Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1995 Dec;147(6):1633–1648.

Transcription factor and liver-specific mRNA expression in facultative epithelial progenitor cells of liver and pancreas.

M D Dabeva 1, E Hurston 1, D A Sharitz 1
PMCID: PMC1869941  PMID: 7495289

Abstract

The pattern of mRNA expression for liver-specific proteins and liver-enriched transcription factors was studied in two models of facultative gut epithelial progenitor cells activation: D-galactosamine (GalN)-induced liver injury and dietary copper depletion leading to pancreatic acinar atrophy. After 5 weeks of copper deficiency (CuD), pancreatic acini of Fischer 344 rats underwent atrophy, associated with intense proliferation of small duct-like cells with oval-shaped nuclei. These cells resemble morphologically epithelial progenitor cells of the liver that proliferate after GalN administration. Activated pancreatic epithelial cells express mRNAs for liver-specific genes normally expressed in fetal liver, including alpha-fetoprotein, albumin, alpha-1 antitrypsin, glucose-6-phosphatase, and others, but not genes that are turned on after birth such as serine dehydratase, tyrosine aminotransferase, and multidrug resistance gene-1b. They express mRNAs for liver-enriched transcription factors including HNF-1 alpha, HNF-3 beta and gamma, HNF-4, and members of the CCAAT-enhancer binding protein (C/EBP) family. The only mRNA for a liver-enriched transcription factor not detected in the pancreas of CuD animals was HNF-3 alpha. Expression of HNF-3 alpha, beta, and gamma, and C/EBP-beta mRNA was highly activated in proliferating liver epithelial cells on days 2 and 3 after GalN injury. Increased expression of C/EBP-delta was observed first in the liver on day 1 after GalN administration and in the pancreas at 4 weeks after initiating CuD. We suggest that C/EBP-delta could be involved in the initial activation of epithelial progenitor cells and that HNF-3 alpha, beta, and gamma, and C/EBP-beta might participate in their maturation. We conclude further that pancreatic epithelial progenitor cells undertake differentiation through the hepatocyte lineage but cannot complete the differentiation program within the pancreatic milieu.

Full text

PDF
1633

Images in this article

1636Figure 2
on p.1636
1637Figure 3
on p.1637
1638Figure 4
on p.1638
1639Figure 5
on p.1639
1640Figure 6
on p.1640
1641Figure 7
on p.1641
1642Figure 8
on p.1642

