Somatic stem cells have been claimed to possess an unexpectedly broad differentiation potential (referred to here as plasticity) that could be induced by exposing stem cells to the extracellular developmental signals of other lineages in mixed-cell cultures1,2,3,4,5,6. Recently, this and other experimental evidence supporting the existence of stem-cell plasticity have been refuted because stem cells have been shown to adopt the functional features of other lineages by means of cell-fusion-mediated acquisition of lineage-specific determinants (chromosomal DNA) rather than by signal-mediated differentiation1,2,5,7,8. In this study we co-cultured mouse neural stem cells (NSCs), which are committed to become neurons and glial cells9,10, with human endothelial cells, which form the lining of blood vessels11. We show that in the presence of endothelial cells six per cent of the NSC population converted to cells that did not express neuronal or glial markers, but instead showed the stable expression of multiple endothelial markers and the capacity to form capillary networks. This was surprising because NSCs and endothelial cells are believed to develop from the ectoderm and mesoderm, respectively. Experiments in which endothelial cells were killed by fixation before co-culture with live NSCs (to prevent cell fusion) and karyotyping analyses, revealed that NSCs had differentiated into endothelial-like cells independently of cell fusion. We conclude that stem-cell plasticity is a true characteristic of NSCs and that the conversion of NSCs to unanticipated cell types can be accomplished without cell fusion.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 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.
Ying, Q. L., Nichols, J., Evans, E. P. & Smith, A. G. Changing potency by spontaneous fusion. Nature 416, 545–548 (2002)
Terada, N. et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416, 542–545 (2002)
Galli, R. et al. Skeletal myogenic potential of human and mouse neural stem cells. Nature Neurosci. 3, 986–991 (2000)
Alexanian, A. R. & Sieber-Blum, M. Differentiating adult hippocampal stem cells into neural crest derivatives. Neuroscience 118, 1–5 (2003)
Spees, J. L. 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 100, 2397–2402 (2003)
Condorelli, G. et al. Cardiomyocytes induce endothelial cells to trans-differentiate into cardiac muscle: implications for myocardium regeneration. Proc. Natl Acad. Sci. USA 98, 10733–10738 (2001)
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. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422, 897–901 (2003)
Turner, D. L. & Cepko, C. L. A common progenitor for neurons and glia persists in rat retina late in development. Nature 328, 131–136 (1987)
Luskin, M. B., Pearlman, A. L. & Sanes, J. R. Cell lineage in the cerebral cortex of the mouse studied in vivo and in vitro with a recombinant retrovirus. Neuron 1, 635–647 (1988)
Risau, W. Mechanisms of angiogenesis. Nature 386, 671–674 (1997)
Palmer, T. D., Willhoite, A. R. & Gage, F. H. Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494 (2000)
Bardin, N. et al. Identification of CD146 as a component of the endothelial junction involved in the control of cell–cell cohesion. Blood 98, 3677–3684 (2001)
St Croix, B. et al. Genes expressed in human tumor endothelium. Science 289, 1197–1202 (2000)
Lampugnani, M. G. et al. A novel endothelial-specific membrane protein is a marker of cell–cell contacts. J. Cell Biol. 118, 1511–1522 (1992)
Breier, G. et al. Molecular cloning and expression of murine vascular endothelial-cadherin in early stage development of cardiovascular system. Blood 87, 630–641 (1996)
Wagner, D. D., Olmsted, J. B. & Marder, V. J. Immunolocalization of von Willebrand protein in Weibel–Palade bodies of human endothelial cells. J. Cell Biol. 95, 355–360 (1982)
