The goal of regenerative medicine is to restore form and function to damaged tissues. One potential therapeutic approach involves the use of autologous cells derived from the bone marrow (bone marrow-derived cells, BMDCs). Advances in nuclear transplantation, experimental heterokaryon formation and the observed plasticity of gene expression and phenotype reported in multiple phyla provide evidence for nuclear plasticity. Recent observations have extended these findings to show that endogenous cells within the bone marrow have the capacity to incorporate into defective tissues and be reprogrammed. Irrespective of the mechanism, the potential for new gene expression patterns by BMDCs in recipient tissues holds promise for developing cellular therapies for both proliferative and post-mitotic tissues.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Blau, H.M., Brazelton, T.R. & Weimann, J.M. The evolving concept of a stem cell: entity or function? Cell 105, 829–841 (2001).
Weissman, I.L. Stem cells: units of development, units of regeneration, and units in evolution. Cell 100, 157–168 (2000).
Alonso, L. & Fuchs, E. Stem cells of the skin epithelium. Proc. Natl Acad. Sci. USA 100, 11830–11835 (2003).
Watt, F.M. & Hogan, B.L. Out of Eden: stem cells and their niches. Science 287, 1427–1430 (2000).
Tosh, D. & Slack, J.M. How cells change their phenotype. Nature Rev. Mol. Cell Biol. 3, 187–194 (2002).
Eguchi, G. & Kodama, R. Transdifferentiation. Curr. Opin. Cell Biol. 5, 1023–1028 (1993).
Beresford, W.A. Direct transdifferentiation: can cells change their phenotype without dividing? Cell Differ. Dev. 29, 81–93 (1990).
Briggs, R., King, T. Transplantation of living nuclei from blastula cells into enucleated frogs' eggs. Proc. Natl Acad. Sci. USA 38, 455–463 (1952).
Gurdon, J.B. Adult frogs derived from the nuclei of single somatic cells. Dev. Biol. 4, 256–273 (1962).
Briggs, R. & King, T.J. in The Cell Vol. 1 (eds Brachet, J. & Mirsky, A.E.) 537–617 (Academic, New York, 1959).
Di Berardino, M.A. & King, T.J. Development and cellular differentiation of neural nuclear-transplants of known karyotype. Dev. Biol. 15, 102–128 (1967).
Gurdon, J.B. & Uehlinger, V. “Fertile” intestine nuclei. Nature 210, 1240–1241 (1966).
Davidson, R.L. Gene expression in somatic cell hybrids. Annu. Rev. Genet. 8, 195–218 (1974).
Ephrussi, B., Davidson, R.L., Weiss, M.C., Harris, H. & Klein, G. Malignancy of somatic cell hybrids. Nature 224, 1314–1316 (1969).
Harris, H., Wiener, F. & Klein, G. The analysis of malignancy by cell fusion. 3. Hybrids between diploid fibroblasts and other tumour cells. J. Cell. Sci. 8, 681–692 (1971).
Blau, H.M. & Baltimore, D. Differentiation requires continuous regulation. J. Cell Biol. 112, 781–783 (1991).
Blau, H.M. How fixed is the differentiated state? Lessons from heterokaryons. Trends Genet. 5, 268–572 (1989).
Ringertz, N. & Savage, R.E. in Cell Hybrids 87–118 (Academic, New York, 1976).
Blau, H.M., Chiu, C.P. & Webster, C. Cytoplasmic activation of human nuclear genes in stable heterocaryons. Cell 32, 1171–1180 (1983).
Blau, H.M., Chiu, C.P., Pavlath, G.K. & Webster, C. Muscle gene expression in heterokaryons. Adv. Exp. Med. Biol. 182, 231–247 (1985).
Chiu, C.P. & Blau, H.M. Reprogramming cell differentiation in the absence of DNA synthesis. Cell 37, 879–887 (1984).
