Semin Liver Dis 2003; 23(4): 363-372
DOI: 10.1055/s-2004-815560
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

The Role of Bone Marrow Stem Cells in Liver Regeneration

Markus Grompe
  • Professor, Department of Molecular and Medical Genetics L103, Oregon Health and Science University, Portland, Oregon
Further Information

Publication History

Publication Date:
14 January 2004 (online)

ABSTRACT

Hepatic oval cells involved in some forms of liver regeneration express many markers also found on hematopoietic stem cells (HSCs). In addition, multiple independent reports have demonstrated that bone marrow cells can give rise to several hepatic epithelial cell types, including oval cells, hepatocytes, and duct epithelium. These observations have resulted in the hypothesis that bone marrow resident stem cells, specifically HSCs, are an important source for liver epithelial cell replacement, particularly during chronic injury. The function of such stem cells in hepatic injury responses is the topic of this article. Taken together, the published data on the role of bone marrow stem cells in liver damage suggest that they do not play a significant physiological role in the replacement of epithelial cells in any known form of hepatic injury. Fully functional bone marrow-derived hepatocytes exist but are extremely rare and are generated by cell fusion, not stem cell differentiation. Nonetheless, bone marrow-derived cells may play important indirect roles in liver regeneration. First, they may serve as a source for the replacement of endothelial cells. Second, hematopoietic cells, including lymphocytes, neutrophils, macrophages, and platelets, may provide crucial factors required for efficient healing of damaged liver.

