Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1991 Sep 1;88(17):7514–7517. doi: 10.1073/pnas.88.17.7514

Long-term reconstitution of the mouse hematopoietic system by embryonic stem cell-derived fetal liver.

L M Forrester 1, A Bernstein 1, J Rossant 1, A Nagy 1
PMCID: PMC52331  PMID: 1881890

Abstract

Murine embryonic stem (ES) cells are permanent blastocyst-derived cell lines capable of contributing to a wide variety of tissues, including the germ line, after injection into host blastocysts. Recently, we have shown that ES cells can produce all of the cells of the developing fetus after aggregation with developmentally compromised tetraploid embryos. Completely ES cell-derived embryos die perinatally, but the liver of these embryos is a source of entirely ES cell-derived hematopoietic progenitors. We have taken 14- to 15-day fetal liver cells from ES cell-tetraploid chimeras and reconstituted the hematopoietic system of lethally irradiated adult recipient mice. ES cell-derived hematopoietic stem cells were capable of long-term (greater than 6 months) repopulation of irradiated recipients, and all hematopoietic cell lineages analyzed (erythrocytes, T cells, mast cells, and macrophages) were derived exclusively from ES cells in such recipients. Thus, ES cells retain the capacity to differentiate into all hematopoietic cell types after prolonged passage in culture. This approach should provide a direct route to the production of mice whose hematopoietic cells carry genetic alterations that would be lethal if passed through the germ line.

Full text

PDF
7514

Images in this article

7515Image
on p.7515
7516Image
on p.7516
7516Image
on p.7516
7516Image
on p.7516
7516Image
on p.7516
7516Image
on p.7516
7516Image
on p.7516

