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.
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References
Krause DS et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001; 105: 369–377.
Lagasse E et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 2000; 6: 1229–1234.
Jiang Y et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418: 41–49.
Tosh D, Shen CN, Slack JM . Conversion of pancreatic cells to hepatocytes. Biochem Soc Trans 2002; 30: 51–55.
Jang YY et al. Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol 2004; 6: 532–539.
Theise ND et al. Radiation pneumonitis in mice: a severe injury model for pneumocyte engraftment from bone marrow. Exp Hematol 2002; 30: 1333–1338.
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.
Camargo FD et al. Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates. Nat Med 2003; 9: 1520–1527.
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.
Terada N et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 2002; 416: 542–545.
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.
Ying QL, Nichols J, Evans EP, Smith AG . Changing potency by spontaneous fusion. Nature 2002; 416: 545–548.
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.
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.
Alvarez-Dolado M et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 2003; 425: 968–973.
Wang X et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 2003; 422: 897–901.
Vassilopoulos G, Wang PR, Russell DW . Transplanted bone marrow regenerates liver by cell fusion. Nature 2003; 422: 901–904.
Camargo FD, Finegold M, Goodell MA . Hematopoietic myelomonocytic cells are the major source of hepatocyte fusion partners. J Clin Invest 2004; 113: 1266–1270.
Willenbring H et al. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med 2004; 10: 744–748.
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.
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.
Almeida-Porada G et al. Formation of human hepatocytes by human hematopoietic stem cells in sheep. Blood 2004; 104: 2582–2590.
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.
Harris RG et al. Lack of a fusion requirement for development of bone marrow-derived epithelia. Science 2004; 305: 90–93.
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.
Schwartz RE et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest 2002; 109: 1291–1302.
Jiang Y et al. Neuroectodermal differentiation from mouse multipotent adult progenitor cells. Proc Natl Acad Sci USA 2003; 100 (Suppl 1): 11854–11860.
Fernandes KJ et al. A dermal niche for multipotent adult skin-derived precursor cells. Nat Cell Biol 2004; 6: 1082–1093.
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.
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.
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.
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.
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.
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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
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DOI: https://doi.org/10.1038/sj.gt.3302571
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