REFERENCES

  • 1 Michalopoulos G K, DeFrances M C. Liver regeneration.  Science . 1997;  276 60-66
  • 2 Bucher N LR, Swaffield M N. The rate of incorporation of labeled thymidine into the deoxyribonucleic acid of regenerating rat liver in relation to the amount of liver excised.  Cancer Res . 1964;  240 1611-1625
  • 3 Stocker E, Pfeifer U. On the manner of proliferation of the liver parenchyma after partial hepatectomy. Autoradiography studies using 3H-thymidine.  Naturwissenschaften . 1965;  52 663
  • 4 Stocker E, Wullstein H K, Brau G. Capacity of regeneration in liver epithelia of juvenile, repeated partially hepatectomized rats. Autoradiographic studies after continous infusion of 3H-thymidine.  Virchows Arch B Cell Pathol . 1973;  14 93-103
  • 5 Sell S, Ilic Z. Liver Stem Cells Austin.  New York: Landes Bioscience, Chapman & Hall; 1997
  • 6 Fausto N. Liver stem cells. In: Arias IM, ed. The Liver-Biology and Pathobiology, 3rd ed New York: Raven Press 1994: 1501-1518
  • 7 Alison M R, Golding M, Sarraf C E. Liver stem cells: when the going gets tough they get going.  Int J Exp Pathol . 1997;  78 365-381
  • 8 Sell S. Liver stem cells.  Mod Pathol . 1994;  7 105-112
  • 9 Thorgeirsson S S. Hepatic stem cells in liver regeneration.  FASEB J . 1996;  10 1249-1256
  • 10 Grompe M, Finegold M. Liver stem cells. In: Marshak DR, Gardner RL, Gottlieb D, eds. Stem Cell Biology Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2001: 455-497
  • 11 Fausto N, Campbell J S. The role of hepatocytes and oval cells in liver regeneration and repopulation.  Mech Dev . 2003;  120 117-130
  • 12 Shinozuka H, Lombardi B, Sell S, Iammarino R M. Early histological and functional alterations of ethionine liver carcinogenesis in rats fed a choline-deficient diet.  Cancer Res . 1978;  38 1092-1098
  • 13 Solt D B, Medline A, Farber E. Rapid emergence of carcinogen-induced hyperplastic lesions in a new model for the sequential analysis of liver carcinogenesis.  Am J Pathol . 1977;  88 595-618
  • 14 Potten C S. Stem Cells.  New York: Academic Press; 1997
  • 15 Alison M, Golding M, Lalani E N. et al . Wholesale hepatocytic differentiation in the rat from ductular oval cells, the progeny of biliary stem cells.  J Hepatol . 1997;  26 343-352
  • 16 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;  139 535-552
  • 17 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
  • 18 Plenat F, Braun L, Fausto N. Demonstration of glucose-6-phosphatase and peroxisomal catalase activity by ultrastructural cytochemistry in oval cells from livers of carcinogen-treated rats.  Zentralbl Allg Pathol . 1990;  136 135-149
  • 19 Golding M, Sarraf C E, Lalani E N. et al . Oval cell differentiation into hepatocytes in the acetylaminofluorene- treated regenerating rat liver.  Gastroenterology . 1996;  110 1182-1190
  • 20 Novikoff P M, Ikeda T, Hixson D C, Yam A. Characterizations of and interactions between bile ductule cells and hepatocytes in early stages of rat hepatocarcinogenesis induced by ethionine.  Am J Pathol . 1991;  139 1351-1368
  • 21 Theise N D, Saxena R, Portmann B C. et al . The canals of Hering and hepatic stem cells in humans.  Hepatology . 1999;  30 1425-1433
  • 22 Petersen B E, Bowen W C, Patrene K D. et al . Bone marrow as a potential source of hepatic oval cells.  Science . 1999;  284 1168-1170
  • 23 Crosby H A, Kelly D A, Strain A J. Human hepatic stem-like cells isolated using c-kit or CD34 can differentiate into biliary epithelium.  Gastroenterology . 2001;  120 534-544
  • 24 Block G D, Locker J, Bowen W C. et al . Population expansion, clonal growth, and specific differentiation patterns in primary cultures of hepatocytes induced by HGF/SF, EGF and TGF alpha in a chemically defined (HGM) medium.  J Cell Biol . 1996;  132 1133-1149
  • 25 Braun K M, Sandgren E P. Cellular origin of regenerating parenchyma in a mouse model of severe hepatic injury.  Am J Pathol . 2000;  157 561-569
  • 26 Coleman W B, Presnell S C. Plasticity of the hepatocyte phenotype in vitro: complex phenotypic transitions in proliferating hepatocyte cultures suggest bipotent differentiation capacity of mature hepatocytes.  Hepatology . 1996;  24 1542-1546
  • 27 Michalopoulos G K, Bowen W C, Mule K. et al . Hepatocytes undergo phenotypic transformation to biliary epithelium in organoid cultures.  Hepatology . 2002;  36 278-283
  • 28 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
  • 29 Spangrude G J, Heimfeld S, Weissman I L. Purification and characterization of mouse hematopoietic stem cells.  Science . 1988;  241 58-62
  • 30 Petersen B E, Goff J P, Greenberger J S, Michalopoulos G K. Hepatic oval cells express the hematopoietic stem cell marker Thy-1 in the rat.  Hepatology . 1998;  27 433-445
  • 31 Petersen B E, Grossbard B, Hatch H. et al . Mouse A6-positive hepatic oval cells also express several hematopoietic stem cell markers.  Hepatology . 2003;  37 632-640
  • 32 Thomas E, Storb R, Clift R A. et al . Bone-marrow transplantation (first of two parts).  N Engl J Med . 1975;  292 832-843
  • 33 Thomas E D, Storb R, Clift R A. et al . Bone-marrow transplantation (second of two parts).  N Engl J Med . 1975;  292 895-902
  • 34 Bjornson C R, Rietze R L, Reynolds B A. et al . Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo.  Science . 1999;  283 534-537
  • 35 Ferrari G, Cusella-De Angelis G, Coletta M. et al . Muscle regeneration by bone marrow-derived myogenic progenitors.  Science . 1998;  279 1528-1530
  • 36 Mezey E, Chandross K J, Harta G. et al . Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow.  Science . 2000;  290 1779-1782
  • 37 Omori M, Evarts R P, Omori N. et al . Expression of alpha-fetoprotein and stem cell factor/c-kit system in bile duct ligated young rats.  Hepatology . 1997;  25 1115-1122