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ang S. L., Wierda A., Wong D., Stevens K. A., Cascio S., Rossant J., Zaret K. S. The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins. Development. 1993 Dec;119(4):1301–1315. doi: 10.1242/dev.119.4.1301. [DOI] [PubMed] [Google Scholar]
  2. Bartles J. R., Rao M. S., Zhang L. Q., Fayos B. E., Nehme C. L., Reddy J. K. Expression and compartmentalization of integral plasma membrane proteins by hepatocytes and their progenitors in the rat pancreas. J Cell Sci. 1991 Jan;98(Pt 1):45–54. doi: 10.1242/jcs.98.1.45. [DOI] [PubMed] [Google Scholar]
  3. Blumenfeld M., Maury M., Chouard T., Yaniv M., Condamine H. Hepatic nuclear factor 1 (HNF1) shows a wider distribution than products of its known target genes in developing mouse. Development. 1991 Oct;113(2):589–599. doi: 10.1242/dev.113.2.589. [DOI] [PubMed] [Google Scholar]
  4. Buck M., Turler H., Chojkier M. LAP (NF-IL-6), a tissue-specific transcriptional activator, is an inhibitor of hepatoma cell proliferation. EMBO J. 1994 Feb 15;13(4):851–860. doi: 10.1002/j.1460-2075.1994.tb06328.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cereghini S., Ott M. O., Power S., Maury M. Expression patterns of vHNF1 and HNF1 homeoproteins in early postimplantation embryos suggest distinct and sequential developmental roles. Development. 1992 Nov;116(3):783–797. doi: 10.1242/dev.116.3.783. [DOI] [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Dabeva M. D., Alpini G., Hurston E., Shafritz D. A. Models for hepatic progenitor cell activation. Proc Soc Exp Biol Med. 1993 Dec;204(3):242–252. doi: 10.3181/00379727-204-43660. [DOI] [PubMed] [Google Scholar]
  8. Dabeva M. D., Shafritz D. A. Activation, proliferation, and differentiation of progenitor cells into hepatocytes in the D-galactosamine model of liver regeneration. Am J Pathol. 1993 Dec;143(6):1606–1620. [PMC free article] [PubMed] [Google Scholar]
  9. De Simone V., Cortese R. Transcription factors and liver-specific genes. Biochim Biophys Acta. 1992 Sep 24;1132(2):119–126. doi: 10.1016/0167-4781(92)90001-g. [DOI] [PubMed] [Google Scholar]
  10. Decker K., Keppler D. Galactosamine hepatitis: key role of the nucleotide deficiency period in the pathogenesis of cell injury and cell death. Rev Physiol Biochem Pharmacol. 1974;(71):77–106. doi: 10.1007/BFb0027661. [DOI] [PubMed] [Google Scholar]
  11. DiPersio C. M., Jackson D. A., Zaret K. S. The extracellular matrix coordinately modulates liver transcription factors and hepatocyte morphology. Mol Cell Biol. 1991 Sep;11(9):4405–4414. doi: 10.1128/mcb.11.9.4405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Diehl A. M., Michaelson P., Yang S. Q. Selective induction of CCAAT/enhancer binding protein isoforms occurs during rat liver development. Gastroenterology. 1994 Jun;106(6):1625–1637. doi: 10.1016/0016-5085(94)90420-0. [DOI] [PubMed] [Google Scholar]
  13. Duncan S. A., Manova K., Chen W. S., Hoodless P., Weinstein D. C., Bachvarova R. F., Darnell J. E., Jr Expression of transcription factor HNF-4 in the extraembryonic endoderm, gut, and nephrogenic tissue of the developing mouse embryo: HNF-4 is a marker for primary endoderm in the implanting blastocyst. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7598–7602. doi: 10.1073/pnas.91.16.7598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dwivedi R. S., Yeldandi A. V., Subbarao V., Feigelson P., Roy A. K., Reddy J. K., Rao M. S. Androgen regulated expression of the alpha 2u-globulin gene in pancreatic hepatocytes of rat. J Cell Biol. 1990 Feb;110(2):263–267. doi: 10.1083/jcb.110.2.263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Elmore L. W., Sirica A. E. Phenotypic characterization of metaplastic intestinal glands and ductular hepatocytes in cholangiofibrotic lesions rapidly induced in the caudate liver lobe of rats treated with furan. Cancer Res. 1991 Oct 15;51(20):5752–5759. [PubMed] [Google Scholar]
  16. Evarts R. P., Nagy P., Marsden E., Thorgeirsson S. S. A precursor-product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis. 1987 Nov;8(11):1737–1740. doi: 10.1093/carcin/8.11.1737. [DOI] [PubMed] [Google Scholar]
