Generation of functional thymic organoids from human pluripotent stem cells

Stephan A. Ramos, Lucas H. Armitage, John J. Morton, Nathaniel Alzofon, Diana Handler, Geoffrey Kelly, Dirk Homann, Antonio Jimeno, Holger A. Russ

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


The thymus is critical for the establishment of a functional and self-tolerant adaptive immune system but involutes with age, resulting in reduced naive T cell output. Generation of a functional human thymus from human pluripotent stem cells (hPSCs) is an attractive regenerative strategy. Direct differentiation of thymic epithelial progenitors (TEPs) from hPSCs has been demonstrated in vitro, but functional thymic epithelial cells (TECs) only form months after transplantation of TEPs in vivo. We show the generation of TECs in vitro in isogenic stem cell-derived thymic organoids (sTOs) consisting of TEPs, hematopoietic progenitor cells, and mesenchymal cells, differentiated from the same hPSC line. sTOs support T cell development, express key markers of negative selection, including the autoimmune regulator (AIRE) protein, and facilitate regulatory T cell development. sTOs provide the basis for functional patient-specific thymic organoid models, allowing for the study of human thymus function, T cell development, and transplant immunity.

Original languageEnglish
Pages (from-to)829-840
Number of pages12
JournalStem Cell Reports
Issue number4
StatePublished - 11 Apr 2023


  • cell therapy
  • human T cell development
  • human pluripotent stem cells
  • positive and negative selection
  • stem cell derived thymic organoids
  • thymic epithelial cells


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