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Lesson from the GFP/CCl4 model — Translational Research Project: the development of cell therapy using autologous bone marrow cells in patients with liver cirrhosis

  • Published:
Journal of Hepato-Biliary-Pancreatic Surgery

Abstract

The plasticity of bone marrow has been confirmed by the analysis of autopsy findings in female recipients of bone marrow cells transplanted from male donors. To establish new clinical cell therapies using autologous bone marrow cells for patients with liver failure, we developed a new in vivo model, the “green fluorescent protein (GFP)/carbon tetrachloride (CCl4) model”. Using the GFP/CCl4 model, we found that transplanted Liv8-negative cells efficiently repopulated into cirrhotic liver tissue and trans-differentiated into albumin-producing hepatocytes under conditions of persistent liver damage induced by CCl4. Moreover, one marrow cell transplantation into liver cirrhosis mice improved their liver function, ameliorated liver fibrosis, and improved their survival rate. Results from the GFP/CCl4 model showed that cell therapy using autologous bone marrow cells has the potential to become an effective treatment for patients with liver failure. Here we describe the findings from the GFP/CCl4 model and the scope of the translational research project.

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References

  1. MR Alison R Poulsom R Jeffery AP Dhillon A Quaglia J Jacob M Novelli (2000) ArticleTitleHepatocytes from non-hepatic adult stem cells Nature 406 257 Occurrence Handle1:CAS:528:DC%2BD3cXlsFKju74%3D Occurrence Handle10917519

    CAS  PubMed  Google Scholar 

  2. ND Theise M Nimmakayalu R Gardnre PB Illei G Morgan L Teperman O Henegariu (2000) ArticleTitleLiver from bone marrow in humans Hepatology 32 11–16 Occurrence Handle1:STN:280:DC%2BD3czjtVShtQ%3D%3D Occurrence Handle10869283

    CAS  PubMed  Google Scholar 

  3. M Korbling RL Katz A Khanna AC Ruifrok G Rondon M Albitar RE Champlin (2002) ArticleTitleHepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells N Engl J Med 346 738–746 Occurrence Handle11882729

    PubMed  Google Scholar 

  4. R Okamoto T Yajima M Yamazaki T Kanai M Mukai S Okamoto Y Ikeda (2002) ArticleTitleDamaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract Nat Med 8 1011–1017 Occurrence Handle1:CAS:528:DC%2BD38Xms1aitL8%3D Occurrence Handle12195435

    CAS  PubMed  Google Scholar 

  5. S Terai N Yamamoto K Omori I Sakaida K Okita (2002) ArticleTitleA new cell therapy using bone marrow cells to repair damaged liver J Gastroenterol 37 IssueIDs14 162–163 Occurrence Handle1:CAS:528:DC%2BD38XpsleqtbY%3D Occurrence Handle12572886

    CAS  PubMed  Google Scholar 

  6. D Orlic J Kajstura S Chimenti I Jakoniuk SM Anderson B Li J Pickel (2001) ArticleTitleBone marrow cells regenerate infarcted myocardium Nature 410 701–705 Occurrence Handle1:CAS:528:DC%2BD3MXivFSmsb4%3D Occurrence Handle11287958

    CAS  PubMed  Google Scholar 

  7. C Stamm B Westphal HD Kleine M Petzsch C Kittner H Klinge C Schumichen (2003) ArticleTitleAutologous bone-marrow stem-cell transplantation for myocardial regeneration Lancet 361 45–46 Occurrence Handle12517467

    PubMed  Google Scholar 

  8. SA Wexler C Donaldson P Denning-Kendall C Rice B Bradley JM Hows (2003) ArticleTitleAdult bone marrow is a rich source of human mesenchymal “stem” cells but umbilical cord and mobilized adult blood are not Br J Haematol 121 368–374 Occurrence Handle12694261

    PubMed  Google Scholar 

  9. K Hamano TS Li T Kobayashi K Hirata M Yano M Kohno M Matsuzaki (2002) ArticleTitleTherapeutic angiogenesis induced by local autologous bone marrow cell implantation Ann thorac Surg 73 1210–1215 Occurrence Handle11996265

    PubMed  Google Scholar 

  10. E Tateishi-Yuyama H Matsubara T Murohara U Ikeda S Shintani H Masaki K Amano (2002) ArticleTitleTherapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial Lancent 360 427–435

