new human stem cell population with hematopoietic and hepatic potential. Proc Natl Acad Sci USA . 2002; 99 10441-10445
36 Schwartz R E, Reyes M, Koodie L. et al . Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest . 2002; 109 1291-1302
37 Jiang Y, Jahagirdar B N, Reinhardt R L. et al . Pluripotency of mesenchymal stem cells derived from adult marrow. Nature . 2002; 418 41-49
38 Yin Y, Lim Y K, Salto-Tellez M. et al . AFP⁺ ESC-derived cells engraft and differentiate into hepatocytes in vivo. Stem Cells . 2002; 20 338-346
39 Yamada T, Yoshikawa M, Kanda S. et al . In vitro differentiation of embryonic stem cells into hepatocyte-like cells identified by cellular uptake of indocyanine green. Stem Cells . 2002; 20 146-154
40 Chinzei R, Tanaka Y, Shimizu-Saito K. et al . Embryoid body cells derived from a mouse embryonic stem cell line show differentiation into functional hepatocytes. Hepatology . 2002; 36 22-29
41 Kamiya A, Kinoshita T, Ito Y. et al . Fetal liver development requires aparacrine action of oncostatin M through the gp 130 signal transducer. EMBO J . 1999; 18 2127-2136
42 Kojima N, Kinoshita T, Kamiya A. et al . Cell density-dependent regulation of hepatic development by a gp130-dependent pathway. Biochem Biophys Res Commun . 2000; 277 152-158
43 Kubota H, Reid L M. Clonogenic hepatoblasts, common precursors for hepatocyte and biliary lineages, are lacking classical major histocompatibility complex class I antigen. Proc Natl Acad Sci USA . 2000; 97 12132-12137
44 Rogler L E. Selective bipotential differentiation of mouse embryonic hepatoblasts in vitro. Am J Pathol . 1997; 150 591-602
45 Spagnoli F M, Cicchini C, Tripodi M, Weiss M C. Inhibition of MMH (Met murine hepatocyte) cell differentiation by TGFβ is abrogated by pre-treatment with the heritable differentiation effector FGF 1. J Cell Sci . 2000; 113 3639-3647
46 Strick-Marchand H, Weiss M C. Inducible differentiation and morphogenesis of bipotential liver cell lines from wild-type mouse embryos. Hepatology . 2002; 36 794-804
47 Talbot N C, Pursel V G, Rexroad Jr E C. et al . Colony isolation and secondary culture of fetal porcine hepatocytes on STO feeder cells. In Vitro Cell Dev Biol Anim . 1994; 30A 851-858
48 Coleman W B, Smith G J, Grisham J W. Development of dexamethasone-inducible tyrosine aminotransferase activity in WB-F344 rat liver epithelial stemlike cells cultured in the presence of sodium butyrate. J Cell Physiol . 1994; 161 463-469
49 Couchie D, Holic N, Chobert M N. et al . In vitro differentiation of WB-F344 rat liver epithelial cells into the biliary lineage. Differentiation . 2002; 69 209-215
50 Schroeder I S, Hironaka K, Sanchez Munoz A. et al . In vitro differentiation of adult liver stem cells into the hepatocyte lineage (Abstract). Proc Am Assoc Cancer Res . 2002; 43 462A
51 Nagai H, Terada K, Watanabe G. et al . Differentiation of liver epithelial (stem-like) cells into hepatocytes induced by coculture with hepatic stellate cells. Biochem Biophys Res Commun . 2002; 293 1420-1425
52 Kano J, Noguchi M, Kodama M, Tokiwa T. The in vitro differentiating capacity of nonparenchymal epithelial cells derived from adult porcine livers. Am J Pathol . 2000; 156 2033-2043
53 Pack R, Heck R, Dienes H P. et al . Isolation, biochemical characterization, long-term culture, and phenotypic modulation of oval cells from carcinogen-fed rats. Exp Cell Res . 1993; 204 198-209
54 Lazaro C A, Rhim J A, Yamada Y, Fausto N. Generation of hepatocytes from oval cell precursors in culture. Cancer Res . 1998; 58 5514-5522
55 Yang L, Li S, Hatch N. et al . In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells. Proc Natl Acad Sci USA . 2002; 99 8078-8083
