This work provides a proof-of-principle that circadian control can drive functional maturation of stem cell-derived organoids destined for human therapeutics. Islet maturity develops between birth and weaning, along with onset of circadian behavioral (sleep, feeding) cycles. We show that recreating fasting/feeding cycles recapitulates metabolic maturation in islet organoids. Entrained organoids develop a capacity to anticipate diurnal changes in insulin demand, and are functional within days – rather than weeks – of transplantation. Circadian entrainment may be harnessed to further functional maturation of other stem cell-derived products, consistent with the ability of clock regulators to bind distinct targets in distinct tissues. Thus, our general approach may inform attempts to control the fate and function of any human cell type.
• Epigenome dynamics show how epigenetic priming steers endocrine cell fates
• Modeling maturation regulatory circuits uncovers roles for circadian controllers
• Circadian entrainment triggers organoid maturation via clock-controlled metabolic cycles
• Entrained organoids gain stable genomic changes and function within days of transplant
The authors 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. 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 the JPB Foundation.
CONFLICT OF INTEREST/DISCLOSURE STATEMENT
D.A.M. is a founder and scientific advisory board member for Semma Therapeutics. All other authors have no conflict of interest to report.
The poster of this report was first presented at: 15th Annual Harvard Stem Cell Institute Retreat: Translating Science to the Clinic, Virtual (Wednesday, May 20, 2020).