    Google Scholar 

  11. N Terada T Hamazaki M Oka M Hoki DM Mastalerz Y Nakano EM Meyer (2002) ArticleTitleBone marrow cells adopt the phenotype of other cells by spontaneous cell fusion Nature 416 542–545 Occurrence Handle1:CAS:528:DC%2BD38XivVOntLk%3D Occurrence Handle11932747

    CAS  PubMed  Google Scholar 

  12. QL Ying J Nichols EP Evans AG Smith (2002) ArticleTitleChanging potency by spontaneous fusion Nature 416 545–548 Occurrence Handle1:CAS:528:DC%2BD38XivVOntb4%3D Occurrence Handle11932748

    CAS  PubMed  Google Scholar 

  13. DS Krause ND Theise MI Collector O Henegariu S Hwang R Gardner S Neutzel (2001) ArticleTitleMulti-organ, multi-lineage engraftment by a single bone marrow derived stem cell. Cell 105 369–377 Occurrence Handle1:CAS:528:DC%2BD3MXjs1aitrY%3D

    CAS  Google Scholar 

  14. A Ianus GG Holz ND Theise MA Hussain (2003) ArticleTitleIn vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion J Clin Invest 111 843–850 Occurrence Handle1:CAS:528:DC%2BD3sXitlOjtr8%3D Occurrence Handle12639990

    CAS  PubMed  Google Scholar 

  15. S Terai I Sakaida N Yamamoto K Omori T Watanabe S Ohata T Katada (2003) ArticleTitleAn in vivo model for monitoring trans-differentiation of bone marrow cells into functional hepatocytes J Biochem Tokyo 134 551–558 Occurrence Handle1:CAS:528:DC%2BD3sXhtVWgtbrK Occurrence Handle14607982

    CAS  PubMed  Google Scholar 

  16. M Okabe M Ikawa K Kominami T Nakanishi Y Nishimune (1997) ArticleTitleldquo;Green mice” as a source of ubiquitous green cells FEBS Lett 407 313–319 Occurrence Handle1:CAS:528:DyaK2sXivFyrsrY%3D Occurrence Handle9175875

    CAS  PubMed  Google Scholar 

  17. K Shinoda S Mori T Ohtsuki Y Osawa (1992) ArticleTitleAn aromatase-associated cytoplasmic inclusion, the “stigmoid body,” in the rat brain: I. distribution in the forebrain J Comp Neurol 322 360–376 Occurrence Handle1:STN:280:By2A1cfltFc%3D Occurrence Handle1325485

    CAS  PubMed  Google Scholar 

  18. N Yamamoto S Terai S Ohata T Watanabe K Omori K Shinoda K Miyamoto (2004) ArticleTitleA subpopulation of bone marrow cells depleted by a novel antibody, anti-Liv8, is useful for cell therapy to repair damaged liver Biochem Biophys Res Commun 313 1110–1118 Occurrence Handle1:CAS:528:DC%2BD2cXosFKg Occurrence Handle14706657

    CAS  PubMed  Google Scholar 

  19. T Watanabe K Nakagawa S Ohata D Kitagawa G Nishitai J Seo S Tanemura (2002) ArticleTitleSEK1/MKK4-Mediated SAPK/JNK signaling participates in embryonic hepatoblast proliferation via a pathway different from NF-kappaB-induced anti apoptosis Dev Biol 250 332–347 Occurrence Handle1:CAS:528:DC%2BD38XnsFSnt7w%3D

    CAS  Google Scholar 

  20. JW Grisham SS Thorgeirsson (1997) Liver stem cells Academic Manchester 233–282

    Google Scholar 

  21. BE Petersen VF Zajac GK Michalopoulos (1998) ArticleTitleHepatic oval cell activation in response to injury following chemically induced periportal or pericentral damage in rates Hepatology 27 1030–1038 Occurrence Handle1:CAS:528:DyaK1cXisFCktrg%3D Occurrence Handle9537443

    CAS  PubMed  Google Scholar 

  22. BE Petersen WC Bowen KD Patrene WM Mars AK Sullivan N Murase SS Boggs (1999) ArticleTitleBone marrow as a potential source of hepatic oval cells Science 284 1168–1170 Occurrence Handle1:CAS:528:DyaK1MXjtlajsL4%3D Occurrence Handle10325227

