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

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.