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衰老通过降低转录因子活性和诱导内质网应激来损害人类胰岛β细胞功能及特性。

Aging compromises human islet beta cell function and identity by decreasing transcription factor activity and inducing ER stress.

作者信息

Shrestha Shristi, Erikson Galina, Lyon James, Spigelman Aliya F, Bautista Austin, Manning Fox Jocelyn E, Dos Santos Cristiane, Shokhirev Maxim, Cartailler Jean-Philippe, Hetzer Martin W, MacDonald Patrick E, Arrojo E Drigo Rafael

机构信息

Creative Data Solutions, Vanderbilt Center for Stem Cell Biology, Nashville, TN 37232, USA.

Integrative Genomics and Bioinformatics Core, Salk Institute of Biological Studies, La Jolla, CA 92037, USA.

出版信息

Sci Adv. 2022 Oct 7;8(40):eabo3932. doi: 10.1126/sciadv.abo3932. Epub 2022 Oct 5.

DOI:10.1126/sciadv.abo3932
PMID:36197983
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9534504/
Abstract

Pancreatic islet beta cells are essential for maintaining glucose homeostasis. To understand the impact of aging on beta cells, we performed meta-analysis of single-cell RNA sequencing datasets, transcription factor (TF) regulon analysis, high-resolution confocal microscopy, and measured insulin secretion from nondiabetic donors spanning most of the human life span. This revealed the range of molecular and functional changes that occur during beta cell aging, including the transcriptional deregulation that associates with cellular immaturity and reorganization of beta cell TF networks, increased gene transcription rates, and reduced glucose-stimulated insulin release. These alterations associate with activation of endoplasmic reticulum (ER) stress and autophagy pathways. We propose that a chronic state of ER stress undermines old beta cell structure function to increase the risk of beta cell failure and type 2 diabetes onset as humans age.

摘要

胰岛β细胞对于维持葡萄糖稳态至关重要。为了解衰老对β细胞的影响，我们对单细胞RNA测序数据集进行了荟萃分析、转录因子（TF）调控子分析、高分辨率共聚焦显微镜检查，并测量了来自涵盖人类大部分寿命的非糖尿病供体的胰岛素分泌。这揭示了β细胞衰老过程中发生的一系列分子和功能变化，包括与细胞不成熟相关的转录失调以及β细胞TF网络的重组、基因转录速率增加和葡萄糖刺激的胰岛素释放减少。这些改变与内质网（ER）应激和自噬途径的激活有关。我们提出，内质网应激的慢性状态会破坏衰老β细胞的结构功能，从而增加人类衰老时β细胞功能衰竭和2型糖尿病发病的风险。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e15/9534504/5558facc0375/sciadv.abo3932-f7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e15/9534504/5558facc0375/sciadv.abo3932-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e15/9534504/0ba8c9a6b96f/sciadv.abo3932-f1.jpg
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