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Bone marrow transplantation results in donor-derived hepatocytes in an animal model of inherited cholestatic liver disease

  • Original Paper
  • Published:
Journal of Biomedical Science

Abstract

Cell transplantation is a potential therapy for acquired or inherited liver diseases. Donor-derived hepatocytes (DDH) have been found in humans and mice after bone marrow transplantation (BMT) but with highly variable frequencies in different disease models. To test the effect of liver repopulation after BMT in inherited cholestatic liver diseases, spgp (sister of P-glycoprotein, or bile salt export pump, abcb11) knockout mice, a model for human progressive intrahepatic cholestasis type 2 with defects in excreting bile salts across the hepatocyte canalicular membrane, were transplanted with bone marrow cells from enhanced green fluorescent protein (EGFP) transgenic donor mice after lethal irradiation. One to 6 months later, scattered EGFP-positive DDHs with positive spgp staining were observed in the liver. These hepatocytes had been incorporated into hepatic plates and stained positively with hepatocyte-specific marker albumin. RT-PCR for the spgp gene revealed positive expression in the liver of sgsp knockout mice that had received the transplant. Bile acid analysis of bile samples showed that these mice also had higher levels of total biliary bile acid and taurocholic acid concentration than knockout mice without transplantation, indicating that BMT partially improved biliary bile acid secretion. Our results indicate that bone marrow cells could serve as a potential source for restoration of hepatic functions in chronic metabolic liver disease.

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References

  1. Fausto N (2004) Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 39:1477–1487

    Article  PubMed  Google Scholar 

  2. Fox IJ, Roy-Chowdhury J (2004) Hepatocyte transplantation. J Hepatol 40:878–886

    Article  PubMed  CAS  Google Scholar 

  3. Brazelton TR, Rossi FM, Keshet GI, Blau HM (2000) From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290:1775–1779

    Article  PubMed  CAS  Google Scholar 

  4. Theise ND, Badve S, Saxena R, Henegariu O, Sell S, Crawford JM, Krause DS (2000) Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology 31:235–240

    Article  PubMed  CAS  Google Scholar 

  5. Gussoni E, Soneoka Y, Strickland CD, Buzney EA, Khan MK, Flint AF, Kunkel LM, Mulligan RC (1999) Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401:390–394

    PubMed  CAS  Google Scholar 

  6. Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P (2001) Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 98:10344–10349

    Article  PubMed  CAS  Google Scholar 

  7. Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, Boggs SS, Greenberger JS, Goff JP (1999) Bone marrow as a potential source of hepatic oval cells. Science 284:1168–1170

    Article  PubMed  CAS  Google Scholar 

  8. Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, Neutzel S, Sharkis SJ (2001) Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105:369–377

    Article  PubMed  CAS  Google Scholar 

  9. Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, Henegariu O, Krause DS (2000) Liver from bone marrow in humans. Hepatology 32:11–16

    Article  PubMed  CAS  Google Scholar 

  10. Korbling M, Katz RL, Khanna A, Ruifrok AC, Rondon G, Albitar M, Champlin RE, Estrov Z (2002) Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. N Engl J Med 346:738–746

    Article  PubMed  Google Scholar 

  11. Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, Wang X, Finegold M, Weissman IL, Grompe M (2000) Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 6:1229–1234

    Article  PubMed  CAS  Google Scholar 

  12. Kanazawa Y, Verma IM (2003) Little evidence of bone marrow-derived hepatocytes in the replacement of injured liver. Proc Natl Acad Sci USA 100(Suppl 1):11850–11853

    Article  PubMed  CAS  Google Scholar 

  13. Wang X, Montini E, Al-Dhalimy M, Lagasse E, Finegold M, Grompe M (2002) Kinetics of liver repopulation after bone marrow transplantation. Am J Pathol 161:565–574

    PubMed  Google Scholar 

  14. Wang R, Salem M, Yousef IM, Tuchweber B, Lam P, Childs SJ, Helgason CD, Ackerley C, Phillips MJ, Ling V (2001) Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis. Proc Natl Acad Sci USA 98:2011–2016

    Article  PubMed  CAS  Google Scholar 

  15. Strautnieks SS, Bull LN, Knisely AS, Kocoshis SA, Dahl N, Arnell H, Sokal E, Dahan K, Childs S, Ling V, Tanner MS, Kagalwalla AF, Nemeth A, Pawlowska J, Baker A, Mieli-Vergani G, Freimer NB, Gardiner RM, Thompson RJ (1998) A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Gen 20:233–238

    Article  CAS  Google Scholar 

  16. Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, Scott EW (2002) Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416:542–545

    Article  PubMed  CAS  Google Scholar 

  17. Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Olson S, Grompe M (2003) Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422:897–901

    Article  PubMed  CAS  Google Scholar 

  18. Vassilopoulos G, Wang PR, Russell DW (2003) Transplanted bone marrow regenerates liver by cell fusion. Nature 422:901–904

    Article  PubMed  CAS  Google Scholar 

  19. Willenbring H, Bailey AS, Foster M, Akkari Y, Dorrell C, Olson S, Finegold M, Fleming WH, Grompe M (2004) Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med 10:744–748

