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. 1978 Dec;75(12):6247–6251. doi: 10.1073/pnas.75.12.6247

Normal blood cells of anemic genotype in teratocarcinoma-derived mosaic mice

Beatrice Mintz 1, Claire Cronmiller 1
PMCID: PMC393157  PMID: 282641

Abstract

In allophenic (mosaic) mice produced from blastocysts injected with teratocarcinoma stem cells of the OTT 6050 transplant line, an unexpected coat phenotype led to the discovery that the tumor-lineage cells carried the steel gene (SlJ/+). Because steel also causes a macrocytic anemia, mosaics comprising both genetically anemic and normal (+/+) cells fortuitously provided a unique opportunity to examine in vivo the etiology of this anemia in light of previous results indicating that the lesion is extrinsic to the erythroid cells. The experiment differs from previous ones, which involved postnatal grafting, in that here hematopoietic stem cells of anemic and normal genotypes coexist throughout all developmental stages, confronted by tissues of the hematopoietic microenvironment that consist partly or solely of genetically normal cells. Therefore, the possibility exists that the anemia might be completely prevented rather than secondarily ameliorated. Moreover, variation in proportion of normal-strain cells in the hematopoietic supporting tissues could serve to “titrate” minimal requirements to promote normal erythropoiesis. Mice with mixed populations of steel- and normal-genotype cells in blood and other tissues were identified by means of independent markers specific for tumor vs. blastocyst strains of origin. The clinical blood picture of these mosaics proved to be indistinguishable from that of normal controls, even when only a small minority of cells in all tissues of one of the animals were genetically normal. Phenotypic blood normalcy was shown, by occurrence of the typical steel anemia among F1 germ-line progeny of mosaics, not to be due to any change in the capacity of the mutant gene to elicit the anemia. The results from the mosaics thus demonstrate that the primary expression of the steel lesion is indeed in the hematopoietic microenvironment. However, they also reveal that a surprisingly small complement of normal cells there appears to be adequate to prevent this anemia permanently. The hypothesis is advanced that relatively short-range diffusible substances, produced by cells in the microenvironment and required for normal erythropoiesis, may account for the inductive effectiveness of small cell numbers.

Keywords: steel macrocytic anemia, erythropoiesis, hematopoietic microenvironment, allophenic mice, blastocyst injection

