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Thymus medulla consisting of epithelial islets each derived from a single progenitor

Nature volume 414, pages 763–768 (2001)Cite this article

Abstract

The thymus is organized into medullary and cortical zones that support distinct stages of T-cell development. The formation of medulla and cortex compartments is thought to occur through invagination of an endodermal epithelial sheet into an ectodermal one at the third pharyngeal pouch and cleft, respectively1,2,3,4,5. Epithelial stem/progenitor cells have been proposed to be involved in thymus development6,7, but evidence for their existence has been elusive. We have constructed chimaeric mice by injecting embryonic stem (ES) cells into blastocysts using ES cells and blastocysts differing in their major histocompatibility complex (MHC) type. Here we show that the MHC class-II-positive medullary epithelium in these chimaeras is composed of cell clusters, most of which derive from either embryonic stem cell or blastocyst, but not mixed, origin. Thus, the medulla comprises individual epithelial ‘islets’ each arising from a single progenitor. One thymic lobe has about 300 medullary areas that originate from as few as 900 progenitors. Islet formation can be recapitulated after implantation of ‘reaggregated fetal thymic organs’8 into mice, which shows that medullary ‘stem’ cells retain their potential until at least day 16.5 in fetal development. Thus, medulla–cortex compartmentalization is established by formation of medullary islets from single progenitors.

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Figure 1: Strategy of the generation and analysis of chimaeric thymic epithelium.
Figure 2: Three-dimensional analysis of medullary islet location in the thymus.
Figure 3: Medulla–cortex re-organization after implantation of thymus epithelial grafts in vivo.
Figure 4: Medullary islets arise in thymus stromal cell grafts generated from two different donor epithelia from either of the two (but not both) donor origins.

References

  1. Crisan, C. Die Entwicklung des thyreo-parathyreo-thymischen Systems der weissen Maus. Z. Anat. Entwicklungsgesch. 104, 327–358 (1935).

    Article  Google Scholar 

  2. Norris, E. H. The morphogenesis and histogenesis of the thymus gland in man: in which the origin of the Hassall's corpuscles of the human thymus is discovered. Contrib. Embryol. 166, 191–221 (1938).

    Google Scholar 

  3. Cordier, A. C. & Haumont, S. M. Development of thymus, parathyroids, and ultimo-branchial bodies in NMRI and nude mice. Am. J. Anat. 157, 227–263 (1980).

    Article  CAS  Google Scholar 

  4. von Gaudecker, B. Functional histology of the human thymus. Anat. Embryol. 183, 1–15 (1991).

    CAS  PubMed  Google Scholar 

  5. Manley, N. R. Thymus organogenesis and molecular mechanisms of thymic epithelial cell differentiation. Semin. Immunol. 12, 421–428 (2000).

    Article  CAS  Google Scholar 

  6. Lampert, I. A. & Ritter, M. A. in Thymus Update (eds Kendall, M. D. & Ritter, R. M.) 5–25 (Harwood Academic, London, 1988).

    Google Scholar 

  7. Ritter, M. A. & Boyd, R. L. Development in the thymus: it takes two to tango. Immunol. Today 14, 462–469 (1993).

    Article  CAS  Google Scholar 

  8. Anderson, G., Jenkinson, E. J., Moore, N. C. & Owen, J. J. MHC class II-positive epithelium and mesenchyme cells are both required for T-cell development in the thymus. Nature 362, 70–73 (1993).

    Article  CAS  ADS  Google Scholar 

  9. Van Ewijk, W., Rouse, R. V. & Weissman, I. L. Distribution of H-2 microenvironments in the mouse thymus. Immunoelectron microscopic identification of I-A and H-2K bearing cells. J. Histochem. Cytochem. 28, 1089–1099 (1980).

    Article  CAS  Google Scholar 

  10. Suniara, R. K., Jenkinson, E. J. & Owen, J. J. Studies on the phenotype of migrant thymic stem cells. Eur. J. Immunol. 29, 75–80 (1999).