Chiu, C.P. & Blau, H.M. 5-Azacytidine permits gene activation in a previously noninducible cell type. Cell 40, 417–424 (1985).
Baron, M.H. & Maniatis, T. Rapid reprogramming of globin gene expression in transient heterokaryons. Cell 46, 591–602 (1986).
Wright, W.E. Expression of differentiated functions in heterokaryons between skeletal myocytes, adrenal cells, fibroblasts and glial cells. Exp. Cell Res. 151, 55–69 (1984).
Wright, W.E. Induction of muscle genes in neural cells. J. Cell Biol. 98, 427–435 (1984).
Spear, B.T. & Tilghman, S.M. Role of α-fetoprotein regulatory elements in transcriptional activation in transient heterokaryons. Mol. Cell Biol. 10, 5047–5054 (1990).
Gurdon, J.B. & Byrne, J.A. The first half-century of nuclear transplantation. Proc. Natl Acad. Sci. USA 100, 8048–8052 (2003).
Rhind, S.M. et al. Human cloning: can it be made safe? Nature Rev. Genet. 4, 855–864 (2003).
Wilmut, I., Schnieke, A.E., McWhir, J., Kind, A.J. & Campbell, K.H. Viable offspring derived from fetal and adult mammalian cells. Nature 385, 810–813 (1997).
Prather, R.S., Sims, M.M. & First, N.L. Nuclear transplantation in early pig embryos. Biol. Reprod. 41, 414–418 (1989).
Stice, S.L. & Robl, J.M. Nuclear reprogramming in nuclear transplant rabbit embryos. Biol. Reprod. 39, 657–664 (1988).
Cheong, H.T., Takahashi, Y. & Kanagawa, H. Birth of mice after transplantation of early cell-cycle-stage embryonic nuclei into enucleated oocytes. Biol. Reprod. 48, 958–963 (1993).
Sims, M. & First, N.L. Production of calves by transfer of nuclei from cultured inner cell mass cells. Proc. Natl Acad. Sci. USA 91, 6143–6147 (1994).
Meng, L., Ely, J.J., Stouffer, R.L. & Wolf, D.P. Rhesus monkeys produced by nuclear transfer. Biol. Reprod. 57, 454–459 (1997).
Hwang, W.S. et al. Evidence of a pluripotent human embryonic stem cell line derived from a cloned blastocyst. Science 303, 1669–1674 (2004).
Hochedlinger, K. & Jaenisch, R. Monoclonal mice generated by nuclear transfer from mature B and T donor cells. Nature 415, 1035–1038 (2002).
Eggan, K. et al. Mice cloned from olfactory sensory neurons. Nature 428, 44–49 (2004).
Rideout, W.M., 3rd, Eggan, K. & Jaenisch, R. Nuclear cloning and epigenetic reprogramming of the genome. Science 293, 1093–1098 (2001).
Hubner, K. et al. Derivation of oocytes from mouse embryonic stem cells. Science 300, 1251–1256 (2003).
Mombaerts, P. Therapeutic cloning in the mouse. Proc. Natl Acad. Sci. USA 100, 11924–11925 (2003).
Cotran, C., Kumar, V. & Tucker, C. Pathologic Basis of Disease, 1425 (W.B. Saunders, Philadelphia, 1999).
Krakowski, M.L. et al. Pancreatic expression of keratinocyte growth factor leads to differentiation of islet hepatocytes and proliferation of duct cells. Am. J. Pathol. 154, 683–691 (1999).
Rao, M.S. et al. Almost total conversion of pancreas to liver in the adult rat: a reliable model to study transdifferentiation. Biochem. Biophys. Res. Commun. 156, 131–136 (1988).
Reddy, J.K., Rao, M.S., Yeldandi, A.V., Tan, X.D. & Dwivedi, R.S. Pancreatic hepatocytes. An in vivo model for cell lineage in pancreas of adult rat. Dig. Dis. Sci. 36, 502–509 (1991).