  17. Evarts R. P., Nagy P., Nakatsukasa H., Marsden E., Thorgeirsson S. S. In vivo differentiation of rat liver oval cells into hepatocytes. Cancer Res. 1989 Mar 15;49(6):1541–1547. [PubMed] [Google Scholar]
  18. FARBER E. Similarities in the sequence of early histological changes induced in the liver of the rat by ethionine, 2-acetylamino-fluorene, and 3'-methyl-4-dimethylaminoazobenzene. Cancer Res. 1956 Feb;16(2):142–148. [PubMed] [Google Scholar]
  19. Flodby P., Antonson P., Barlow C., Blanck A., Porsch-Hällström I., Xanthopoulos K. G. Differential patterns of expression of three C/EBP isoforms, HNF-1, and HNF-4 after partial hepatectomy in rats. Exp Cell Res. 1993 Sep;208(1):248–256. doi: 10.1006/excr.1993.1244. [DOI] [PubMed] [Google Scholar]
  20. Glisin V., Crkvenjakov R., Byus C. Ribonucleic acid isolated by cesium chloride centrifugation. Biochemistry. 1974 Jun 4;13(12):2633–2637. doi: 10.1021/bi00709a025. [DOI] [PubMed] [Google Scholar]
  21. Griffo G., Hamon-Benais C., Angrand P. O., Fox M., West L., Lecoq O., Povey S., Cassio D., Weiss M. HNF4 and HNF1 as well as a panel of hepatic functions are extinguished and reexpressed in parallel in chromosomally reduced rat hepatoma-human fibroblast hybrids. J Cell Biol. 1993 May;121(4):887–898. doi: 10.1083/jcb.121.4.887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Haber B. A., Chin S., Chuang E., Buikhuisen W., Naji A., Taub R. High levels of glucose-6-phosphatase gene and protein expression reflect an adaptive response in proliferating liver and diabetes. J Clin Invest. 1995 Feb;95(2):832–841. doi: 10.1172/JCI117733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hoover K. L., Poirier L. A. Hepatocyte-like cells within the pancreas of rats fed methyl-deficient diets. J Nutr. 1986 Aug;116(8):1569–1575. doi: 10.1093/jn/116.8.1569. [DOI] [PubMed] [Google Scholar]
  24. Kimbrough R. D. Pancreatic-type tissue in livers of rats fed polychlorinated biphenyls. J Natl Cancer Inst. 1973 Aug;51(2):679–681. [PubMed] [Google Scholar]
  25. Kuo C. F., Xanthopoulos K. G., Darnell J. E., Jr Fetal and adult localization of C/EBP: evidence for combinatorial action of transcription factors in cell-specific gene expression. Development. 1990 Jun;109(2):473–481. doi: 10.1242/dev.109.2.473. [DOI] [PubMed] [Google Scholar]
  26. Kuo C. J., Conley P. B., Chen L., Sladek F. M., Darnell J. E., Jr, Crabtree G. R. A transcriptional hierarchy involved in mammalian cell-type specification. Nature. 1992 Jan 30;355(6359):457–461. doi: 10.1038/355457a0. [DOI] [PubMed] [Google Scholar]
  27. Lai E., Darnell J. E., Jr Transcriptional control in hepatocytes: a window on development. Trends Biochem Sci. 1991 Nov;16(11):427–430. doi: 10.1016/0968-0004(91)90169-v. [DOI] [PubMed] [Google Scholar]
  28. Lai E., Prezioso V. R., Smith E., Litvin O., Costa R. H., Darnell J. E., Jr HNF-3A, a hepatocyte-enriched transcription factor of novel structure is regulated transcriptionally. Genes Dev. 1990 Aug;4(8):1427–1436. doi: 10.1101/gad.4.8.1427. [DOI] [PubMed] [Google Scholar]
  29. Lemire J. M., Shiojiri N., Fausto N. Oval cell proliferation and the origin of small hepatocytes in liver injury induced by D-galactosamine. Am J Pathol. 1991 Sep;139(3):535–552. [PMC free article] [PubMed] [Google Scholar]
  30. Lesch R., Reutter W., Keppler D., Decker K. Liver restitution after acute galactosamine hepatitis: autoradiographic and biochemical studies in rats. Exp Mol Pathol. 1970 Feb;12(1):58–69. doi: 10.1016/0014-4800(70)90075-4. [DOI] [PubMed] [Google Scholar]
  31. Medline A., Schaffner F., Popper H. Ultrastructural features in galactosamine-induced hepatitis. Exp Mol Pathol. 1970 Apr;12(2):201–211. doi: 10.1016/0014-4800(70)90050-x. [DOI] [PubMed] [Google Scholar]