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Selected References

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

  1. Altus M. S., Bernstein S. E., Russell E. S., Carsten A. L., Upton A. C. Defect extrinsic to stem cells in spleens of steel anemic mice. Proc Soc Exp Biol Med. 1971 Dec;138(3):985–988. doi: 10.3181/00379727-138-36032. [DOI] [PubMed] [Google Scholar]
  2. Bernstein S. E. Tissue transplantation as an analytic and therapeutic tool in hereditary anemias. Am J Surg. 1970 Apr;119(4):448–451. doi: 10.1016/0002-9610(70)90148-0. [DOI] [PubMed] [Google Scholar]
  3. Bosma M. J., Marks R., De Witt C. L. Quantitation of mouse immunoglobulin allotypes by a modified solid-phase radioimmune assay. J Immunol. 1975 Nov;115(5):1381–1386. [PubMed] [Google Scholar]
  4. Chui D. H., Russell E. S. Fetal erythropoiesis in steel mutant mice. I. A morphological study of erythroid cell development in fetal liver. Dev Biol. 1974 Oct;40(2):256–269. doi: 10.1016/0012-1606(74)90128-6. [DOI] [PubMed] [Google Scholar]
  5. Cole R. J., Tarbutt R. G., Cheek E. M., White S. L. Expression of congenital defects in the haemopoietic micro-environment: pre-natal erythropoiesis in anaemic 'Steel' (Slj-Slj) mice. Cell Tissue Kinet. 1974 Sep;7(5):463–477. doi: 10.1111/j.1365-2184.1974.tb00430.x. [DOI] [PubMed] [Google Scholar]
  6. Dewey M. J., Martin D. W., Jr, Martin G. R., Mintz B. Mosaic mice with teratocarcinoma-derived mutant cells deficient in hypoxanthine phosphoribosyltransferase. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5564–5568. doi: 10.1073/pnas.74.12.5564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dewey M. J., Mintz B. Direct visualization, by beta-galactosidase histochemistry, of differentiated normal cells derived from malignant teratocarcinoma in allophenic mice. Dev Biol. 1978 Oct;66(2):550–559. doi: 10.1016/0012-1606(78)90259-2. [DOI] [PubMed] [Google Scholar]
  8. Fried W., Chamberlin W., Knospe W. H., Husseini S., Trobaugh F. E., Jr Studies on the defective haematopoietic microenvironment of Sl/Sl d mice. Br J Haematol. 1973 May;24(5):643–650. doi: 10.1111/j.1365-2141.1973.tb01690.x. [DOI] [PubMed] [Google Scholar]
  9. Gearhart J. D., Mintz B. Clonal origins of somites and their muscle derivatives: evidence from allophenic mice. Dev Biol. 1972 Sep;29(1):27–37. doi: 10.1016/0012-1606(72)90040-1. [DOI] [PubMed] [Google Scholar]
  10. Harrison D. E., Russell E. S. The response of W-W v and Sl-Sl d anaemic mice to haemopoietic stimuli. Br J Haematol. 1972 Feb;22(2):155–168. doi: 10.1111/j.1365-2141.1972.tb08797.x. [DOI] [PubMed] [Google Scholar]
  11. Illmensee K., Mintz B. Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts. Proc Natl Acad Sci U S A. 1976 Feb;73(2):549–553. doi: 10.1073/pnas.73.2.549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Keighley G. H., Lowy P., Russel E. S., Thompson M. W. Analysis of erythroid homeostatic mechanisms in normal and genetically anaemic mice. Br J Haematol. 1966 Jul;12(4):461–477. doi: 10.1111/j.1365-2141.1966.tb05655.x. [DOI] [PubMed] [Google Scholar]
  13. McCulloch E. A., Siminovitch L., Till J. E., Russell E. S., Bernstein S. E. The cellular basis of the genetically determined hemopoietic defect in anemic mice of genotype Sl-Sld. Blood. 1965 Oct;26(4):399–410. [PubMed] [Google Scholar]
  14. Mintz B. Gene expression in neoplasia and differentiation. Harvey Lect. 1978;71:193–246. [PubMed] [Google Scholar]
  15. Mintz B. Genetic mosaicism in vivo: development and disease in allophenic mice. Fed Proc. 1971 May-Jun;30(3):935–943. [PubMed] [Google Scholar]
  16. Mintz B., Illmensee K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3585–3589. doi: 10.1073/pnas.72.9.3585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Moore M. A., Metcalf D. Ontogeny of the haemopoietic system: yolk sac origin of in vivo and in vitro colony forming cells in the developing mouse embryo. Br J Haematol. 1970 Mar;18(3):279–296. doi: 10.1111/j.1365-2141.1970.tb01443.x. [DOI] [PubMed] [Google Scholar]
  18. RANNEY H. M., SMITH G. M., GLUECKSOHN-WAELSCH S. Haemoglobin differences in inbred strains of mice. Nature. 1960 Oct 15;188:212–214. doi: 10.1038/188212a0. [DOI] [PubMed] [Google Scholar]
  19. RUSSELL E. S., BERNSTEIN S. E., LAWSON F. A., SMITH L. J. Long-continued function of normal blood-forming tissue transplanted into genetically anemic hosts. J Natl Cancer Inst. 1959 Sep;23:557–566. [PubMed] [Google Scholar]
  20. Stevens L. C. The development of transplantable teratocarcinomas from intratesticular grafts of pre- and postimplantation mouse embryos. Dev Biol. 1970 Mar;21(3):364–382. doi: 10.1016/0012-1606(70)90130-2. [DOI] [PubMed] [Google Scholar]
  21. Watanabe T., Dewey M. J., Mintz B. Teratocarcinoma cells as vehicles for introducing specific mutant mitochondrial genes into mice. Proc Natl Acad Sci U S A. 1978 Oct;75(10):5113–5117. doi: 10.1073/pnas.75.10.5113. [DOI] [PMC free article] [PubMed] [Google Scholar]

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