Thymic epithelial cell fate and potency in early organogenesis assessed by single cell transcriptional and functional analysis

Alison Mary Farley, Chengrui An, Sam Palmer, Dong Liu, Anastasia I. Kousa, Paul Rouse, Viktoria Major, Joanna Sweetman, Jan Morys, Andrea Corsinotti, Jennifer Nichols, Jan Ure, Renee McLay, Luke Boulter, S. Jon Chapman, Simon R Tomlinson, C. Clare Blackburn

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

During development, cortical (c) and medullary (m) thymic epithelial cells (TEC) arise from the third pharyngeal pouch endoderm. Current models suggest that within the thymic primordium most TEC exist in a bipotent/common thymic epithelial progenitor cell (TEPC) state able to generate both cTEC and mTEC, at least until embryonic day 12.5 (E12.5) in the mouse. This view, however, is challenged by recent transcriptomics and genetic evidence. We therefore set out to investigate the fate and potency of TEC in the early thymus. Here using single cell (sc) RNAseq we identify a candidate mTEC progenitor population at E12.5, consistent with recent reports. Via lineage-tracing we demonstrate this population as mTEC fate-restricted, validating our bioinformatics prediction. Using potency analyses we also establish that most E11.5 and E12.5 progenitor TEC are cTECfated. Finally we show that overnight culture causes most if not all E12.5 cTEC-fated TEPC to acquire functional bipotency, and provide a likely molecular mechanism for this changed differentiation potential. Collectively, our data overturn the widely held view that a common TEPC predominates in the E12.5 thymus, showing instead that sublineage-primed progenitors are present from the earliest stages of thymus organogenesis but that these early fetal TEPC exhibit cell-fate plasticity in response to extrinsic factors. Our data provide a significant advance in the understanding of fetal thymic epithelial development and thus have implications for thymus-relatedclinical research, in particular research focussed on generating TEC from pluripotent stem cells.
Original languageEnglish
Article number1202163
JournalFrontiers in Immunology
Volume14
DOIs
Publication statusPublished - 25 Jul 2023

Keywords / Materials (for Non-textual outputs)

  • thymus
  • epithelial cells
  • cell fate
  • single cell
  • transcriptome
  • potency
  • cell identity
  • cell state plasticity

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