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Circadian Entrainment Triggers Maturation of Human In Vitro Islets.
Cell Stem Cell ( IF 19.8 ) Pub Date : 2019-12-12 , DOI: 10.1016/j.stem.2019.11.011
Juan R Alvarez-Dominguez 1 , Julie Donaghey 1 , Niloofar Rasouli 1 , Jennifer H R Kenty 1 , Aharon Helman 1 , Jocelyn Charlton 2 , Juerg R Straubhaar 1 , Alexander Meissner 2 , Douglas A Melton 1
Affiliation  

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.

中文翻译:

昼夜节律诱导人体外胰岛成熟。

干细胞衍生组织可以改变疾病研究和治疗,但大多数方法会产生功能不成熟的产品。我们通过分析 DNA 甲基化、染色质可及性和组蛋白修饰变化来研究人类多能干细胞 (hPSC) 如何在体外分化成胰岛。我们发现增强子的潜力在谱系承诺后被重置,并展示了普遍的表观遗传启动如何引导内分泌细胞的命运。对胰岛分化和成熟调节回路进行建模揭示了对产生内分泌细胞至关重要的基因,并将昼夜节律控制确定为限制体外胰岛功能。昼夜节律进食/禁食循环通过诱导能量代谢和胰岛素分泌效应器的循环合成来触发胰岛代谢成熟,包括反相胰岛素和胰高血糖素脉冲。夹带后,hPSC 衍生的胰岛获得持续的染色质变化和节律的胰岛素反应,葡萄糖阈值升高,这是功能成熟的标志,并在移植后几天内发挥作用。因此,hPSC 衍生的组织可以通过昼夜调节来改善功能。
更新日期:2019-12-13
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