Goldstein, I. J. & Hayes, C. E. The lectins: carbohydrate-binding proteins of plants and animals. Adv. Carbohydr. Chem. Biochem. 35, 127–340 (1978)
Newman, P. J. & Albelda, S. M. Cellular and molecular aspects of PECAM-1. Nouv. Rev. Fr. Hematol. 34 (suppl), S9–13 (1992)
Sato, T. N., Qin, Y., Kozak, C. A. & Audus, K. L. Tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. Proc. Natl Acad. Sci. USA 90, 9355–9358 (1993)
Weibel, E. R. & Palade, G. E. New cytoplasmic components in arterial endothelia. J. Cell Biol. 23, 101–112 (1964)
Grant, D. S., Lelkes, P. I., Fukuda, K. & Kleinman, H. K. Intracellular mechanisms involved in basement membrane induced blood vessel differentiation in vitro. In Vitro Cell. Dev. Biol. 27A, 327–336 (1991)
Bjornson, C. R., Rietze, R. L., Reynolds, B. A., Magli, M. C. & Vescovi, A. L. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science 283, 534–537 (1999)
Clarke, D. L. et al. Generalized potential of adult neural stem cells. Science 288, 1660–1663 (2000)
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)
Chen, T. R. Cytogenetics of somatic cell hybrids. I. Progression of stemlines in continuous uncloned cultures of man–mouse cell hybrids. Cytogenet. Cell Genet. 23, 221–230 (1979)
Schall, D. & Rechsteiner, M. Kinetics of human chromosome loss from 3T3–human hybrid cells. Somatic Cell Genet. 4, 661–676 (1978)
Vacquier, V. D. The fertilizing capacity of sea urchin sperm rapidly decreases after induction of the acrosome reaction. Dev. Growth Differ. 21, 61–69 (1979)
Weissman, I. L. Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science 287, 1442–1446 (2000)
Palmer, T. D., Markakis, E. A., Willhoite, A. R., Safar, F. & Gage, F. H. Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J. Neurosci. 19, 8487–8497 (1999)
We thank M. G. Farquhar and R. V. Stan for critically evaluating Weibel–Palade bodies; D. Chambers for conducting FACS analysis; J. Simon for help in constructing figures; L. Moore, B. Miller, A. Hyunh and S. Thuret for technical assistance; J. D. Esko's laboratory for advice; V. A. Sciorra and M. L. Gage for critical reading of the manuscript. This work was supported by the National Institutes of Health (National Institute on Aging) and the Lookout Fund. A.E.W. is a Damon Runyon fellow supported by The Damon Runyon Cancer Research Foundation. K.N. was supported by a JSPS Postdoctoral Fellowship for Research Abroad. F.H.G. is supported by the Vi and John Adler Chair.
While I do not believe there is a real financial interest, there could be a perceived competing interest with three companies that I am on the SAB for: CEREGENE inc., Stem Cells inc. and B.C. inc.
Documents the expression of multiple endothelial markers by NSC-derived ECs using immunofluorescence and RT-PCR. (JPG 64 kb)
NSC-derived EC marker-expressing cells form capillary networks in vitro. NSCs, human ECs and NSC-derived EC candidates (clone 1 is shown) were introduced onto Matrigel coated plates at the 0 h time point and monitored for the capacity to form vascular cords. Scale bar=100 µm. (MOV 2657 kb)
About this article
Cite this article
Wurmser, A., Nakashima, K., Summers, R. et al. Cell fusion-independent differentiation of neural stem cells to the endothelial lineage. Nature 430, 350–356 (2004). https://doi.org/10.1038/nature02604
Cell Reports (2020)
International Journal of Molecular Sciences (2020)
Central nervous system and peripheral cell labeling by vascular endothelial cadherin-driven lineage tracing in adult mice
Neural Regeneration Research (2020)
Reconstituting neurovascular unit based on the close relations between neural stem cells and endothelial cells: an effective method to explore neurogenesis and angiogenesis
Reviews in the Neurosciences (2020)
Human Umbilical Cord Mesenchymal Stem Cells Extricate Bupivacaine-Impaired Skeletal Muscle Function via Mitigating Neutrophil-Mediated Acute Inflammation and Protecting against Fibrosis
International Journal of Molecular Sciences (2019)