    CAS  PubMed  Google Scholar 

  23. E Lagasse H Connors M Al-Dhalimy M Reitsma M Dohse L Osborne X Wang (2000) ArticleTitlePurified hematopoietic stem cells can differentiate into hepatocyes in vivo Nat Med 6 1229–1234 Occurrence Handle1:CAS:528:DC%2BD3cXotVaqtLY%3D Occurrence Handle11062533

    CAS  PubMed  Google Scholar 

  24. N Uchida T Fujisaki AC Eaves CJ Eaves (2001) ArticleTitleTransplantable hematopoietic stem cells in human fetal liver have a CD34(+) side population (SP) phenotype J Clin Invest 108 1071–1077 Occurrence Handle1:CAS:528:DC%2BD3MXnt1Crs74%3D Occurrence Handle11581308

    CAS  PubMed  Google Scholar 

  25. MF Pittenger AM Mackay SC Beck RK Jaiswal R Douglas JD Mosca MA Moorman (1999) ArticleTitleMultilineage potential of adult human mesenchymal stem cells Science 284 143–147 Occurrence Handle1:CAS:528:DyaK1MXitlCnu7o%3D Occurrence Handle10102814

    CAS  PubMed  Google Scholar 

  26. T Kinoshita A Miyajima (2002) ArticleTitleCytokine regulation of liver development Biochim Biophys Acta 1592 303–312 Occurrence Handle1:CAS:528:DC%2BD38Xotl2nsrs%3D Occurrence Handle12421674

    CAS  PubMed  Google Scholar 

  27. I Sakaida S Terai N Yamamoto K Aoyama T Ishikawa H Nishina K Okita (2004) ArticleTitleTransplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice Hepatology 40 1304–1311 Occurrence Handle15565662

    PubMed  Google Scholar 

  28. X Wang H Willenbring Y Akkari Y Torimaru M Foster M Al-Dhalimy E Lagasse (2003) ArticleTitleCell fusion is the principal source of bone-marrow-derived hepatocytes Nature 422 897–901 Occurrence Handle1:CAS:528:DC%2BD3sXjtFCitLs%3D Occurrence Handle12665832

    CAS  PubMed  Google Scholar 

  29. G Vassilopoulos PR Wang DW Russell (2003) ArticleTitleTransplanted bone marrow regenerates liver by cell fusion Nature 422 901–904 Occurrence Handle1:CAS:528:DC%2BD3sXjtFCitLg%3D Occurrence Handle12665833

    CAS  PubMed  Google Scholar 

  30. SD Tran SR Pillemer A Dutra AJ Barrett MJ Brownstein S Key E Pak (2003) ArticleTitleDifferentiation of human bone marrow-derived cells into buccal epithelial cells in vivo: a molecular analytical study Lancet 361 1084–1088 Occurrence Handle12672312

    PubMed  Google Scholar 

  31. M Schena D Shalon RW Davis PO Brown (1995) ArticleTitleQuantitative monitoring of gene expression patterns with a complementary DNA microarray Science 270 467–470 Occurrence Handle1:CAS:528:DyaK2MXovVersLk%3D Occurrence Handle7569999

    CAS  PubMed  Google Scholar 

  32. L Xiao K Wang Y Teng J Zhang (2003) ArticleTitleComponent plane presentation integrated self-organizing map for microarray data analysis FEBS Lett 538 117–124 Occurrence Handle1:CAS:528:DC%2BD3sXhvFKisL8%3D Occurrence Handle12633864

    CAS  PubMed  Google Scholar 

  33. K Omori S Terai T Ishikawa K Aoyama I Sakaida H Nishina (2004) ArticleTitleMolecular signature associated with plasticity of bone marrow cells under prsistent liver damage by self-organizing-map-based gene expression FEBS Lett 578 10–20 Occurrence Handle1:CAS:528:DC%2BD2cXhtVClt7jE Occurrence Handle15581608

    CAS  PubMed  Google Scholar 

Download references

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Terai, S., Sakaida, I., Nishina, H. et al. Lesson from the GFP/CCl4 model — Translational Research Project: the development of cell therapy using autologous bone marrow cells in patients with liver cirrhosis. J Hepatobiliary Pancreat Surg 12, 203–207 (2005). https://doi.org/10.1007/s00534-005-0977-0

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  • DOI: https://doi.org/10.1007/s00534-005-0977-0

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