Silva, I. G. | Search bioRxiv

bioRxiv2024

Cyborg islets: implanted flexible electronics reveal principles of human islet electrical maturation

Flexible electronics implanted during tissue formation enable chronic studies of tissue-wide electrophysiology. Here, we integrate tissue-like stretchable electronics during organogenesis of human stem cell-derived pancreatic islets, stably tracing single-cell extracellular spike bursting dynamics over months of functional maturation. Adapting spike sorting methods from neural studies reveals maturation-dependent electrical patterns of and {beta}-like (SC- and {beta}) cells, and their stimulus-coupled dynamics. We identified two major electrical states for both SC- and {beta} cells, distinguished by their glucose threshold for action potential firing. We find that improved hormone stimulation capacity during extended culture reflects increasing numbers of SC-/{beta} cells in low basal firing states, linked to energy and hormone metabolism gene upregulation. Continuous recording during further maturation by entrainment to daily feeding cycles reveals that circadian islet-level hormone secretion rhythms reflect sustained and coordinate oscillation of cell-level SC- and {beta} electrical activities. We find that this correlates with cell-cell communication and exocytic network induction, indicating a role for circadian rhythms in coordinating system-level stimulus-coupled responses. Cyborg islets thus reveal principles of electrical maturation that will be useful to build fully functional in vitro islets for research and therapeutic applications.

bioengineering↗

bioRxiv2022

Timing of TORC1 inhibition dictates Pol III involvement in longevity in Caenorhabditis elegans

Organismal growth and lifespan are inextricably linked. Target of Rapamycin (TOR) signalling regulates protein production for growth and development, but if reduced extends lifespan across species. Reduction of the enzyme RNA polymerase III, which transcribes tRNAs and 5S rRNA, also extends longevity. Here, we identify a temporal genetic relationship between TOR and Pol III in C. elegans, showing that they collaborate to regulate progeny production and lifespan. Interestingly, the lifespan interaction between Pol III and TOR is only revealed when TOR signaling is reduced specifically in adulthood demonstrating the importance of timing to control TOR regulated developmental vs adult programs. Additionally, we show that Pol III acts in C. elegans muscle to promote both longevity and healthspan and that reducing Pol III even in late adulthood is sufficient to extend lifespan. This demonstrates the importance of Pol III for lifespan and age-related health in adult C. elegans.

genetics↗