Dabeva, M.D. et al. Differentiation of pancreatic epithelial progenitor cells into hepatocytes following transplantation into rat liver. Proc. Natl Acad. Sci. USA 94, 7356–7361 (1997).
Hadorn, E. in The Genetics and Biology of Drosophila (ed. Ashburner, M.) 556–617 (Academic, San Diego, 1976).
Lawrence, P.A. & Morata, G. The elements of the bithorax complex. Cell 35, 595–601 (1983).
Lo, D.C., Allen, F. & Brockes, J.P. Reversal of muscle differentiation during urodele limb regeneration. Proc. Natl Acad. Sci. USA 90, 7230–7234 (1993).
Brockes, J.P. & Kumar, A. Plasticity and reprogramming of differentiated cells in amphibian regeneration. Nature Rev. Mol. Cell Biol. 3, 566–574 (2002).
Okada, T.S. Transdifferentiation Flexibility in Cell Differentiation, (Clarendon, Oxford, 1991).
Poss, K.D., Keating, M.T. & Nechiporuk, A. Tales of regeneration in zebrafish. Dev. Dyn. 226, 202–210 (2003).
Echeverri, K. & Tanaka, E.M. Ectoderm to mesoderm lineage switching during axolotl tail regeneration. Science 298, 1993–1996 (2002).
Reader, J.R. et al. Pathogenesis of mucous cell metaplasia in a murine asthma model. Am. J. Pathol. 162, 2069–2078 (2003).
Ferrari, G. et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279, 1528–1530 (1998).
Ianus, A., Holz, G.G., Theise, N.D. & Hussain, M.A. In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J. Clin. Invest. 111, 843–850 (2003).
Krause, D.S. et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105, 369–377 (2001).
Jackson, K.A., Mi, T. & Goodell, M.A. Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc. Natl Acad. Sci. USA 96, 14482–14486 (1999).
LaBarge, M.A. & Blau, H.M. Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell 111, 589–601 (2002).
Lagasse, E. et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nature Med. 6, 1229–1234 (2000).
Gussoni, E. et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401, 390–394 (1999).
Camargo, F.D., Green, R., Capetenaki, Y., Jackson, K.A. & Goodell, M.A. Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates. Nature Med. 9, 1520–1527 (2003).
Corbel, S.Y. et al. Contribution of hematopoietic stem cells to skeletal muscle. Nature Med. 9, 1528–1532 (2003).
Vassilopoulos, G., Wang, P.R. & Russell, D.W. Transplanted bone marrow regenerates liver by cell fusion. Nature 422, 901–904 (2003).
Wang, X. et al. Kinetics of liver repopulation after bone marrow transplantation. Am. J. Pathol. 161, 565–574 (2002).
Weimann, J.M., Charlton, C.A., Brazelton, T.R., Hackman, R.C. & Blau, H.M. Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains. Proc. Natl Acad. Sci. USA 100, 2088–2093 (2003).
Priller, J. et al. Neogenesis of cerebellar Purkinje neurons from gene-marked bone marrow cells in vivo. J. Cell Biol. 155, 733–738 (2001).
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, 1779–1782 (2000).
Brazelton, T.R., Rossi, F.M., Keshet, G.I. & Blau, H.M. From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290, 1775–1779 (2000).
Kale, S. et al. Bone marrow stem cells contribute to repair of the ischemically injured renal tubule. J. Clin. Invest. 112, 42–49 (2003).
Petersen, B.E. et al. Bone marrow as a potential source of hepatic oval cells. Science 284, 1168–1170 (1999).
Wagers, A.J. & Weissman, I.L. Plasticity of adult stem cells. Cell 116, 639–648 (2004).
Korbling, M. & Estrov, Z. Adult stem cells for tissue repair — a new therapeutic concept? N. Engl. J. Med. 349, 570–582 (2003).