    Article  CAS  Google Scholar 

  11. Boyd, R. L. et al. The thymic microenvironment. Immunol. Today 14, 445–459 (1993).

    Article  CAS  Google Scholar 

  12. Kontgen, F., Suss, G., Stewart, C., Steinmetz, M. & Bluethmann, H. Targeted disruption of the MHC class II Aa gene in C57BL/6 mice. Int. Immunol. 5, 957–964 (1993).

    Article  CAS  Google Scholar 

  13. Grusby, M. J., Johnson, R. S., Papaioannou, V. E. & Glimcher, L. H. Depletion of CD4+ T cells in major histocompatibility complex class II-deficient mice. Science 253, 1417–1420 (1991).

    Article  CAS  ADS  Google Scholar 

  14. Gosgrove, D. et al. Mice lacking MHC class II molecules. Cell 66, 1051–1066 (1991).

    Article  Google Scholar 

  15. van Ewijk, W. T-cell differentiation is influenced by thymic microenvironments. Annu. Rev. Immunol. 9, 591–615 (1991).

    Article  CAS  Google Scholar 

  16. Rodewald, H. R., Brocker, T. & Haller, C. Developmental dissociation of thymic dendritic cell and thymocyte lineages revealed in growth factor receptor mutant mice. Proc. Natl Acad. Sci. USA 96, 15068–15073 (1999).

    Article  CAS  ADS  Google Scholar 

  17. Beschorner, W. E., Di Gennaro, K. A., Hess, A. D. & Santos, G. W. Cyclosporine and the thymus: influence of irradiation and age on thymic immunopathology and recovery. Cell. Immunol. 110, 350–364 (1987).

    Article  CAS  Google Scholar 

  18. Stewart, J. J. The female X-inactivation mosaic in systemic lupus erythematosus. Immunol. Today 19, 352–357 (1998).

    Article  CAS  Google Scholar 

  19. Weissman, I. L. Stem cells: Units of development, units of regeneration, units in evolution. Cell 100, 157–168 (2000).

    Article  CAS  Google Scholar 

  20. Rodewald, H.-R., Ogawa, M., Haller, C., Waskow, W. & DiSanto, J. P. Pro-thymocyte expansion by c-kit and the common cytokine receptor γ chain is essential for repertoire formation. Immunity 6, 265–272 (1997).

    Article  CAS  Google Scholar 

  21. Rodewald, H.-R., Kretzschmar, K., Swat, W. & Takeda, S. Intrathymically expressed c-kit ligand (stem cell factor) is a major factor driving expansion of very immature thymocytes in vivo. Immunity 3, 313–319 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank V. Bührmann, B. Kugelberg and Y. Lang for technical assistance; F. Melchers, S. Gilfillan, J. Fehling, U. Grawunder and W. Knöchel for discussions; S.-S. Tan for collaborating on early stages related to this work; R. Boyd for antibodies and discussion; and G. Anderson, E. Jenkinson and J. J. T. Owen for an introduction to epithelial reaggregation. H.R.R. was supported by the Deutsche Forschungsgemeinschaft and Landesforschungsschwerpunkt Baden-Württemberg. The Basel Institute for Immunology was founded and supported by F. Hoffmann La Roche, Basel.

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Authors and Affiliations

  1. Department for Immunology, University of Ulm, Albert-Einstein-Allee 11, Ulm, D-89081, Germany

    Hans-Reimer Rodewald, Sabine Paul & Carmen Blum

  2. Basel Institute for Immunology, Grenzacherstrasse 487, Basel, CH-4005, Switzerland

    Corinne Haller

  3. Roche Genetics, F. Hoffmann-La Roche, Grenzacherstr. 124, Basel, CH-4070, Switzerland

    Horst Bluethmann

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  1. Hans-Reimer Rodewald
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Correspondence to Hans-Reimer Rodewald.

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Rodewald, HR., Paul, S., Haller, C. et al. Thymus medulla consisting of epithelial islets each derived from a single progenitor. Nature 414, 763–768 (2001). https://doi.org/10.1038/414763a

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