Thymic epithelial cells

As primary lymphoid organ, the thymus provides the essential environment for maturation and selection of functional T lymphocytes. Thymic epithelial (TE) cells derive from the endoderm, and more specifically, from the third pharyngeal pouch. The thymic epithelium is organized in a three-dimensional architecture that does not easily fit into standard classifications of simple or stratified epithelia. Moreover, the mechanisms that maintain the epithelial compartment in the post-natal thymus remain unclear. Although they have been postulated to exist as in all epithelia, thymic stem cells have not been clearly identified to date. One crucial property of adult multipotent stem cells (SCs) in the skin and other stratified epithelia is clonogenicity, i.e the ability of a single cell to give rise to a cell population. Epidermal clonogenic keratinocytes can be propagated for several generations in vitro and can permanently engraft when transplanted onto patients. In the absence of reliable molecular markers to identify and purify multipotent SCs, the demonstration that they can selfrenew in vitro and in vivo represents, to date, the best method to assess stemness. Likewise, the thymus contains epithelial cells that express genes usually only expressed in the skin or other stratified epithelia, thus suggesting the existence of a possible relationship. In the work described in this thesis, we investigated the potentialities of rat primary TE cells through clonal analysis and functional assays. We demonstrate that embryonic and postnatal rat primary TE cells have a clonogenic growth pattern in vitro. We also describe the molecular signature of subtypes of thymic keratinocytes and address the postnatal role of developmentally regulated genes which are commonly expressed in skin and thymus. Clones of rat TE cells have been transplanted onto developing skin in order to evaluate their response to skin morphogenetic signals. Similarly, the response of these clones, as well as of clones obtained from hair follicles, to a thymic environment has been investigated. We demonstrate that cultured TE cells share morphological, phenotypic and functional characteristics with skin multipotent stem cells. When challenged in thymic or skin in vivo assays the clonal progeny of a single TE cell is able to integrate into a functional thymus or give rise to all skin derivatives respectively, i.e. epidermis, hair follicle and sebaceous gland. Conversely skin cells cannot participate to thymic reconstitution. Uncovering the relationship of TE cells with stem cells of stratified epithelia may provide important insights into the molecular basis of diseases involving both thymus and skin.