An iPSC-based in vitro model recapitulates human thymic epithelial development and multi-lineage specification
- Yann Pretemer
- Yuxian Gao
- Kaho Kanai
- Takuya Yamamoto
- Kohei Kometani
- Manami Ozaki
- Karin Nishigishi
- Tadashi Ikeda
- Huaigeng Xu
- Akitsu Hotta
- Yoko Hamazaki
2025-08-25
Thymic epithelial cells (TEC) are crucial in supporting T cell development, but their high heterogeneity and difficulty of isolation pose obstacles to their study in humans. Particularly, how diverse TEC lineages arise from a common progenitor remains poorly understood. To address this, here we establish a human iPSC-based model of thymus organogenesis capable of deriving these lineages in vitro. Through controlled retinoid signaling followed by self-directed differentiation, we obtain FOXN1 + TEC progenitor-like cells and diverse mature MHCII + populations resembling cortical and medullary TECs, allowing us to infer their developmental trajectories. Upon thymocyte co-culture, induced TECs support the generation of naïve T cells with diverse TCR repertoires and further develop into AIRE + and mimetic TEC subpopulations. Our system provides a fully in vitro model of human TEC differentiation from early fate specification to late-stage maturation, offering new insights into human thymus development and potential regenerative applications for congenital thymic disorders.