Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Gene Therapy Progress and Prospects: Stem cell plasticity

Gene Therapy volume 12, pages 1229–1234 (2005)Cite this article

Abstract

With the identification of stem cell plasticity several years ago, multiple reports raised hopes that tissue repair by stem cell transplantation could be within reach in the near future. Krause et al reported that a single purified hematopoietic stem cell not only repopulated the bone marrow of a host animal, but also integrated into unrelated tissues. Lagasse et al demonstrated that in a genetic model of liver disease, purified hematopoietic stem cells can give rise to hepatocytes and rescue fatal liver damage. More recent work by Jiang et al demonstrated that cultured cells can retain their stem cell potential. There are a number of possible mechanisms that could explain these phenomena, and recent experiments have raised controversy about which mechanism is prevalent. One possibility is transdifferentiation of a committed cell directly into another cell type as a response to environmental cues. Transdifferentiation has been shown mainly in vitro, but some in vivo data also support this mechanism. Direct transdifferentiation would clinically be limited by the number of cells that can be introduced into an organ without removal of resident cells. If bone marrow cells could on the other hand give rise to stem cells of another tissue, then they could in theory repopulate whole organs from a few starting cells. This model of dedifferentiation is consistent with recent data from animal models. Genetic analysis of cells of donor origin in vivo and in vitro has brought to light another possible mechanism. The fusion of host and donor cells can give rise to mature tissue cells without trans- or dedifferentiation. The resulting heterokaryons are able to cure a lethal genetic defect and do not seem to be prone to give rise to cancer. All these models will clinically face the problem of accessibility of healthy primary cells for transplantation. This underlines the importance of the recent identification of a population of mesenchymal stem cells (MSCs) with stem cell properties similar to embryonic stem (ES) cells. These cells can be cultured and expanded in vitro without losing their stem cell potential making them an attractive target for cell therapy. Finally, it is still not clear if stem cells for various tissues are present in peripheral blood, or bone marrow and thus can be directly purified from these sources. Identification of putative tissue stem cells would be necessary before purification strategies can be devised. In this review, we discuss the evidence for these models, and the conflicting results obtained to date.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Krause DS et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001; 105: 369–377.

    Article  CAS  Google Scholar 

  2. Lagasse E et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 2000; 6: 1229–1234.

    Article  CAS  Google Scholar 

  3. Jiang Y et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418: 41–49.

    Article  CAS  Google Scholar 

  4. Tosh D, Shen CN, Slack JM . Conversion of pancreatic cells to hepatocytes. Biochem Soc Trans 2002; 30: 51–55.

    Article  CAS  Google Scholar 

  5. Jang YY et al. Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol 2004; 6: 532–539.

    Article  CAS  Google Scholar 

  6. Theise ND et al. Radiation pneumonitis in mice: a severe injury model for pneumocyte engraftment from bone marrow. Exp Hematol 2002; 30: 1333–1338.

    Article  Google Scholar 

  7. LaBarge MA, Blau HM . Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell 2002; 111: 589–601.

    Article  CAS  Google Scholar 

  8. Camargo FD et al. Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates. Nat Med 2003; 9: 1520–1527.

    Article  CAS  Google Scholar 

  9. Lapidos KA et al. Transplanted hematopoietic stem cells demonstrate impaired sarcoglycan expression after engraftment into cardiac and skeletal muscle. J Clin Invest 2004; 114: 1577–1585.

    Article  CAS  Google Scholar 

  10. Terada N et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 2002; 416: 542–545.

    Article  CAS  Google Scholar 

  11. Shi D, Reinecke H, Murry CE, Torok-Storb B . Myogenic fusion of human bone marrow stromal cells, but not hematopoietic cells. Blood 2004; 104: 290–294.

