Thymic epithelial stem cells


Olga Ucar



In the adult mouse thymus, mature mTECs and cTECs undergo a constant turnover, with the half-life of mature mTECs estimated to be around 2 weeks. This relatively high turnover rate implies the existence of a pool of adult tissue-specific stem and/or progenitor cells.

Multiple studies in the past aimed at the identification of the elusive thymic epithelial stem/progenitor cells. Bipotent cells able to give rise to both cortical and medullary lineages have been shown to exist in the embryonic thymus. However, neither had the stemness of these cells been formally demonstrated, nor was it possible to prospectively enrich these cells or study the molecular mechanisms underlying lineage commitment decisions of these TEC stem/progenitor cells, in part due to the absence of a reliable clonal assay .

We identified and characterized thymic epithelial stem cells of the adult mouse thymus based on their ability to form spherical colonies in vitro under low attachment conditions (the thymosphere method). These thymosphere-forming cells (TSFCs) represent adult thymic epithelial stem cells according to the three main criteria of stemness: low cycling rate (label retention), ability to self-renew and bipotency. Of note, TSFCs can be derived from embryonic mouse thymi as well as from involuted thymi of 18 month-old mice. They are also present in the rat and in the human thymus.

We showed that the lineage commitment into mTEC and cTEC lineages happens already during sphere growth, which makes this clonal assay highly suitable for studying the molecular mechanisms regulating stem cell maintenance and lineage commitment. By using the thymosphere method, we were able to show that thymic epithelial stem cells do not depend on the master regulator of TEC fate, FoxN1, for their maintenance. Moreover, we demonstrated that TSFCs are derived exclusively from the FoxN1-negative lineage, and that FoxN1-deficient stem cells can undergo lineage commitment in vitro.

 We currently investigate the molecular mechanisms regulating the thymic epithelial stem cell fate and lineage decision. Thus, embryonic and adult TSFCs seem to differ with respect to their surface antigen profiles, gene expression signatures and responsiveness to exogenous signalling molecules. This probably reflects the condensed development of the thymus in the fetal period (as opposed to its slow steady postnatal maintenance) and the higher regenerative capacity of the embryonic thymic epithelial primordium. Understanding the molecular mechanisms that distinguish embryonic from adult TSFCs might provide clues to triggering thymic regeneration in the adult. In addition, we apply the same sphere approach to characterize TEC stem cells in healthy humans and thymoma-bearing patients.

Selected Publication

Ucar, A., O. Ucar, P. Klug, S. Matt, F. Brunk, T.G. Hofmann, and B. Kyewski. 2014. The adult thymus contains FoxN1-negative epithelial stem cells that are bipotent for medullary and cortical thymic epithelial lineages. Immunity 41:257-269.

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