Combinatory differentiation of human induced pluripotent stem cells generates functional thymic epithelium driving dendritic cell and CD4/CD8 T cell development
- Nathan Provin
- Manon d’Arco
- Antoine Le Bozec
- Erwan Kervagoret
- Alexandre Bruneau
- Lucas Brusselle
- Cynthia Fourgeux
- Jeremie Poschmann
- Philippe Hulin
- Pierre Maminirina
- Olivier Baron
- Xavier Saulquin
- Carole Guillonneau
- Laurent David
- Matthieu Giraud
2026-01-23
The thymus educates thymocytes through a selection process mediated by thymic epithelial cells (TECs). Recent advances have made the generation of T lymphocytes from induced pluripotent stem cells (iPSc) a promising therapeutic strategy. However, current approaches often fail to replicate the thymic niche, leading to impaired T cell generation. Here we address the production of functional mature iPSc-derived TECs supporting in vitro T cell generation. We optimize thymic lineage differentiation through an unbiased multifactorial experimental design. By modulating specific signaling pathways, we generate progenitors that mature into medullary and cortical TECs. Co-culture with primary hematopoietic progenitors in a 3D thymic organoid setup induces their differentiation into CD4 + and CD8 + T cells. Importantly, thymic organoids support multilineage differentiation, with dendritic cell populations also emerging. Thus, the presented thymic organoid model provides a practical platform for studying thymic cellular interactions and thymopoiesis in vitro, and opens further research perspectives towards cell-based therapies.