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昼夜节律可诱导人体外胰岛成熟
作者:小柯机器人 发布时间:2020/1/3 14:57:04

美国哈佛大学Douglas A. Melton课题组的近期研究揭示昼夜节律可诱导人体外胰岛成熟。该项研究成果发表在2020年1月2日出版的《细胞—干细胞》上。

研究人员通过分析DNA甲基化、染色质可及性和组蛋白修饰变化来研究了人类多能干细胞(hPSC)在体外如何分化为胰岛。研究人员发现,增强子潜力会在谱系确立时重置,并发现普遍的表观遗传启动如何引导内分泌细胞命运。胰岛分化的模拟和调节回路的成熟揭示了对产生内分泌细胞至关重要的基因,并将昼夜节律鉴定为体外胰岛功能的限制因素。昼夜进食/禁食周期的诱因通过诱导能量代谢和胰岛素分泌效应物(包括反相胰岛素和胰高血糖素变化)的循环合成来触发胰岛代谢成熟。节律形成之后,hPSC产生的胰岛获得持续的染色质变化和节律性胰岛素反应,其中葡萄糖阈值升高、功能成熟和在移植后几天内发挥功能。因此,源自hPSC的组织能够通过昼夜节律调节进行功能改善。

据了解,干细胞来源的组织可以改变疾病的研究和治疗方法,但是大多数方法会产生功能不成熟的产物。

附:英文原文

Title: Circadian Entrainment Triggers Maturation of Human In Vitro Islets

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

Issue&Volume: 2020/01/02

Abstract: Stem-cell-derived tissues could transform disease research and therapy, yet most methodsgenerate functionally immature products. We investigate how human pluripotent stemcells (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 pervasiveepigenetic priming steers endocrine cell fates. Modeling islet differentiation andmaturation regulatory circuits reveals genes critical for generating endocrine cellsand identifies circadian control as limiting for in vitro islet function. Entrainment to circadian feeding/fasting cycles triggers islet metabolicmaturation by inducing cyclic synthesis of energy metabolism and insulin secretioneffectors, including antiphasic insulin and glucagon pulses. Following entrainment,hPSC-derived islets gain persistent chromatin changes and rhythmic insulin responseswith a raised glucose threshold, a hallmark of functional maturity, and function withindays of transplantation. Thus, hPSC-derived tissues are amenable to functional improvementby circadian modulation.

DOI: 10.1016/j.stem.2019.11.011

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30466-7

期刊信息

Cell Stem Cell:《细胞—干细胞》,创刊于2007年。隶属于细胞出版社,最新IF:21.464
官方网址:https://www.cell.com/cell-stem-cell/home
投稿链接:https://www.editorialmanager.com/cell-stem-cell/default.aspx