  • 38 Theise 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
  • 39 Theise N D, Nimmakayalu M, Gardner R. et al . Liver from bone marrow in humans.  Hepatology . 2000;  32 11-16
  • 40 Alison M R, Poulsom R, Jeffery R. et al . Hepatocytes from non-hepatic adult stem cells.  Nature . 2000;  406 257
  • 41 Korbling M, Katz R L, Khanna A. et al . Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells.  N Engl J Med . 2002;  346 738-746
  • 42 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
  • 43 Krause D S, Theise N D, Collector M I. et al . Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell.  Cell . 2001;  105 369-377
  • 44 Lanzkron S M, Collector M I, Sharkis S J. Hematopoietic stem cell tracking in vivo: a comparison of short-term and long-term repopulating cells.  Blood . 1999;  93 1916-1921
  • 45 Jiang Y, Jahagirdar B N, Reinhardt R L. et al . Pluripotency of mesenchymal stem cells derived from adult marrow.  Nature . 2002;  418 41-49
  • 46 Reyes M, Verfaillie C M. Characterization of multipotent adult progenitor cells, a subpopulation of mesenchymal stem cells.  Ann N Y Acad Sci . 2001;  938 231-233
  • 47 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
  • 48 Grompe M. Adult versus embryonic stem cells: it's still a tie.  Mol Ther . 2002;  6 303-305
  • 49 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
  • 50 Danet G H, Luongo J L, Butler G. et al . C1qRp defines a new human stem cell population with hematopoietic and hepatic potential.  Proc Natl Acad Sci USA . 2002;  99 10441-10445
  • 51 Ponder K P, Gupta S, Leland F. et al . Mouse hepatocytes migrate to liver parenchyma and function indefinitely after intrasplenic transplantation.  Proc Natl Acad Sci USA . 1991;  88 1217-1221
  • 52 Gao Z, McAlister V C, Williams G M. Repopulation of liver endothelium by bone-marrow-derived cells.  Lancet . 2001;  357 932-933
  • 53 Mallet V O, Mitchell C, Mezey E. et al . Bone marrow transplantation in mice leads to a minor population of hepatocytes that can be selectively amplified in vivo.  Hepatology . 2002;  35 799-804
  • 54 Wagers A J, Sherwood R I, Christensen J L, Weissman I L. Little evidence for developmental plasticity of adult hematopoietic stem cells.  Science . 2002;  297 2256-2259
  • 55 Wang X, Montini E, Al-Dhalimy M. et al . Kinetics of liver repopulation after bone marrow transplantation.  Am J Pathol . 2002;  161 565-574
  • 56 Wang X, Foster M, Al-Dhalimy M. et al . The origin and liver repopulating capacity of murine oval cells (in press).  Proc Natl Acad Sci USA 2003.
  • 57 Preisegger K H, Factor V M, Fuchsbichler A. et al . Atypical ductular proliferation and its inhibition by transforming growth factor beta1 in the w mouse model for chronic alcoholic liver disease.  Lab Invest . 1999;  79 103-109
  • 58 Hattori K, Heissig B, Wu Y. et al . Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment.  Nat Med . 2002;  8 841-849
  • 59 Murayama T, Asahara T. Bone marrow-derived endothelial progenitor cells for vascular regeneration.  Curr Opin Mol Ther . 2002;  4 395-402
  • 60 Grant M B, May W S, Caballero S. et al . Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization.  Nat Med . 2002;  8 607-612
  • 61 Matsumoto K, Yoshitomi H, Rossant J, Zaret K S. Liver organogenesis promoted by endothelial cells prior to vascular function.  Science . 2001;  294 559-563
  • 62 Orlic D, Kajstura J, Chimenti S. et al . Transplanted adult bone marrow cells repair myocardial infarcts in mice.  Ann N Y Acad Sci . 2001;  938 221-229
  • 63 Orlic D, Kajstura J, Chimenti S. et al . Bone marrow cells regenerate infarcted myocardium.  Nature . 2001;  410 701-705
  • 64 Orlic D, Kajstura J, Chimenti S. et al . Mobilized bone marrow cells repair the infarcted heart, improving function and survival.  Proc Natl Acad Sci USA . 2001;  98 10344-10349
  • 65 Pereira R F, Halford K W, O'Hara M D. et al . Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice.  Proc Natl Acad Sci USA . 1995;  92 4857-4861
  • 66 Prockop D J. Marrow stromal cells as stem cells for nonhematopoietic tissues.  Science . 1997;  276 71-74
  • 67 Petersen B E. Hepatic “stem” cells: coming full circle.  Blood Cells Mol Dis . 2001;  27 590-600
  • 68 Ying Q L, Nichols J, Evans E P, Smith A G. Changing potency by spontaneous fusion.  Nature . 2002;  416 545-548
  • 69 Terada N, Hamazaki T, Oka M. et al . Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion.  Nature . 2002;  416 542-545
  • 70 Wang X, Willenbring H, Akkari Y. et al . Cell fusion is the principal source of bone-marrow-derived hepatocytes.  Nature . 2003;  422 897-901
  • 71 Vassilopoulos G, Wang P R, Russell D W. Transplanted bone marrow regenerates liver by cell fusion.  Nature . 2003;  422 901-904
  • 72 Yim A P. Some flow-cytofluorimetric studies of the nuclear ploidy of mouse hepatocytes: iii. Further observations on early changes in nuclear ploidy of mouse hepatocytes following various experimental procedures.  Br J Exp Pathol . 1982;  63 458-461
  • 73 Auvigne I, Pichard V, Aubert D. et al . In vivo cell lineage analysis in cyproterone acetate-treated rat liver using genetic labeling of hepatocytes.  Hepatology . 2002;  35 281-288
  • 74 Faktor V M, Uryvaeva I V. Progressive polyploidy in mouse liver following repeated hepatectomy.  Tsitologiia . 1975;  17 909-916
  • 75 Martin G M, Sprague C A. Vinblastine induces multipolar mitoses in tetraploid human cells.  Exp Cell Res . 1970;  63 466-467
  • 76 Mitchell C, Fausto N. Bone marrow-derived hepatocytes: rare but promising.  Am J Pathol . 2002;  161 349-350
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