Using 2D and 3D adrenal gland tissues to investigate developmental and disease paradigms

Project summary/Abstract The adrenal glands are vital endocrine organs, comprising the medulla and cortex, that control stress responses, metabolism, blood pressure, and immunity. We hypothesize that better understanding of medulla and cortex development, their interaction and pathologies will unlock novel treatment options for adrenal gland disorders. Our long-term goal is to use human pluripotent stem cell (hPSC)-derived 2D and 3D models to explore adrenal gland development, disorders, and therapies. Using hPSCs, we have made progress in generating adrenal gland cell types in 2D and 3D, laying the foundation for the proposed studies. Medullary chromaffin cells originate from neural crest (NC, ~20%) and Schwann cell progenitors (SCPs, ~80%), but the reason for this dual origin remains unknown. We will differentiate NC- and SCP-derived chromaffin cells in 2D and 3D and assess differences in their functions and physiological responsibilities. Adrenal gland insufficiencies are treated with hormone- replacement therapies targeting the cortex only. There is evidence that the influence of the medulla is substantial in homeostasis and disease, but it remains unknown if and which paracrine signals mediate this communication. We will use co-culture systems to identify molecules that mediate this interaction and will explore the role of defective communication in Congenital Adrenal Hyperplasia (CAH) 3D organoids. Current standard of care hormone-replacement therapy falls short of addressing daily, dynamic and demand-based patient’s needs. We generate 3D adrenal gland organoids for a cell replacement therapy approach for adrenal insufficiency. Our research efforts will advance our understanding of adrenal gland development, the significance of its multiple developmental origins, and medulla-cortex communication's role in health. Additionally, we'll gain insights into potential cell therapy approaches for adrenal gland diseases.