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 and Yoko Hamazaki ()
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Yann Pretemer: Kyoto University
Yuxian Gao: Kyoto University
Kaho Kanai: Kyoto University
Takuya Yamamoto: Kyoto University
Kohei Kometani: Kyoto University
Manami Ozaki: Kyoto University
Karin Nishigishi: Kyoto University
Tadashi Ikeda: Kyoto University
Huaigeng Xu: Kyoto University
Akitsu Hotta: Kyoto University
Yoko Hamazaki: Kyoto University

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract 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.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62523-1

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DOI: 10.1038/s41467-025-62523-1

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