56 Tosh D, Shen C N, Slack J MW. Differentiated properties of hepatocyes induced from pancreatic cells. Hepatology . 2002; 36 534-543
57 Zulewski H, Abraham E J, Gerlach M J. et al . Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes . 2001; 50 521-533
58 Fiegel H C, Lioznov M V, Cortes-Dericks L. et al . Liver-specific gene expression in cultured human hematopocetic stem cells. Stem Cells . 2003; 21 98-104
59 Zhao Y, Glesne D, Huberman E. A human peripheral blood monocyte-derived subset acts as pluripotent stem cells. Proc Natl Acad Sci USA . 2003; 100 2426-2431
60 Hamazaki T, Iiboshi Y, Oka M. et al . Hepatic maturation in differentiating embryonic stem cells in vitro. FEBS Lett . 2001; 497 15-19
61 Jones E A, Tosh D, Wilson D I. et al . Hepatic differentiation of murine embryonic stem cells. Exp Cell Res . 2002; 272 15-22
62 Paku S, Schnur J, Nagy P, Thorgeirsson S S. Origin and structural evolution of the early proliferating oval cells in rat liver. Am J Pathol . 2001; 158 1313-1323
63 Okihiro M S, Hinton D E. Partial hepatectomy and bile duct ligation in rainbow trout (Oncorhynchus mykiss): histologic, immunohistochemical and enzyme histochemical characterization of hepatic regeneration and biliary hyperplasia. Toxicol Pathol . 2000; 28 342-356
64 Gao Z, McAlister V C, Williams G M. Repopulation of liver endothelium by bone-marrow-derived cells. Lancet . 2001; 357 932-933
65 Krause D S, Theise N D, Collector M I. et al . Multiorgan, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell . 2001; 105 369-377
66 Mallet V O, Mitchell C, Mezy E. et al . Bone marrow transplantation leads to a minor population of hepatocytes that can be selectively amplified in vivo. Hepatology . 2002; 35 799-804
67 Wagers A J, Sherwood R I, Christensen J L, Weissman I L. Little evidence for developmental plasticity of hematopoietic stem cells. Science . 2002; 297 2256-2259
68 Fujii H, Hirose T, Oe S. et al . Contribution of bone marrow cells to liver regeneration after partial hepatectomy in mice. J Hepatol . 2002; 36 653-659
69 Wang X, Montini E, Al-Dhalimy M. et al . Kinetics of liver repopulation after bone marrow transplantation. Am J Pathol . 2002; 161 565-574
70 Stroncek D F, Clay M E, Smith J. et al . Composition of peripheral blood progenitor cell components collected from healthy donors. Transfusion . 1997; 37 411-417
71 Taniguchi H, Toyoshima T, Fukao K, Nakauchi H. Presence of hematopoietic stem cells in the adult liver. Nat Med . 1996; 2 198-203
72 Grompe M. The role of bone marrow stem cells in liver regeneration. Semin Liver Dis . 2003; 23 363-372
73 Anderson D J, Gage F H, Weissman I L. Can stem cells cross lineage boundaries?. Nat Med . 2001; 7 393-395
74 Koizumi N, Inatomi T, Suzuki T. et al . Cultivated corneal epithelial stem cell transplantation in ocular surface disorders. Ophthalmology . 2001; 108 1569-1574
75 Myers S, Navsaria H, Sanders R. et al . Transplantation of keratinocytes in the treatment of wounds. Am J Surg . 1995; 170 75-83
76 Reya T, Duncan A W, Ailles L. et al . A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature . 2003; 423 409-414
77 Evans M J, Kaufman M H. Establishment in culture of pluripotential cells from mouse embryos. Nature . 1981; 292 154-156
78 Martin G R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA . 1981; 78 7634-7638
79 Fujio K, Evarts R P, Hu Z. et al . Expression of stem cell factor and its receptor, c-kit, during liver regeneration from putative stem cells in adult rat. Lab Invest . 1994; 70 511-516
80 Omori N, Evarts R P, Omori M. et al . Expression of leukemia inhibitory factor and its receptor during liver regeneration in the adult rat. Lab Invest . 1996; 75 15-24