Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells

Abstract

The thymus develops from the third pharyngeal pouch of the anterior gut and provides the necessary environment for thymopoiesis (the process by which thymocytes differentiate into mature T lymphocytes) and the establishment and maintenance of self-tolerance1,2,3. It contains thymic epithelial cells (TECs) that form a complex three-dimensional network organized in cortical and medullary compartments, the organization of which is notably different from simple or stratified epithelia4. TECs have an essential role in the generation of self-tolerant thymocytes through expression of the autoimmune regulator Aire5,6, but the mechanisms involved in the specification and maintenance of TECs remain unclear7,8,9. Despite the different embryological origins of thymus and skin (endodermal and ectodermal, respectively), some cells of the thymic medulla express stratified-epithelium markers10,11,12, interpreted as promiscuous gene expression. Here we show that the thymus of the rat contains a population of clonogenic TECs that can be extensively cultured while conserving the capacity to integrate in a thymic epithelial network and to express major histocompatibility complex class II (MHC II) molecules and Aire. These cells can irreversibly adopt the fate of hair follicle multipotent stem cells when exposed to an inductive skin microenvironment; this change in fate is correlated with robust changes in gene expression. Hence, microenvironmental cues are sufficient here to re-direct epithelial cell fate, allowing crossing of primitive germ layer boundaries and an increase in potency13.

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Figure 1: Clonogenic TECs maintain thymic identity in culture.
Figure 2: Cultured thymic epithelial cells can incorporate into a thymic network and express MHC class II and Aire.
Figure 3: Thymic epithelial cells have skin potency.
Figure 4: Fate of skin-recovered thymic epithelial cells.

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Acknowledgements

We are grateful to M. Nicolas and A. Smith for discussions and support, M. Okabe for supplying EGFP rats, J. Roberts, M. Garcia and R. Teisanu for help with cell sorting, J. C. Sarria and T. Laroche for confocal imaging, and K. Harsman, O. Hagenbüchle and S. Pradervand from the DAFL for microarray analyses. Y.B was supported in this work by the Swiss National Science Foundation (grant 3100A0-104160), the Juvenile Diabetes Research Foundation, the EPFL and the CHUV. C.B. was supported by a Leukaemia Research Fund grant. The European Union (EU) supported Y.B. and C.B. through the sixth (EuroStemCell) and seventh (EuroSyStem, OptiStem) framework programmes. A.W.A. was supported by a fellowship from the Heiwa Nakajima Foundation.

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P.B., C.C.B. and Y.B. contributed to the design of the experiments and the interpretation of the results, S.C., A.W.A., A.F. and P.B. performed experiments, and Y.B. and P.B wrote the paper.

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Correspondence to Yann Barrandon.

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The authors declare no competing financial interests.

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Raw and normalized microarray data are accessible through the NCBI Gene Expression Omnibus public (http://www.ncbi.nlm.nih.gov/geo) data base (series record GSE21686).

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This file contains Supplementary Figures 1-3 with legends and Supplementary Tables 1-6. (PDF 4434 kb)

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Bonfanti, P., Claudinot, S., Amici, A. et al. Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. Nature 466, 978–982 (2010). https://doi.org/10.1038/nature09269

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