Modeling Human Thyroid Development by Fetal Tissue-Derived Organoid Culture

Area of Science:

• Developmental Biology
• Endocrinology
• Stem Cell Biology

Background:

• Euthyroidism is crucial for lifelong health, yet early diagnosis and treatment of thyroid developmental defects remain challenging.
• Limited understanding of human thyroid development and the absence of suitable research models hinder progress.
• Identifying key developmental stages and regulatory pathways is essential for advancing thyroid research.

Purpose of the Study:

• To create a cell atlas and identify regulatory signaling pathways during human fetal thyroid development (12-16 gestational weeks).
• To establish a long-term culture system of human fetal thyroid organoids (hFTOs) that recapitulates key developmental events.
• To utilize the hFTO system for studying thyroid hormone production and maturation.

Main Methods:

• Detailed cell atlas construction of heterogeneous thyrocyte populations during specific gestational weeks.
• Development and long-term culture of human fetal thyroid organoids (hFTOs).
• Assessment of hFTOs' ability to generate functional thyroid follicles post-transplantation and response to cAMP signaling activators (e.g., forskolin).

Main Results:

• A comprehensive cell atlas of human fetal thyroid development was generated, revealing heterogeneous thyrocyte populations and regulatory signaling.
• The established hFTO system successfully retained fetal thyroid lineages and molecular signatures.
• Activation of cAMP signaling in hFTOs enhanced follicle maturation and thyroid hormone (T4) secretion, demonstrating recapitulation of fetal thyroid development. Enhanced chromatin accessibility at key thyroid maturation genes (TPO, TG) was observed.

Conclusions:

• This study provides a valuable cell atlas and a functional organoid model for human thyroid development.
• The human fetal thyroid organoid (hFTO) system serves as a powerful ex vivo platform for studying thyroid development and function.
• These findings will significantly facilitate future thyroid research and the development of prospective therapeutic strategies for thyroid disorders.