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Cell fusion is the principal source of bone-marrow-derived hepatocytes

Nature volume 422, pages 897–901 (2003)Cite this article

Abstract

Evidence suggests that haematopoietic stem cells might have unexpected developmental plasticity, highlighting therapeutic potential. For example, bone-marrow-derived hepatocytes can repopulate the liver of mice with fumarylacetoacetate hydrolase deficiency and correct their liver disease1. To determine the underlying mechanism in this murine model, we performed serial transplantation of bone-marrow-derived hepatocytes. Here we show by Southern blot analysis that the repopulating hepatocytes in the liver were heterozygous for alleles unique to the donor marrow, in contrast to the original homozygous donor cells. Furthermore, cytogenetic analysis of hepatocytes transplanted from female donor mice into male recipients demonstrated 80,XXXY (diploid to diploid fusion) and 120,XXXXYY (diploid to tetraploid fusion) karyotypes, indicative of fusion between donor and host cells. We conclude that hepatocytes derived form bone marrow arise from cell fusion and not by differentiation of haematopoietic stem cells.

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Figure 1: Serial transplantation of bone-marrow-derived hepatocytes.
Figure 2: Example of cytogenetic analysis.

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References

  1. Lagasse, E. et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nature Med. 6, 1229–1234 (2000)

    Article  CAS  Google Scholar 

  2. Spangrude, G. J., Heimfeld, S. & Weissman, I. L. Purification and characterization of mouse hematopoietic stem cells. Science 241, 58–62 (1988)

    Article  ADS  CAS  Google Scholar 

  3. Pereira, R. F. et al. Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. Science 276, 71–74 (1997)

    Article  Google Scholar 

  4. Jiang, Y. et al. Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain. Exp. Hematol. 30, 896–904 (2002)

    Article  CAS  Google Scholar 

  5. Ferrari, G. et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Hum. Immunol. 59, 137–148 (1998)

    Article  Google Scholar 

  6. Mezey, E., Chandross, K. J., Harta, G., Maki, R. A. & McKercher, S. R. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290, 1959–1962 (2000)

    Article  Google Scholar 

  7. Orlic, D. et al. Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705 (2001)

    Article  ADS  CAS  Google Scholar 

  8. Krause, D. S. et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105, 369–377 (2001)

    Article  CAS  Google Scholar 

  9. Petersen, B. E. et al. Bone marrow as a potential source of hepatic oval cells. Science 284, 1168–1170 (1999)

    Article  ADS  CAS  Google Scholar 

  10. Theise, N. D. et al. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology 31, 235–240 (2000)

    Article  CAS  Google Scholar 

  11. Alison, M. R. et al. Hepatocytes from non-hepatic adult stem cells. Nature 406, 257 (2000)

    Article  ADS  CAS  Google Scholar 

  12. Terada, N. et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416, 542–545 (2002)

    Article  ADS  CAS  Google Scholar 

  13. Ying, Q. L., Nichols, J., Evans, E. P. & Smith, A. G. Changing potency by spontaneous fusion. Nature 416, 545–548 (2002)

    Article  ADS  CAS  Google Scholar 

  14. Whitney, M. A. et al. Germ cell defects and hematopoietic hypersensitivity to γ-interferon in mice with a targeted disruption of the Fanconi anemia C gene. Blood 88, 49–58 (1996)

    CAS  PubMed  Google Scholar 

  15. Overturf, K. et al. Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I. Nature Genet. 12, 266–273 (1996)

    Article  CAS  Google Scholar 

  16. Wang, X. et al. Kinetics of liver repopulation after bone marrow transplantation. Am. J. Pathol. 161, 565–574 (2002)

    Article  Google Scholar 

  17. Mombaerts, P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992)

    Article  CAS  Google Scholar 

  18. Overturf, K. et al. Ex vivo hepatic gene therapy of a mouse model of Hereditary Tyrosinemia Type I. Hum. Gene Ther. 9, 295–304 (1998)

    Article  CAS  Google Scholar 

  19. Overturf, K., Al-Dhalimy, M., Ou, C. N., Finegold, M. & Grompe, M. Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes. Am. J. Pathol. 151, 1273–1280 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Mitchell, G. A., Grompe, M., Lambert, M. & Tanguay, R. M. in The Metabolic and Molecular Basis of Inherited Disease (eds Scriver, C. R., Beaudet, A. L., Sly, W. & Valle, D.) 1777–1805 (MacGraw-Hill, New York, 2001)

    Google Scholar 

  21. Martin, G. M. & Sprague, C. A. Vinblastine induces multipolar mitoses in tetraploid human cells. Exp. Cell Res. 63, 466–467 (1970)

    Article  CAS  Google Scholar 

  22. Faktor, V. M. & Uryvaeva, I. V. Progressive polyploidy in mouse liver following repeated hepatectomy. Tsitologiia 17, 909–916 (1975)

    CAS  PubMed  Google Scholar 

  23. Friedrich, G. & Soriano, P. Promoter traps in embryonic stem cells: a genetic screen to identify and mutate developmental genes in mice. Genes Dev. 5, 1513–1523 (1991)

    Article  CAS  Google Scholar 

  24. Grompe, M. et al. Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice. Genes Dev. 7, 2298–2307 (1993)

    Article  CAS  Google Scholar 

  25. Grompe, M. et al. Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I. Nature Genet. 10, 453–460 (1995)

    Article  CAS  Google Scholar 

  26. Berry, M. N. & Friend, D. S. High-yield preparation of isolated rat liver parenchymal cells: a biochemical and fine structural study. J. Cell Biol. 43, 506–520 (1969)

    Article  CAS  Google Scholar 

  27. Overturf, K., Al-Dhalimy, M., Finegold, M. & Grompe, M. The repopulation potential of hepatocyte populations differing in size and prior mitotic expansion. Am. J. Pathol. 155, 2135–2143 (1999)

    Article  CAS  Google Scholar 

  28. Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning: A Laboratory Manual (eds Ford, N., Nolan, C. & Ferguson, M.) (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1989)

    Google Scholar 

  29. Labelle, Y., Puymirat, J. & Tanguay, R. M. Localization of cells in the rat brain expressing fumarylacetoacetate hydrolase, the deficient enzyme in hereditary tyrosinemia type 1. Biochim. Biophys. Acta 1180, 250–256 (1993)

    Article  CAS  Google Scholar 

  30. MacGregor, G. R., Mogg, A. E., Burke, J. F. & Caskey, C. T. Histochemical staining of clonal mammalian cell lines expressing E. coli β-galactosidase indicate heterogeneous expression of the bacterial gene. Somat. Cell Mol. Genet. 13, 253–265 (1987)

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by NIH grants to MG., E.L., Y.A. and S.O. X.W. is supported by the Juvenile Diabetes Foundation and H.W. by the Deutsche Forschungsgemeinschaft.

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Authors and Affiliations

  1. Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, 97239, USA

    Xin Wang, Holger Willenbring, Yassmine Akkari, Yumi Torimaru, Mark Foster, Muhsen Al-Dhalimy, Susan Olson & Markus Grompe

  2. Stem Cells Inc., Palo Alto, California, 94304, USA

    Eric Lagasse

  3. Department of Pathology, Texas Children's Hospital, Houston, Texas, 77030, USA

    Milton Finegold

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  1. Xin Wang
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Correspondence to Markus Grompe.

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The authors declare that they have no competing financial interests.

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Wang, X., Willenbring, H., Akkari, Y. et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422, 897–901 (2003). https://doi.org/10.1038/nature01531

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