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  Circadian Entrainment Triggers Maturation of Human In Vitro Islets

Alvarez-Dominguez, J. R., Donaghey, J., Rasouli, N., Kenty, J. H. R., Helman, A., Charlton, J., et al. (2020). Circadian Entrainment Triggers Maturation of Human In Vitro Islets. Cell Stem Cell, 26(1): e10, pp. 108-122. doi:10.1016/j.stem.2019.11.011.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-B055-4 Version Permalink: http://hdl.handle.net/21.11116/0000-0005-B056-3
Genre: Journal Article

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 Creators:
Alvarez-Dominguez, Juan R. 1, Author
Donaghey, Julie 1, Author
Rasouli, Niloofar 1, Author
Kenty, Jennifer H. R. 1, Author
Helman, Aharon 1, Author
Charlton, Jocelyn1, 2, Author              
Straubhaar, Juerg R. 1, Author
Meissner, Alexander1, 2, Author              
Melton, Douglas A. 1, Author
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
2Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA, ou_persistent22              

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Free keywords: hESCs in vitro differentiation pancreas islets of Langerhans β cells epigenome enhancers pioneer factors circadian clock tissue maturation
 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.

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Language(s): eng - English
 Dates: 2019-11-192019-12-122020-01-02
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1016/j.stem.2019.11.011
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Title: Cell Stem Cell
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: 15 Volume / Issue: 26 (1) Sequence Number: e10 Start / End Page: 108 - 122 Identifier: ISSN: 1934-5909
CoNE: https://pure.mpg.de/cone/journals/resource/1934-5909