Qiang Li, Ren Liu, Zuwan Lin, Xinhe Zhang, Wenbo Wang, Israeli M. Galicia-Silva, Mai Liu, Zihan Gao, Samuel D. Pollock, Juan R. Alvarez-Dominguez, Jia Liu
Understanding how human pancreatic α and β cell electrical activities mature is critical for building fully functional stem cell-derived (SC-) pancreatic organoids for research and therapeutics. We implanted tissue-like, stretchable electronics during organogenesis of human pancreatic organoids, enabling months-long, single cell-resolved electrophysiology. Longitudinal single-cell tracking suggested that improved hormone responsiveness reflects increasing activity of SC-α and -β cells with low and high basal firing, linked to induction of energy and hormone metabolism genes. Daily metabolic entrainment showed that circadian hormone secretion rhythms reflect daily oscillation of SC-α and -β electrical characteristics, tied to induction of cell-cell communication and exocytic gene networks, revealing circadian coordination of cell-level, stimulus-coupled responses. Lastly, we showed that electrical stimulation, via implanted actuators, enhances SC-α and -β glucose responsiveness. Our results establish a bioelectronic framework to trace and modulate functional organoid maturation.