Skip to main content
NCBI home page
Cytotechnology logoLink to Cytotechnology
. 2003 Mar;41(2-3):139–144. doi: 10.1023/A:1024826823194

Liver stem cells

Neil D Theise 1,✉
PMCID: PMC3466695  PMID: 19002950

Abstract

The capacity of hepatocytes and cholangiocytes to contribute to their own maintenance has long been recognized. More recently, studies have indicated the presence of both intra-hepatic and extra-hepatic stem/progenitor cell populations. The intraorgan compartment probably derives primarily from the biliary tree, most particularly the most proximal branches, i.e. the canals of Hering and smallest ductules. The extra-organ compartment is at least in part derived from diverse populations of cells from the bone marrow. These three tiers of liver cell regeneration serve to maintain the normal organ and to regenerate damaged parenchyma in response to a variety of insults. The nature and extent of the insult determines the balance between these stem/progenitor compartments.

Keywords: bone marrow, liver, plasticity, progenitorcells, stem cells

Full Text

The Full Text of this article is available as a PDF (71.6 KB).

References

  1. Alison MR, Poulsom R, Jeffery R, Dhillon AP, Quaglia A, Jacob J, Novelli M, Prentice G, Williamson J, Wright NA. Hepatocytes from non-hepatic adult stem cells. Nature. 2000;406:257. doi: 10.1038/35018642. [DOI] [PubMed] [Google Scholar]
  2. Baumann U, Crosby HA, Ramani P, Kelly DA, Strain AJ. Expression of the stem cell factor receptor c-kit in normal and diseased pediatric liver: Identification of a human hepatic progenitor cell? Hepatology. 1999;30:112–117. doi: 10.1002/hep.510300140. [DOI] [PubMed] [Google Scholar]
  3. Beerheide W, Von Mach MA, Ringel M, Fleckenstein C, Schumann S, Renzing N, Hildebrandt A, Brenner W, Jensen O, Gebhard S, Reifenberg K, Bender J, Oesch F, Hengstler JG. Downregulation of beta2-microglobulin in human cord blood somatic stem cells after transplantation into livers of SCID-mice: An escape mechanism of stem cells? Biochem Biophys Res Commun. 2002;294:1052–1063. doi: 10.1016/S0006-291X(02)00596-X. [DOI] [PubMed] [Google Scholar]
  4. Crosby HA, Kelly DA, Strain AJ. Human hepatic stem-like cells isolated using c-kit or CD34 can differentiate into biliary epithelium. Gastroenterol. 2001;120:534–544. doi: 10.1053/gast.2001.21175. [DOI] [PubMed] [Google Scholar]
  5. Dabeva MD, Shafritz DA. Activation, proliferation, and differentiation of progenitor cells into hepatocytes in the D-galactosamine model of liver regeneration. Am J Pathol. 1993;143:1606–1620. [PMC free article] [PubMed] [Google Scholar]
  6. Faa G, Van Eyken P, Roskams T, Miyazaki H, Serreli S, Ambu R, Desmet VJ. Expression of cytokeratin 20 in developing rat liver and in experimental models of ductular and oval cell proliferation. J Hepatol. 1998;29:628–633. doi: 10.1016/S0168-8278(98)80158-X. [DOI] [PubMed] [Google Scholar]
  7. Faktor VM, Radaeva SA. The formation of oval-cell ducts during hepatic carcinogenesis in mice. Its relationship to the preexisting canals of Hering. Ontogenez. 1992;23:407–418. [PubMed] [Google Scholar]
  8. Fausto N, Lemire JM, Shiojiri N. Cell lineages in hepatic development and the identification of progenitor cells in normal and injured liver. Proc Soc Exp Biol Med. 1992;204:237–241. doi: 10.3181/00379727-204-43659. [DOI] [PubMed] [Google Scholar]
  9. Fiel MI, Antonio LB, Nalesnik MA, Thung SN, Gerber MA. Characterization of ductular hepatocytes in primary liver allograft failure. Mod Pathol. 1997;10:348–353. [PubMed] [Google Scholar]
  10. Gerber MA, Thung SN, Shen S, Stormeyer FW & Ishak K (1983) Phenotypic characterization of hepatic proliferation: Antigenic expression by proliferating epithelial cells in fetal liver, massive hepatic necrosis, and nodular transformation of the liver. Am J Pathol: 110–114. [PMC free article] [PubMed]
