Dissecting thyroid development and diseases using PSC-derived organoids

Our research focuses on unraveling the molecular mechanisms and gene networks that govern thyroid organogenesis and contribute to thyroid disorders. By leveraging stem cell-derived thyroid organoids (both mouse and human), we aim to dissect the key molecular pathways that drive proper thyroid development and identify cellular defects underlying various thyroid diseases.

Thyroid Specification

The signaling mechanisms that control the specification of endoderm-derived organs—such as the thyroid, lung, liver, and pancreas—remain poorly understood. To address the fundamental question of how distinct cell types are specified from the gut endoderm, we use thyroid organoids as an experimental model.

Thyroid organogenesis can be broadly divided into three key phases: Thyroid precursor cell specification, budding and migration of the thyroid primordium and functional differentiation of thyroid follicular cells. While some critical factors regulating thyroid migration, differentiation, and growth have been identified in mouse knockout models, the molecular events driving thyroid precursor cell specification remain largely unknown.

To elucidate the genetic basis of early thyroid formation, we integrate data from multiple experimental models, including ESC- and iPSC-derived thyroid cells as well as zebrafish studies. Using global gene expression and chromatin remodeling data, we apply a reverse genetics approach by employing CRISPR/Cas9 to generate knockout alleles of candidate genes in PSC-derived thyroid progenitors, enabling us to assess their role in thyroid specification.

Thyroid Congenital Diseases

Congenital Hypothyroidism (CH) is the most common neonatal metabolic disorder, significantly impacting brain and muscle development if left untreated. Despite its prevalence, the genetic causes of CH remain largely unknown, and many cases are linked to genes not traditionally associated with thyroid development. Understanding the impact of these genetic variants is crucial for unraveling the mechanisms behind thyroid formation defects.

In our lab, we use PSC-derived thyroid organoids to identify unknown genetic causes of CH and explore novel mechanisms contributing to thyroid developmental abnormalities. These organoid models offer a powerful tool to study disease progression and pave the way for potential therapeutic strategies.

Resistance to TSH (RTSH) is a syndrome characterized by an abnormal response to thyroid-stimulating hormone (TSH), often caused by loss-of-function mutations in the TSH receptor (TSHR). However, some RTSH cases present an identical phenotype without detectable TSHR mutations. Recently, Refetoff’s team identified mutations in a short tandem repeat (STR) on chromosome 15 in families affected by RTSH.

To investigate the functional consequences of this mutation, our lab is generating CRISPR-Cas9-modified hESC-derived thyroid organoids to assess TSH responsiveness, providing new insights into RTSH pathology and potential therapeutic targets.

By combining stem cell technologies, gene editing, and multi-model analysis, our research aims to bridge fundamental developmental biology with clinical applications, ultimately improving our understanding of thyroid disorders and paving the way for innovative treatments.