Nature 336, 684 - 687 (15 December 1988); doi:10.1038/336684a0

Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells

R. Lindsay Williams^*, Douglas J. Hilton^†, Shirley Pease^*, Tracy A. Willson^†, Colin L. Stewart^*, David P. Gearing^†, Erwin F. Wagner^*, Donald Metcalf^†, Nicos A. Nicola^† & Nicholas M. Gough^†

^*European Molecular Biology Laboratory, Meyerhofstrasse 1, 6900 Heidelberg, FRG
^†The Walter and Eliza Hall Institute of Medical Research, Post Office, Royal Melbourne Hospital, Victoria 3050, Australia
Present addresses: Roche Institute for Molecular Biology, Nutley, New Jersey (C.L.S.); Institute for Molecular Pathology, Dr Bohr-Gasse 7, 1030 Vienna, Austria (E.F.W.).

Embryonic stem (ES) cells, the totipotent outgrowths of bias-tocysts^1,2, can be cultured and manipulated in vitro and then returned to the embryonic environment where they develop normally and can contribute to all cell lineages^3–9. Maintenance of the stem-cell phenotype in vitro requires the presence of a feeder layer of fibroblasts^1,2,10 or of a soluble factor, differentiation inhibitory activity (DIA) produced by a number of sources^5,11,12; in the absence of DIA the ES cells differentiate into a wide variety of cell types. We recently noted several similarities between partially purified DIA and a haemopoietic regulator, myeloid leukaemia inhibitory factor (LIF), a molecule which induces differentiation in Ml myeloid leukaemic cells and which we have recently purified, cloned and characterized^13–18. We demonstrate here that purified, recombinant LIF can substitute for DIA in the maintenance of totipotent ES cell lines that retain the potential to form chimaeric mice.

References

1.	Evans, M. J. & Kaufman, M. H. Nature 292, 154−156 (1981). | Article | PubMed | ISI | ChemPort |
2.	Martin, G. R. Proc. natn. Acad. Sci. U.S.A. 78, 7634−7638 (1981). | ChemPort |
3.	Bradley, A., Evans, M., Kaufman, M. H. & Robertson, E. Nature 309, 255−256 (1984). | Article | PubMed | ISI | ChemPort |
4.	Robertson, E. J., Bradley, A., Kuehn, M. & Evans, M. Nature 323, 445−448 (1986). | Article | PubMed | ChemPort |
5.	Hooper, M., Hardy, K., Handyside, A., Hunter, S. & Monk, M. Nature 326, 292−295 (1987). | Article | PubMed | ISI | ChemPort |
6.	Kuehn, M. R., Bradley, A., Robertson, E. J. & Evans, M. J. Nature 326, 295−298 (1987). | Article | PubMed | ISI | ChemPort |
7.	Williams, R. L., Courtneidge, S. A. & Wagner, E. F. Cell 52, 121−131 (1988). | Article | PubMed | ISI | ChemPort |
8.	Stewart, C. L., Vanek, M. & Wagner, E. F. EMBO J. 4, 383−388 (1985). | PubMed |
9.	Gossler, A., Doetschmann, T., Korn, R., Serfling, E. & Kemler, R. Proc. natn. Acad. Sci. U.S.A. 83, 9065−9069 (1986). | ChemPort |
10.	Martin, G. R. & Evans, M. J. Proc. natn. Acad. Sci. U.S.A. 72, 1441−1445 (1975). | ChemPort |
11.	Smith, A. G. & Hooper, M. L. Devl Biol. 121, 1−9 (1987). | ChemPort |
12.	Koopman, P. & Cotton, R. G. H. Exptl Cell Res. 154, 233−242 (1984). | Article | PubMed | ChemPort |
13.	Gearing, D. P. et al. EMBO J. 6, 3995−4002 (1987). | PubMed | ISI | ChemPort |
14.	Gough, N. M. et al. Proc. natn. Acad. Sci. U.S.A. 85, 2623−2627 (1988). | ChemPort |
15.	Hilton, D. J., Nicola, N. A., Gough, N. M. & Metcalf, D. J. biol. Chem. 263, 9238−9443 (1988). | PubMed | ChemPort |
16.	Metcalf, D., Hilton, D. J. & Nicola, N. A. Leukaemia 2, 216−221 (1988). | ChemPort |
17.	Hilton, D. J., Nicola, N. A. & Metcalf, D. Analyt. Biochem. 173, 359−367 (1988). | PubMed | ChemPort |
18.	Simpson, R. J. et al. Eur. J. Biochem. 175, 541−547 (1988). | Article | PubMed | ISI | ChemPort |
19.	Hilton, D. J., Nicola, N. A. & Metcalf, D. Proc. natn. Acad. Sci. U.S.A. 85, 5971−5975 (1988). | ChemPort |
20.	Wagner, E. F., Keller, G., Gilboa, E., Rüther, U. & Stewart, C. Cold Spring Harb. Symp. quant. Biol. 50, 691−700 (1985). | PubMed | ChemPort |
21.	Jakob, J., Bonn, T., Gaillard, J., Nicolas, J. F. & Jacob, F. Ann. Microbiol. (Inst. Pasteur) 124B, 269−282 (1973).
22.	Rudnicki, M. A. & McBurney, M. W. in Teratocarcinomas and Embryonic Stem Cells, a Practical Approach (ed. E. J. Robertson) 19−49 (IRL, Oxford, 1987).
23.	Doetschman, T., Eistetter, H., Katz, M., Schmidt, W. & Kemler, R. J. Embryol. exp. Morphol. 87, 27−45 (1985). | PubMed | ISI | ChemPort |
24.	Dewey, M. J., Martin, D. W., Martin, G. R. & Mintz, B. Proc. natn. Acad. Sci. U.S.A. 74, 5564−5568 (1977). | ChemPort |
25.	Kemler, R. in Progress in Developmental Biology Band 26 (ed. Sauer, H. W.) 175 (Fisher, Stuttgart, 1980).
26.	Thomas, K. R. & Capecchi, M. R. Cell 51, 503−512 (1987). | Article | PubMed | ISI | ChemPort |
27.	Doetschman, T. et al. Nature 330, 576−577 (1987). | Article | PubMed | ISI | ChemPort |
28.	Munson, P. J. & Rodbard, D. Analyt. Biochem. 107, 220−237 (1980). | PubMed | ISI | ChemPort |
29.	Nicola, N. A. & Metcalf, D. J. cell. Physiol. 124, 313−321 (1985). | Article | PubMed | ChemPort |
30.	Smith, D. B. & Johnson, K. S. Gene 67, 31−40 (1988). | Article | PubMed | ISI | ChemPort |
31.	Smith, A. G. et al. Nature 336, 688−690 (1988). | Article | PubMed | ISI | ChemPort |