  11. Grisham JW. Hepatic epithelial stem-like cells. Verh Dtch Ges Pathol. 1995;79:47–54. [PubMed] [Google Scholar]
  12. Hatch HM, Zheng D, Jorgensen ML & Petersen BE (in press) SDF-1/CXCR4: Amechanism for hepatic oval cell activation and bone marrow stem cell recruitment to the liver in rats. Cloning and Stem Cells. [DOI] [PubMed]
  13. Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, Crystal RG, Besmer P, Lyden D, Moore MA, Werb Z, Rafii S. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell. 2002;109:625–637. doi: 10.1016/S0092-8674(02)00754-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002;418:41–49. doi: 10.1038/nature00870. [DOI] [PubMed] [Google Scholar]
  15. Korbling M, Katz RL, Khanna A, Ruifrok AC, Rondon G, Albitar M, Champlin RE, Estrov Z. Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. N Engl J Med. 2002;346:738–746. doi: 10.1056/NEJMoa3461002. [DOI] [PubMed] [Google Scholar]
  16. Koukoulis G, Rayner A, Tan K-C, Williams R, Portmann B. Immunolocalization of regenerating cells after submassive liver necrosis using PCNA staining. J Pathol. 1992;166:359–368. doi: 10.1002/path.1711660407. [DOI] [PubMed] [Google Scholar]
  17. Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, Wang X, Finegold M, Weissman IL, Grompe M. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med. 2000;6:1229–1234. doi: 10.1038/81326. [DOI] [PubMed] [Google Scholar]
  18. Mallet VO, Mitchell C, Mezey E, Fabre M, Guidotti JE, Renia L, Coulombel L, Kahn A, Gilgenkrantz H. Bone marrow transplantation in mice leads to a minor population of hepatocytes that can be selectively amplified in vivo. Hepatology. 2002;35:799–804. doi: 10.1053/jhep.2002.32530. [DOI] [PubMed] [Google Scholar]
  19. Marceau N. Epithelial cell lineages in developing, restoring, and transforming liver: Evidence for the existence of a 'differentiation window'. Gut. 1994;35:294–296. doi: 10.1136/gut.35.3.294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Omori N, Omori M, Evarts RP, Teramoto T, Miller MJ, Hoang TN, Thorgeirsson SS. Partial cloning of rat CD34 cDNA and expression during stem cell-dependent liver regeneration in the adult rat. Hepatology. 1997;26:720–727. doi: 10.1002/hep.510260325. [DOI] [PubMed] [Google Scholar]
  21. Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA. 2001;98:10344–10349. doi: 10.1073/pnas.181177898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Overturf K, Al-Dhalimy M, Ou CN, Finegold M, Grompe M. Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes. Am J Pathol. 1997;151:1273–1280. [PMC free article] [PubMed] [Google Scholar]
  23. Petersen BE, Bowen WC, Patrene KD, Mars MW, Sullivan AK, Murase N, Boggs SS. Bone marrow as a potential source of hepatic oval cells. Science. 1999;284:1168–1170. doi: 10.1126/science.284.5417.1168. [DOI] [PubMed] [Google Scholar]
  24. Petersen BE, Goff JP, Greenberger JS, Michalopoulos GK. Hepatic oval cells express the hematopoietic stem cell marker Thy-1 in the rat. Hepatology. 1998;27:433–445. doi: 10.1002/hep.510270218. [DOI] [PubMed] [Google Scholar]
  25. Roskams T, Desmet V. Ductular reaction and its diagnostic significance. Sem Diag Pathol. 1998;15:259–269. [PubMed] [Google Scholar]
  26. Roskams T, De Vos R, Van Eyken P, Myazaki H, Van Damme B, Desmet V. Hepatic OV-6 expression in human liver disease and rat experiments: Evidence for hepatic progenitor cells in man. J Hepatol. 1998;29:455–463. doi: 10.1016/S0168-8278(98)80065-2. [DOI] [PubMed] [Google Scholar]
  27. Schwartz RE, Reyes M, Koodie L, Jiang Y, Blackstad M, Lund T, Lenvik T, Johnson S, Hu WS, Verfaillie CM. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest. 2002;109:1291–1302. doi: 10.1172/JCI200215182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sell S. Distribution of alpha-fetoprotein and albumin containing cells in the livers of Fischer rats fed four cycles of N-2-fluroenylacteamide. Cancer Res. 1978;38:3107–3113. [PubMed] [Google Scholar]