    Article  PubMed  CAS  Google Scholar 

  20. Camargo FD, Finegold M, Goodell MA (2004) Hematopoietic myelomonocytic cells are the major source of hepatocyte fusion partners. J Clin Invest 113:1266–1270

    PubMed  CAS  Google Scholar 

  21. Piscaglia AC, Shupe TD, Oh SH, Gasbarrini A, Petersen BE (2007) Granulocyte-colony stimulating factor promotes liver repair and induces oval cell migration and proliferation in rats. Gastroenterology 133:619–631

    Article  PubMed  CAS  Google Scholar 

  22. Mallet VO, Mitchell C, Mezey E, Fabre M, Guidotti JE, Renia L, Coulombel L, Kahn A, Gilgenkrantz H (2002) Bone marrow transplantation in mice leads to a minor population of hepatocytes that can be selectively amplified in vivo. Hepatology 35:799–804

    Article  PubMed  Google Scholar 

  23. Wang R, Lam P, Liu L, Forrest D, Yousef IM, Mignault D, Phillips MJ, Ling V (2003) Severe cholestasis induced by cholic acid feeding in knockout mice of sister of P-glycoprotein. Hepatology 38:1489–1499

    PubMed  CAS  Google Scholar 

  24. Schatteman GC, Hanlon HD, Jiao C, Dodds SG, Christy BA (2000) Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice. J Clin Invest 106:571–578

    Article  PubMed  CAS  Google Scholar 

  25. Yu S, Tanabe T, Dezawa M, Ishikawa H, Yoshimura N (2006) Effects of bone marrow stromal cell injection in an experimental glaucoma model. Biochem Biophys Res Commun 344:1071–1079

    Article  PubMed  CAS  Google Scholar 

  26. Sakaida I, Terai S, Yamamoto N, Aoyama K, Ishikawa T, Nishina H, Okita K (2004) Transplantation of bone marrow cells reduce CCl4-induced liver fibrosis in mice. Hepatology 40:1304–1311

    Article  PubMed  Google Scholar 

  27. Baba S, Fujii H, Hirose T, Yasuchika K, Azuma H, Hoppo T, Naito M, Machimoto T, Ikai I (2004) Commitment of bone marrow cells to hepatic stellate cells in mouse. J Hepatol 40:255–260

    Article  PubMed  Google Scholar 

  28. Gao Z, McAlister VC, Williams GM (2001) Repopulation of liver endothelium by bone-marrow-derived cells. Lancet 357:932–933

    Article  PubMed  CAS  Google Scholar 

  29. Terai S, Ishikawa T, Omori K, Aoyama K, Marumoto Y, Urata Y, Yokoyama Y, Uchida K, Yamasaki T, Fujii Y, Okita K, Sakaida I (2006) Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells 24:2292–2298

    Article  PubMed  CAS  Google Scholar 

  30. Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR, Warkentin PI, Dorko K, Sauter BV, Strom SC (1998) Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med 338:1422–1426

    Article  PubMed  CAS  Google Scholar 

  31. Muraca M, Gerunda G, Neri D, Vilei MT, Granato A, Feltracco P, Meroni M, Giron G, Burlina AB (2002) Hepatocyte transplantation as a treatment for glycogen storage disease type 1a. Lancet 359:317–318

    Article  PubMed  Google Scholar 

  32. Oertel M, Menthena A, Dabeva MD, Shafritz DA (2006) Cell competition leads to a high level of normal liver reconstitution by transplanted fetal liver stem/progenitor cells. Gastroenterology 130:507–520

    Article  PubMed  Google Scholar 

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Acknowledgements

This project was in part supported by grant from the Canadian Institute of Health Research (MOP 42560), National Taiwan University Hospital (NTUH 93A12-1), and the National Science Council, Taiwan, ROC (NSC 96-2752-B-002-010-PAE). The authors thank Kevin Kao, Camila Alverez, Rebecca Ng, Yu-Jung Liu, and Shi-Ping Chou for technical assistance.

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Authors and Affiliations

  1. Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan, ROC

    Huey-Ling Chen, Wuh-Liang Hwu & Mei-Hwei Chang

  2. Department of Primary Care Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan, ROC

    Huey-Ling Chen

  3. Department of Cancer Genetics, British Columbia Cancer Research Center, British Columbia Cancer Agency, Vancouver, BC, Canada, V5Z 1L3

    Renxue Wang & Victor Ling

  4. Department of Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan, ROC

    Hui-Ling Chen

  5. Department of Pathology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan, ROC

    Yung-Ming Jeng

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  1. Huey-Ling Chen
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  2. Renxue Wang
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Correspondence to Victor Ling.

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Chen, HL., Wang, R., Chen, HL. et al. Bone marrow transplantation results in donor-derived hepatocytes in an animal model of inherited cholestatic liver disease. J Biomed Sci 15, 615–622 (2008). https://doi.org/10.1007/s11373-008-9255-x

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  • DOI: https://doi.org/10.1007/s11373-008-9255-x

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