  32. Meehan R. R., Barlow D. P., Hill R. E., Hogan B. L., Hastie N. D. Pattern of serum protein gene expression in mouse visceral yolk sac and foetal liver. EMBO J. 1984 Aug;3(8):1881–1885. doi: 10.1002/j.1460-2075.1984.tb02062.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Miquerol L., Lopez S., Cartier N., Tulliez M., Raymondjean M., Kahn A. Expression of the L-type pyruvate kinase gene and the hepatocyte nuclear factor 4 transcription factor in exocrine and endocrine pancreas. J Biol Chem. 1994 Mar 25;269(12):8944–8951. [PubMed] [Google Scholar]
  34. Mischoulon D., Rana B., Bucher N. L., Farmer S. R. Growth-dependent inhibition of CCAAT enhancer-binding protein (C/EBP alpha) gene expression during hepatocyte proliferation in the regenerating liver and in culture. Mol Cell Biol. 1992 Jun;12(6):2553–2560. doi: 10.1128/mcb.12.6.2553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Monaghan A. P., Kaestner K. H., Grau E., Schütz G. Postimplantation expression patterns indicate a role for the mouse forkhead/HNF-3 alpha, beta and gamma genes in determination of the definitive endoderm, chordamesoderm and neuroectoderm. Development. 1993 Nov;119(3):567–578. doi: 10.1242/dev.119.3.567. [DOI] [PubMed] [Google Scholar]
  36. Müller H. B. Der Einfluss kupferarmer Kost auf das Pankreas. Lichtmikroskopische Untersuchungen am exokrinen Teil der Bauschspeicheldrüsen weisser Ratten. Virchows Arch A Pathol Pathol Anat. 1970;350(4):353–367. [PubMed] [Google Scholar]
  37. Nagy P., Bisgaard H. C., Thorgeirsson S. S. Expression of hepatic transcription factors during liver development and oval cell differentiation. J Cell Biol. 1994 Jul;126(1):223–233. doi: 10.1083/jcb.126.1.223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Noda C., Fukushima C., Fujiwara T., Matsuda K., Kobune Y., Ichihara A. Developmental regulation of rat serine dehydratase gene expression: evidence for the presence of a repressor in fetal hepatocytes. Biochim Biophys Acta. 1994 Mar 1;1217(2):163–173. doi: 10.1016/0167-4781(94)90030-2. [DOI] [PubMed] [Google Scholar]
  39. Panduro A., Shalaby F., Shafritz D. A. Changing patterns of transcriptional and post-transcriptional control of liver-specific gene expression during rat development. Genes Dev. 1987 Dec;1(10):1172–1182. doi: 10.1101/gad.1.10.1172. [DOI] [PubMed] [Google Scholar]
  40. Perlino E., Cortese R., Ciliberto G. The human alpha 1-antitrypsin gene is transcribed from two different promoters in macrophages and hepatocytes. EMBO J. 1987 Sep;6(9):2767–2771. doi: 10.1002/j.1460-2075.1987.tb02571.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Philippe J., Morel C., Prezioso V. R. Glucagon gene expression is negatively regulated by hepatocyte nuclear factor 3 beta. Mol Cell Biol. 1994 May;14(5):3514–3523. doi: 10.1128/mcb.14.5.3514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Rana B., Mischoulon D., Xie Y., Bucher N. L., Farmer S. R. Cell-extracellular matrix interactions can regulate the switch between growth and differentiation in rat hepatocytes: reciprocal expression of C/EBP alpha and immediate-early growth response transcription factors. Mol Cell Biol. 1994 Sep;14(9):5858–5869. doi: 10.1128/mcb.14.9.5858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Rao M. S., Dwivedi R. S., Subbarao V., Usman M. I., Scarpelli D. G., Nemali M. R., Yeldandi A., Thangada S., Kumar S., Reddy J. K. Almost total conversion of pancreas to liver in the adult rat: a reliable model to study transdifferentiation. Biochem Biophys Res Commun. 1988 Oct 14;156(1):131–136. doi: 10.1016/s0006-291x(88)80814-3. [DOI] [PubMed] [Google Scholar]
  44. Rao M. S., Dwivedi R. S., Yeldandi A. V., Subbarao V., Tan X. D., Usman M. I., Thangada S., Nemali M. R., Kumar S., Scarpelli D. G. Role of periductal and ductular epithelial cells of the adult rat pancreas in pancreatic hepatocyte lineage. A change in the differentiation commitment. Am J Pathol. 1989 May;134(5):1069–1086. [PMC free article] [PubMed] [Google Scholar]
  45. Rao M. S., Reddy M. K., Reddy J. K., Scarpelli D. G. Response of chemically induced hepatocytelike cells in hamster pancreas to methyl clofenapate, a peroxisome proliferator. J Cell Biol. 1982 Oct;95(1):50–56. doi: 10.1083/jcb.95.1.50. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Rao M. S., Subbarao V., Luetteke N., Scarpelli D. G. Further characterization of carcinogen-induced hepatocytelike cells in hamster pancreas. Am J Pathol. 1983 Jan;110(1):89–94. [PMC free article] [PubMed] [Google Scholar]