  29. Sell S. Heterogeneity and plasticity of hepatocyte lineage cells. Hepatology. 2001;33:738–750. doi: 10.1053/jhep.2001.21900. [DOI] [PubMed] [Google Scholar]
  30. Sell S, Sala-Trepat JM, Sargent TH, et al. Molecular mechanisms of control of albumin and alpha-fetoprotein production; A system to study the early effects of chemical hepatocarcinogens. Cell Biol Int Rep. 1980;4:134–254. doi: 10.1016/0309-1651(80)90056-9. [DOI] [PubMed] [Google Scholar]
  31. Sell S, Osborn K, Leffert H. Autoradiography of 'oval cells' appearing rapidly in the livers of rats fed N-2-fluorenylacetamide in a choline devoid diet. Carcinogenesis. 1981;2:7–14. doi: 10.1093/carcin/2.1.7. [DOI] [PubMed] [Google Scholar]
  32. Sell S, Leffert JL. An evaluation of cellular lineages in the pathogenesis of experimental hepatocellular carcinomas. Hepatology. 1982;2:77–86. doi: 10.1002/hep.1840020113. [DOI] [PubMed] [Google Scholar]
  33. Tan J, Hytiroglou P, Wieczorek R, Park YN, Thung SN, Arias B, Theise ND. Immunohistochemical evidence for hepatic progenitor cells in liver diseases. Liver. 2001;22:365–373. doi: 10.1034/j.1600-0676.2002.01622.x. [DOI] [PubMed] [Google Scholar]
  34. Theise ND, Saxena R, Portmann BC, Thung SN, Yee H, Chiriboga L, Kumar A, Crawford JM. The canals of Hering and hepatic stem cells in humans. Hepatology. 1999;30:1425–1433. doi: 10.1002/hep.510300614. [DOI] [PubMed] [Google Scholar]
  35. Theise ND, Badve S, Saxena R, Henegariu O, Sell S, Crawford JM, Krause DS. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology. 2000;31:235–240. doi: 10.1002/hep.510310135. [DOI] [PubMed] [Google Scholar]
  36. Theise ND, Nimmakayalu M, Gardner R, Illei P, Morgan G, Teperman L, Henegariu O, Krause DS. Liver from bone marrow in humans. Hepatology. 2000;32:11–16. doi: 10.1053/jhep.2000.9124. [DOI] [PubMed] [Google Scholar]
  37. Theise ND, Krause DS. Toward a new paradigm of cell differentation capacity. Leukemia. 2002;16:542–548. doi: 10.1038/sj.leu.2402445. [DOI] [PubMed] [Google Scholar]
  38. Theise ND (in press) New principles of cell plasticity. Comptes Rendus Biologies. [DOI] [PubMed]
  39. Thorgeirsson SS. Hepatic stem cells in liver regeneration. FASEB J. 1996;10:1249–1256. [PubMed] [Google Scholar]
  40. Thung SN. The development of proliferating ductular structures in liver disease: An immunohistochemical study. Arch Pathol Lab Med. 1990;114:407–411. [PubMed] [Google Scholar]
  41. Van Eyken P, Sciot R, Desmet VJ. A cytokeratin immunohistochemical study of cholestatic liver disease: Evidence that hepatocytes can express 'bile duct type' cytokeratins. Histopathology. 1988;13:605–617. doi: 10.1111/j.1365-2559.1988.tb02092.x. [DOI] [PubMed] [Google Scholar]
  42. Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science. 2002;297:2256–2259. doi: 10.1126/science.1074807. [DOI] [PubMed] [Google Scholar]
  43. Wang X, Montini E, Al-Dhalimy M, Lagasse E, Finegold M, Grompe M. Kinetics of liver repopulation after bone marrow transplantation. Am J Pathol. 2002;161:565–574. doi: 10.1016/S0002-9440(10)64212-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wilson JW, Leduc RH. Role of cholangioles in restoration of the liver of the mouse after dietary injury. J Pathol Bacteriol. 1958;76:441–449. doi: 10.1002/path.1700760213. [DOI] [PubMed] [Google Scholar]
  45. Yavorkovsky L, Lai E, Ilic Z, Sell S. Participation of small intraportal stem cells in the restitutive response of the liver to periportal necrosis induced by allyl alcohol. Hepatology. 1995;21:1702–1712. doi: 10.1016/0270-9139(95)90478-6. [DOI] [PubMed] [Google Scholar]

Articles from Cytotechnology are provided here courtesy of Springer Science+Business Media B.V.

RESOURCES