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 language | American English |
|---|---|
| Pages (from-to) | 108-122.e10 |
| Journal | Cell Stem Cell |
| Volume | 26 |
| Issue number | 1 |
| DOIs | |
| State | Published - 2 Jan 2020 |
| Externally published | Yes |
Bibliographical note
Funding Information:We thank Deanne Watson, Dani Swain, Jeff Davis, Ramona Pop, and Samantha Collins for reagents and assistance with experiments; the HSCRB histology and flow cytometry, BPF next-gen sequencing, and Bauer flow cytometry and sequencing core facilities at Harvard University for technical support and critical discussions; and N. Slavov, A. Yuan, K. Villa, and members of the Melton and Meissner laboratories for critical feedback on this manuscript. J.R.A.-D. is a Howard Hughes Medical Institute Fellow of the Life Sciences Research Foundation . D.A.M. is an investigator of the Howard Hughes Medical Institute . This work was supported by the Max Planck Society and NIH grants DP3K111898 and P01GM099117 (A.M.) and by grants from the Juvenile Diabetes Research Foundation , Helmsley Charitable Trust , and JPB Foundation .
Funding Information:
We thank Deanne Watson, Dani Swain, Jeff Davis, Ramona Pop, and Samantha Collins for reagents and assistance with experiments; the HSCRB histology and flow cytometry, BPF next-gen sequencing, and Bauer flow cytometry and sequencing core facilities at Harvard University for technical support and critical discussions; and N. Slavov, A. Yuan, K. Villa, and members of the Melton and Meissner laboratories for critical feedback on this manuscript. J.R.A.-D. is a Howard Hughes Medical Institute Fellow of the Life Sciences Research Foundation. D.A.M. is an investigator of the Howard Hughes Medical Institute. This work was supported by the Max Planck Society and NIH grants DP3K111898 and P01GM099117 (A.M.) and by grants from the Juvenile Diabetes Research Foundation, Helmsley Charitable Trust, and JPB Foundation. J.R.A.-D. J.D. N.R. J.H.R.K. and A.H. performed experiments. J.R.A.-D. J.D. J.C. and J.R.S. conducted bioinformatics analyses. J.R.A.-D. J.D. J.H.R.K. A.M. and D.A.M. designed the research, interpreted results, and wrote the manuscript. D.A.M. serves on the scientific advisory board of Semma/Vertex. The remaining authors declare no competing interests.
Publisher Copyright:
© 2019 Elsevier Inc.
Keywords
- circadian clock
- enhancers
- epigenome
- hESCs
- in vitro differentiation
- islets of Langerhans
- pancreas
- pioneer factors
- tissue maturation
- β cells