  47. Rao M. S., Yeldandi A. V., Subbarao V., Reddy J. K. Role of apoptosis in copper deficiency-induced pancreatic involution in the rat. Am J Pathol. 1993 Jun;142(6):1952–1957. [PMC free article] [PubMed] [Google Scholar]
  48. Ruiz i Altaba A., Prezioso V. R., Darnell J. E., Jessell T. M. Sequential expression of HNF-3 beta and HNF-3 alpha by embryonic organizing centers: the dorsal lip/node, notochord and floor plate. Mech Dev. 1993 Dec;44(2-3):91–108. doi: 10.1016/0925-4773(93)90060-b. [DOI] [PubMed] [Google Scholar]
  49. Sasaki H., Hogan B. L. Differential expression of multiple fork head related genes during gastrulation and axial pattern formation in the mouse embryo. Development. 1993 May;118(1):47–59. doi: 10.1242/dev.118.1.47. [DOI] [PubMed] [Google Scholar]
  50. Sell S. Is there a liver stem cell? Cancer Res. 1990 Jul 1;50(13):3811–3815. [PubMed] [Google Scholar]
  51. Shalaby F., Shafritz D. A. Exon skipping during splicing of albumin mRNA precursors in Nagase analbuminemic rats. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2652–2656. doi: 10.1073/pnas.87.7.2652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Shiojiri N., Lemire J. M., Fausto N. Cell lineages and oval cell progenitors in rat liver development. Cancer Res. 1991 May 15;51(10):2611–2620. [PubMed] [Google Scholar]
  53. Sladek F. M., Zhong W. M., Lai E., Darnell J. E., Jr Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev. 1990 Dec;4(12B):2353–2365. doi: 10.1101/gad.4.12b.2353. [DOI] [PubMed] [Google Scholar]
  54. Smith P. A., Sunter J. P., Case R. M. Progressive atrophy of pancreatic acinar tissue in rats fed a copper-deficient diet supplemented with D-penicillamine or triethylene tetramine: morphological and physiological studies. Digestion. 1982;23(1):16–30. doi: 10.1159/000198706. [DOI] [PubMed] [Google Scholar]
  55. Tatematsu M., Kaku T., Medline A., Farber E. Intestinal metaplasia as a common option of oval cells in relation to cholangiofibrosis in liver of rats exposed to 2-acetylaminofluorene. Lab Invest. 1985 Apr;52(4):354–362. [PubMed] [Google Scholar]
  56. Thorgeirsson S. S. Hepatic stem cells. Am J Pathol. 1993 May;142(5):1331–1333. [PMC free article] [PubMed] [Google Scholar]
  57. Thorgeirsson S. S., Huber B. E., Sorrell S., Fojo A., Pastan I., Gottesman M. M. Expression of the multidrug-resistant gene in hepatocarcinogenesis and regenerating rat liver. Science. 1987 May 29;236(4805):1120–1122. doi: 10.1126/science.3576227. [DOI] [PubMed] [Google Scholar]
  58. Tian J. M., Schibler U. Tissue-specific expression of the gene encoding hepatocyte nuclear factor 1 may involve hepatocyte nuclear factor 4. Genes Dev. 1991 Dec;5(12A):2225–2234. doi: 10.1101/gad.5.12a.2225. [DOI] [PubMed] [Google Scholar]
  59. Wu K. J. Activation of albumin and other liver-specific gene expression in fibroblast-pancreatic cell hybrids: different roles of transcription factors. Exp Cell Res. 1993 Sep;208(1):241–247. doi: 10.1006/excr.1993.1243. [DOI] [PubMed] [Google Scholar]
  60. Xanthopoulos K. G., Mirkovitch J. Gene regulation in rodent hepatocytes during development, differentiation and disease. Eur J Biochem. 1993 Sep 1;216(2):353–360. doi: 10.1111/j.1432-1033.1993.tb18152.x. [DOI] [PubMed] [Google Scholar]
  61. Yeh W. C., Cao Z., Classon M., McKnight S. L. Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Genes Dev. 1995 Jan 15;9(2):168–181. doi: 10.1101/gad.9.2.168. [DOI] [PubMed] [Google Scholar]
  62. Yeldandi A. V., Tan X. D., Dwivedi R. S., Subbarao V., Smith D. D., Jr, Scarpelli D. G., Rao M. S., Reddy J. K. Coexpression of glutamine synthetase and carbamoylphosphate synthase I genes in pancreatic hepatocytes of rat. Proc Natl Acad Sci U S A. 1990 Feb;87(3):881–885. doi: 10.1073/pnas.87.3.881. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES