Towards a Human Endocrine System-on-a-Chip to Study Circadian Chromaffin Function

Circadian rhythms orchestrate daily physiology, synchronizing behavior and endocrine function with environmental cycles. Disruption of circadian timing contributes to sleep disorders, chronic stress, and metabolic disease. The adrenal gland integrates neuronal, metabolic, and endocrine signals to maintain homeostasis, with the cortex producing rhythmic cortisol under HPA-axis control and the medulla releasing catecholamines driven by sympathetic innervation. How glucocorticoid and cholinergic inputs interact to maintain or disrupt adrenal circadian function remains unclear, particularly under pathological or misaligned conditions.

In the context of a project funded by the Schwyzer-Winiker Foundation, we aim to establish a primary human chromaffin cell platform to study circadian physiology and misalignment. Using tissue from transplant donors, we will combine luciferase-based circadian reporters, high-density microelectrode arrays (HD-MEAs), and targeted misalignment protocols including conflicting glucocorticoid and cholinergic stimuli. First, we will assess circadian entrainment and phase-shifting power of glucocorticoid and cholinergic signaling in driving daily circadian rhythms as well as excitability. Then, we will model misalignment under blunted endocrine function by delivering constant or out-of-phase pharmacological treatment of both glucocorticoid and cholinergic stimuli.

This proof-of-concept platform will provide the first functional insights into how human adrenal chromaffin cells respond to conflicting circadian cues. As a future prospect, we aim to expand the system by including cortisol-overproducing adenomas and chromaffin cells from the same patients to model circadian dysfunction in clinically relevant endocrine pathologies. Hereby, the collaboration with the Beuschlein lab is central to have access to organ donor and patient material. The approach lays the groundwork for a modular “human endocrine system-on-a-chip,” enabling future integration of additional adrenal and sympathetic cell types. This platform will advance understanding of inter-individual circadian variability, tissue-specific misalignment, and their contribution to human disease.