    Article  CAS  Google Scholar 

  12. Ying QL, Nichols J, Evans EP, Smith AG . Changing potency by spontaneous fusion. Nature 2002; 416: 545–548.

    Article  CAS  Google Scholar 

  13. Spees JL et al. Differentiation, cell fusion, and nuclear fusion during ex vivo repair of epithelium by human adult stem cells from bone marrow stroma. Proc Natl Acad Sci USA 2003; 100: 2397–2402.

    Article  CAS  Google Scholar 

  14. Weimann JM, Johansson CB, Trejo A, Blau HM . Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nat Cell Biol 2003; 5: 959–966.

    Article  CAS  Google Scholar 

  15. Alvarez-Dolado M et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 2003; 425: 968–973.

    Article  CAS  Google Scholar 

  16. Wang X et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 2003; 422: 897–901.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Willenbring H et al. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med 2004; 10: 744–748.

    Article  CAS  Google Scholar 

  20. Stadtfeld M, Graf T . Assessing the role of hematopoietic plasticity for endothelial and hepatocyte development by non-invasive lineage tracing. Development 2005; 132: 203–213.

    Article  CAS  Google Scholar 

  21. Almeida-Porada G, Porada C, Zanjani ED . Plasticity of human stem cells in the fetal sheep model of human stem cell transplantation. Int J Hematol 2004; 79: 1–6.

    Article  Google Scholar 

  22. Almeida-Porada G et al. Formation of human hepatocytes by human hematopoietic stem cells in sheep. Blood 2004; 104: 2582–2590.

    Article  CAS  Google Scholar 

  23. Brittan M et al. Bone marrow cells engraft within the epidermis and proliferate in vivo with no evidence of cell fusion. J Pathol 2005; 205: 1–13.

    Article  Google Scholar 

  24. Harris RG et al. Lack of a fusion requirement for development of bone marrow-derived epithelia. Science 2004; 305: 90–93.

    Article  CAS  Google Scholar 

  25. Ianus A, Holz GG, Theise ND, Hussain MA . In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest 2003; 111: 843–850.

    Article  CAS  Google Scholar 

  26. Schwartz RE et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest 2002; 109: 1291–1302.

    Article  CAS  Google Scholar 

  27. Jiang Y et al. Neuroectodermal differentiation from mouse multipotent adult progenitor cells. Proc Natl Acad Sci USA 2003; 100 (Suppl 1): 11854–11860.

    Article  CAS  Google Scholar 

  28. Fernandes KJ et al. A dermal niche for multipotent adult skin-derived precursor cells. Nat Cell Biol 2004; 6: 1082–1093.

    Article  CAS  Google Scholar 

  29. Kogler G et al. A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med 2004; 200: 123–135.

    Article  Google Scholar 

  30. D'Ippolito G et al. Marrow-isolated adult multilineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential. J Cell Sci 2004; 117: 2971–2981.

    Article  CAS  Google Scholar 

  31. Ratajczak MZ et al. Stem cell plasticity revisited: CXCR4-positive cells expressing mRNA for early muscle, liver and neural cells ‘hide out’ in the bone marrow. Leukemia 2004; 18: 29–40.

    Article  CAS  Google Scholar 

  32. Ratajczak MZ et al. Expression of functional CXCR4 by muscle satellite cells and secretion of SDF-1 by muscle-derived fibroblasts is associated with the presence of both muscle progenitors in bone marrow and hematopoietic stem/progenitor cells in muscles. Stem Cells 2003; 21: 363–371.

    Article  CAS  Google Scholar 

  33. Kollet O et al. HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver. J Clin Invest 2003; 112: 160–169.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Haematopoietic Stem Cell Lab, Cancer Research UK, London Research Institute, London, UK

    K Kashofer & D Bonnet

Authors
  1. K Kashofer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Bonnet
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kashofer, K., Bonnet, D. Gene Therapy Progress and Prospects: Stem cell plasticity. Gene Ther 12, 1229–1234 (2005). https://doi.org/10.1038/sj.gt.3302571

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302571

Keywords

This article is cited by

Search

Advanced search

Quick links