An iPSC-based in vitro model recapitulates human thymic epithelial development and multi-lineage specification.

Area of Science:

• Immunology
• Developmental Biology
• Stem Cell Biology

Background:

• Thymic epithelial cells (TECs) are vital for T cell development but challenging to study in humans due to heterogeneity and isolation difficulties.
• Understanding the differentiation pathways of diverse TEC lineages from common progenitors is crucial but remains poorly understood.

Purpose of the Study:

• To establish a human induced pluripotent stem cell (iPSC)-based model for in vitro thymus organogenesis.
• To investigate the differentiation trajectories of various TEC lineages and their role in T cell development.

Main Methods:

• Controlled retinoid signaling and self-directed differentiation of human iPSCs to generate TEC progenitor-like and mature TEC populations.
• Co-culture of induced TECs with thymocytes to assess their function in T cell generation and maturation.
• Characterization of TEC subpopulations, including MHCII+, AIRE+, and mimetic TECs.

Main Results:

• Successfully derived FOXN1+ TEC progenitor-like cells and mature MHCII+ TECs resembling cortical and medullary subtypes in vitro.
• Induced TECs supported the generation of naive T cells with diverse T cell receptor (TCR) repertoires.
• Demonstrated in vitro differentiation into AIRE+ and mimetic TEC subpopulations.

Conclusions:

• The developed iPSC model enables comprehensive in vitro study of human TEC differentiation from specification to maturation.
• Provides novel insights into human thymus development and offers potential for regenerative medicine in congenital thymic disorders.