Trends in Immunology
OpinionOne for all and all for one: thymic epithelial stem cells and regeneration
Section snippets
Thymic ontogeny: single or dual embryonic origin?
Early histological studies of thymus organogenesis in nude and wild-type mice resulted in a model in which the cortical and medullary epithelial components originated from different embryonic germ layers: the ectoderm and endoderm, respectively (Box 1) [6]. Although other histological analyses contradicted this conclusion ([7]; reviewed in [8]) and chick–quail chimera grafting experiments demonstrated that endoderm alone could generate both cortical and medullary epithelial compartments [9],
Evidence from marker studies
If a common TEC precursor does exist, it should be present from the earliest stages of thymus organogenesis, and comprise most if not all epithelial cells in the thymic rudiment prior to differentiation of cortical and medullary TECs. Such a precursor population might include not only TEC progenitors but also TEC stem cells that, in addition to their potency to differentiate, would be capable of self-renewal.
Analysis of early thymus ontogeny in the mouse has shown that, from day 10.5 to day 12
Can parallels be drawn between the thymus and other epithelial cell types?
Precedence for the existence of a TEC stem cell comes from studies in the skin, where multipotent stem cells in the follicular bulge region give rise to cells of the hair follicle and sebaceous gland as well as to interfollicular stem cells that develop, via ‘transit amplifying cells’, into terminally differentiated keratinocytes (reviewed in [32]). Similarly, gut epithelial stem cells develop via ‘dividing transit cells’ before differentiating to at least four distinct mature cell types:
A lineage model of thymic epithelial development and maintenance
The emerging view of lineage relationships within the thymic epithelium thus differs from that suggested by previous models, which predominantly favoured the idea that cortical and medullary epithelial components have independent origins [6]. Collective data present a strong case for a developmental hierarchy in which a common TEC stem or progenitor cell gives rise to both cortical and medullary epithelial subtypes. A summary scheme is presented in Fig. 3. The issues of whether multipotent TEC
Relevance of thymic regeneration in the clinical setting
In the light of recent developments in understanding the role of organ-specific stem cells in maintaining other adult tissues, the apparent existence of a common TEC precursor opens several exciting medical possibilities. Identification of the signals required to stimulate TEC stem/progenitor cell expansion and differentiation in situ could, for instance, lead to thymic, and hence peripheral T cell, enhancement and regeneration in the elderly 43., 44., 45.. Alternatively, epithelial stem cell
Acknowledgements
We thank Heather Ladyman, Andrea Bennett, Jason Gill and Mark Malin for invaluable research contributions and discussions, and Andrew George for stimulating discussion and critical reading of this manuscript. Our work is supported by: the Leukaemia Research Fund, UK (C.B.); the Medical Research Council, UK (G.A., D.P., M.R.); the National Institute for Child Health and Human Development, USA (N.M.); The Wellcome Trust (C.B., N.M., M.R.); and the National Health and Medical Research Council,
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