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abramson S., Miller R. G., Phillips R. A. The identification in adult bone marrow of pluripotent and restricted stem cells of the myeloid and lymphoid systems. J Exp Med. 1977 Jun 1;145(6):1567–1579. doi: 10.1084/jem.145.6.1567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beddington R. S., Robertson E. J. An assessment of the developmental potential of embryonic stem cells in the midgestation mouse embryo. Development. 1989 Apr;105(4):733–737. doi: 10.1242/dev.105.4.733. [DOI] [PubMed] [Google Scholar]
  3. Bishop C. E., Boursot P., Baron B., Bonhomme F., Hatat D. Most classical Mus musculus domesticus laboratory mouse strains carry a Mus musculus musculus Y chromosome. Nature. 1985 May 2;315(6014):70–72. doi: 10.1038/315070a0. [DOI] [PubMed] [Google Scholar]
  4. Bradley A., Evans M., Kaufman M. H., Robertson E. Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines. Nature. 1984 May 17;309(5965):255–256. doi: 10.1038/309255a0. [DOI] [PubMed] [Google Scholar]
  5. Capecchi M. R. Altering the genome by homologous recombination. Science. 1989 Jun 16;244(4910):1288–1292. doi: 10.1126/science.2660260. [DOI] [PubMed] [Google Scholar]
  6. Capel B., Hawley R., Covarrubias L., Hawley T., Mintz B. Clonal contributions of small numbers of retrovirally marked hematopoietic stem cells engrafted in unirradiated neonatal W/Wv mice. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4564–4568. doi: 10.1073/pnas.86.12.4564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cudennec C., Nicolas J. F. Blood formation in a clonal cell line of mouse teratocarcinoma. J Embryol Exp Morphol. 1977 Apr;38:203–210. [PubMed] [Google Scholar]
  8. Dexter T. M., Spooncer E. Growth and differentiation in the hemopoietic system. Annu Rev Cell Biol. 1987;3:423–441. doi: 10.1146/annurev.cb.03.110187.002231. [DOI] [PubMed] [Google Scholar]
  9. Dick J. E., Magli M. C., Huszar D., Phillips R. A., Bernstein A. Introduction of a selectable gene into primitive stem cells capable of long-term reconstitution of the hemopoietic system of W/Wv mice. Cell. 1985 Aug;42(1):71–79. doi: 10.1016/s0092-8674(85)80102-1. [DOI] [PubMed] [Google Scholar]
  10. Doetschman T. C., Eistetter H., Katz M., Schmidt W., Kemler R. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J Embryol Exp Morphol. 1985 Jun;87:27–45. [PubMed] [Google Scholar]
  11. Evans M. J., Kaufman M. H. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981 Jul 9;292(5819):154–156. doi: 10.1038/292154a0. [DOI] [PubMed] [Google Scholar]
  12. Hanahan D. Transgenic mice as probes into complex systems. Science. 1989 Dec 8;246(4935):1265–1275. doi: 10.1126/science.2686032. [DOI] [PubMed] [Google Scholar]
  13. Hollands P. Differentiation of embryonic haemopoietic stem cells from mouse blastocysts grown in vitro. Development. 1988 Jan;102(1):135–141. doi: 10.1242/dev.102.1.135. [DOI] [PubMed] [Google Scholar]
  14. Jaenisch R. Transgenic animals. Science. 1988 Jun 10;240(4858):1468–1474. doi: 10.1126/science.3287623. [DOI] [PubMed] [Google Scholar]
  15. Jordan C. T., Lemischka I. R. Clonal and systemic analysis of long-term hematopoiesis in the mouse. Genes Dev. 1990 Feb;4(2):220–232. doi: 10.1101/gad.4.2.220. [DOI] [PubMed] [Google Scholar]
  16. Jordan C. T., McKearn J. P., Lemischka I. R. Cellular and developmental properties of fetal hematopoietic stem cells. Cell. 1990 Jun 15;61(6):953–963. doi: 10.1016/0092-8674(90)90061-i. [DOI] [PubMed] [Google Scholar]
  17. Keller G., Paige C., Gilboa E., Wagner E. F. Expression of a foreign gene in myeloid and lymphoid cells derived from multipotent haematopoietic precursors. Nature. 1985 Nov 14;318(6042):149–154. doi: 10.1038/318149a0. [DOI] [PubMed] [Google Scholar]
  18. Lemischka I. R., Raulet D. H., Mulligan R. C. Developmental potential and dynamic behavior of hematopoietic stem cells. Cell. 1986 Jun 20;45(6):917–927. doi: 10.1016/0092-8674(86)90566-0. [DOI] [PubMed] [Google Scholar]
  19. Lindenbaum M. H., Grosveld F. An in vitro globin gene switching model based on differentiated embryonic stem cells. Genes Dev. 1990 Dec;4(12A):2075–2085. doi: 10.1101/gad.4.12a.2075. [DOI] [PubMed] [Google Scholar]
  20. Lord B. I., Spooncer E. Isolation of haemopoietic spleen colony forming cells. Lymphokine Res. 1986 Winter;5(1):59–72. [PubMed] [Google Scholar]
  21. Magli M. C., Dick J. E., Huszar D., Bernstein A., Phillips R. A. Modulation of gene expression in multiple hematopoietic cell lineages following retroviral vector gene transfer. Proc Natl Acad Sci U S A. 1987 Feb;84(3):789–793. doi: 10.1073/pnas.84.3.789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Martin G. R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7634–7638. doi: 10.1073/pnas.78.12.7634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nagy A., Gócza E., Diaz E. M., Prideaux V. R., Iványi E., Markkula M., Rossant J. Embryonic stem cells alone are able to support fetal development in the mouse. Development. 1990 Nov;110(3):815–821. doi: 10.1242/dev.110.3.815. [DOI] [PubMed] [Google Scholar]
  24. Prümmer O., Fliedner T. M. The fetal liver as an alternative stem cell source for hemolymphopoietic reconstitution. Int J Cell Cloning. 1986 Jul;4(4):237–249. doi: 10.1002/stem.5530040402. [DOI] [PubMed] [Google Scholar]
  25. Reith A. D., Rottapel R., Giddens E., Brady C., Forrester L., Bernstein A. W mutant mice with mild or severe developmental defects contain distinct point mutations in the kinase domain of the c-kit receptor. Genes Dev. 1990 Mar;4(3):390–400. doi: 10.1101/gad.4.3.390. [DOI] [PubMed] [Google Scholar]
  26. Snodgrass R., Keller G. Clonal fluctuation within the haematopoietic system of mice reconstituted with retrovirus-infected stem cells. EMBO J. 1987 Dec 20;6(13):3955–3960. doi: 10.1002/j.1460-2075.1987.tb02737.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Spangrude G. J., Heimfeld S., Weissman I. L. Purification and characterization of mouse hematopoietic stem cells. Science. 1988 Jul 1;241(4861):58–62. doi: 10.1126/science.2898810. [DOI] [PubMed] [Google Scholar]
  28. TILL J. E., McCULLOCH E. A. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res. 1961 Feb;14:213–222. [PubMed] [Google Scholar]
  29. Till J. E., McCulloch E. A. Hemopoietic stem cell differentiation. Biochim Biophys Acta. 1980 Nov 26;605(4):431–459. doi: 10.1016/0304-419x(80)90009-8. [DOI] [PubMed] [Google Scholar]
  30. Tushinski R. J., Oliver I. T., Guilbert L. J., Tynan P. W., Warner J. R., Stanley E. R. Survival of mononuclear phagocytes depends on a lineage-specific growth factor that the differentiated cells selectively destroy. Cell. 1982 Jan;28(1):71–81. doi: 10.1016/0092-8674(82)90376-2. [DOI] [PubMed] [Google Scholar]
  31. UPHOFF D. E. Perclusion of secondary phase of irradiation syndrome by inoculation of fetal hematopoietic tissue following lethal total-body x-irradiation. J Natl Cancer Inst. 1958 Mar;20(3):625–632. [PubMed] [Google Scholar]
  32. Visser J. W., Bauman J. G., Mulder A. H., Eliason J. F., de Leeuw A. M. Isolation of murine pluripotent hemopoietic stem cells. J Exp Med. 1984 Jun 1;159(6):1576–1590. doi: 10.1084/jem.159.6.1576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wiles M. V., Keller G. Multiple hematopoietic lineages develop from embryonic stem (ES) cells in culture. Development. 1991 Feb;111(2):259–267. doi: 10.1242/dev.111.2.259. [DOI] [PubMed] [Google Scholar]
  34. te Riele H., Maandag E. R., Clarke A., Hooper M., Berns A. Consecutive inactivation of both alleles of the pim-1 proto-oncogene by homologous recombination in embryonic stem cells. Nature. 1990 Dec 13;348(6302):649–651. doi: 10.1038/348649a0. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES