Circadian Entrainment Triggers Maturation of Human In Vitro Islets

Juan R. Alvarez-Dominguez, Julie Donaghey, Niloofar Rasouli, Jennifer H.R. Kenty, Aharon Helman, Jocelyn Charlton, Juerg R. Straubhaar, Alexander Meissner, Douglas A. Melton*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

Stem-cell-derived tissues could transform disease research and therapy, yet most methods generate functionally immature products. We investigate how human pluripotent stem cells (hPSCs) differentiate into pancreatic islets in vitro by profiling DNA methylation, chromatin accessibility, and histone modification changes. We find that enhancer potential is reset upon lineage commitment and show how pervasive epigenetic priming steers endocrine cell fates. Modeling islet differentiation and maturation regulatory circuits reveals genes critical for generating endocrine cells and identifies circadian control as limiting for in vitro islet function. Entrainment to circadian feeding/fasting cycles triggers islet metabolic maturation by inducing cyclic synthesis of energy metabolism and insulin secretion effectors, including antiphasic insulin and glucagon pulses. Following entrainment, hPSC-derived islets gain persistent chromatin changes and rhythmic insulin responses with a raised glucose threshold, a hallmark of functional maturity, and function within days of transplantation. Thus, hPSC-derived tissues are amenable to functional improvement by circadian modulation. Epigenomic studies reveal mechanisms driving differentiation of human stem cells into pancreatic islets and uncover a role for circadian rhythms in their functional maturation. Circadian-clock-entrained islets gain metabolic oscillations and stable chromatin changes that trigger cyclic insulin responses with a raised glucose threshold and function within days of transplant.

Original languageAmerican English
Pages (from-to)108-122.e10
JournalCell Stem Cell
Volume26
Issue number1
DOIs
StatePublished - 2 Jan 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • circadian clock
  • enhancers
  • epigenome
  • hESCs
  • in vitro differentiation
  • islets of Langerhans
  • pancreas
  • pioneer factors
  • tissue maturation
  • β cells

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