Anderson, D.J., Gage, F.H. & Weissman, I.L. Can stem cells cross lineage boundaries? Nature Med. 7, 393–395 (2001).
Smith, C. et al. Purification and partial characterization of a human hematopoietic precursor population. Blood 77, 2122–2128 (1991).
Spangrude, G.J., Heimfeld, S. & Weissman, I.L. Purification and characterization of mouse hematopoietic stem cells. Science 241, 58–62 (1988).
Morrison, S.J. & Weissman, I.L. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1, 661–673 (1994).
Osawa, M., Hanada, K., Hamada, H. & Nakauchi, H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273, 242–245 (1996).
Uchida, N. & Weissman, I.L. Searching for hematopoietic stem cells: evidence that Thy-1.1lo Lin− Sca-1+ cells are the only stem cells in C57BL/Ka-Thy-1.1 bone marrow. J. Exp. Med. 175, 175–184 (1992).
Weimann, J.M., Johansson, C.B., Trejo, A. & Blau, H.M. Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nature Cell Biol. 5, 959–966 (2003).
Alvarez-Dolado, M. et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425, 968–973 (2003).
Wagers, A.J., Sherwood, R.I., Christensen, J.L. & Weissman, I.L. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 297, 2256–2259 (2002).
Wang, X. et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422, 897–901 (2003).
Raff, M. Adult stem cell plasticity: fact or artifact? Annu. Rev. Cell Dev. Biol 19, 1–22 (2003).
Harris, R.G. et al. Lack of a fusion requirement for development of bone marrow-derived epithelia. Science 305, 90–93 (2004).
Dreyfus, P.A. et al. Adult bone marrow-derived stem cells in muscle connective tissue and satellite cell niches. Am. J. Pathol. 164, 773–779 (2004).
Fukada, S. et al. Muscle regeneration by reconstitution with bone marrow or fetal liver cells from green fluorescent protein-gene transgenic mice. J. Cell Sci. 115, 1285–1293 (2002).
Blau, H.M. A twist of fate. Nature 419, 437 (2002).
Doyonnas, R., LaBarge, M.A., Sacco, A., Charlton, C. & Blau, H.M. Hematopoietic contribution to skeletal muscle by myelomonocytic precursors. Proc. Natl Acad. Sci. USA. (in the press).
Camargo, F.D., Finegold, M. & Goodell, M.A. Hematopoietic myelomonocytic cells are the major source of hepatocyte fusion partners. J. Clin. Invest. 113, 1266–1270 (2004).
Willenbring, H. et al. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nature Med. 10, 744–748 (2004).
Grove, J.E. et al. Marrow-derived cells as vehicles for delivery of gene therapy to pulmonary epithelium. Am. J. Respir. Cell Mol. Biol. 27, 645–651 (2002).
Pavlath, G.K. & Blau, H.M. Expression of muscle genes in heterokaryons depends on gene dosage. J. Cell Biol. 102, 124–130 (1986).
We thank M. LaBarge, A. Palermo, R. Doyonnas, T. Brazelton, D. Spiegel and other members of the Blau laboratory for helpful discussions and critical reading of the manuscript. We especially thank C. Johansson for contributing the Purkinje cell image. We apologize to those whose important work we were not able to cover owing to space and reference limitations. J.P. is supported by an NIH training grant (HD 07249) as a postdoctoral fellow at Stanford University, and is a resident in the Division of Plastic and Reconstructive Surgery, Department of Surgery at the University of California, San Francisco (U.C.S.F.). H.M.B. is supported by: NIH grants AG 020961, AG 009521, HD 018179, Ellison AG-SS-0817, the McKnight Endowment Fund for Neuroscience and the Baxter Foundation.
About this article
Journal of Cellular Physiology (2019)
Advances in Wound Care (2016)
The EFF-1A Cytoplasmic Domain Influences Hypodermal Cell Fusions in C. elegans But Is Not Dependent on 14-3-3 Proteins
PLOS ONE (2016)