衰老牙周韧带干细胞的干性受损由早衰素/内质网应激/p53 轴介导

IF 11.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research Pub Date : 2024-10-28 DOI:10.1016/j.jare.2024.10.029

Xige Zhang, Yazheng Wang, Jinjin Wang, Yang Zhang, Rui Li, Xiaoyu Wang, Xiaotong Ge, Qingyuan Ye, Jiyun Ji, Dongdong Fei, Qintao Wang

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引用次数: 0

摘要

导言牙周韧带干细胞（PDLSCs）干细胞减少是与年龄相关的牙槽骨丧失的一个关键因素。内质网（ER）应激与年龄相关疾病和间充质干细胞（MSC）干性密切相关。方法检测年轻PDLSCs（YPDLSCs）和OPDLSCs的ER应激水平，并调节ER应激以观察其对PDLSCs干性的影响。通过转染实验，ER压力传感器（蛋白激酶R样ER激酶（PERK）、活化转录因子6（ATF6）、肌醇需要酶1（IRE1））的表达水平在YPDLSCs中上调，而在OPDLSCs中下调，从而验证了未折叠蛋白反应（UPR）途径的详细情况。从机制上探讨了UPR通路对p53/p21通路的调控作用。进一步研究了衰老过程中早衰素积累对ER应激、UPR和p53/p21通路的重要作用。ER应激活化导致YPDLSCs干性降低，而ER应激抑制则挽救了OPDLSCs受损的干性。转染试验证实，ATF6通路通过p53/p21信号传导调控OPDLSC干性。结论衰老过程中早老素的积累可导致ER应激激活，从而通过ATF6/p53/p21轴抑制OPDLSC干性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Impaired stemness in aging periodontal ligament stem cells is mediated by the progerin/endoplasmic reticulum stress/p53 axis

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Impaired stemness in aging periodontal ligament stem cells is mediated by the progerin/endoplasmic reticulum stress/p53 axis

Introduction

Decreased periodontal ligament stem cells (PDLSCs) stemness is a key factor in age-related alveolar bone loss. Endoplasmic reticulum (ER) stress is closely related to age-related diseases and the mesenchymal stem cell (MSC) stemness. However, the role of ER stress in regulating the stemness of senescent PDLSCs and its potential mechanism remain unclear.

Objectives

To investigate the detailed effect and mechanism of ER stress on impaired stemness in old periodontal ligament stem cells (OPDLSCs).

Methods

The level of ER stress of Young PDLSCs (YPDLSCs) and OPDLSCs were detected, and ER stress was regulated to observe its effect on PDLSCs stemness. The expression levels of ER stress sensors (protein kinase R-like ER kinase (PERK), activating transcription factor 6 (ATF6), inositol requiring enzyme 1 (IRE1)) were upregulated in YPDLSCs and downregulated in OPDLSCs by transfection experiments to verify the detailed unfolded protein response (UPR) pathway. Mechanismly, the regulatory effect of UPR pathway on p53/p21 pathway was explored. Further study was performed to investigated the important role of progerin accumulation during aging process on ER stress, UPR and p53/p21 pathway.

Results

Decreased stemness and ER stress activation were found in OPDLSCs. ER stress activation resulted in decreased stemness of YPDLSCs, while ER stress inhibition rescued compromised stemness of OPDLSCs. Mechanismly, ATF6 pathway regulated the OPDLSC stemness via the p53/p21 signaling as confirmed by transfection assay. Further study showed that progerin was accumulated in PDLSCs and progerin overexpression could resulted in ER stress activation, activating the ATF6/p53/p21 axis, leading to decreased stemness of aging PDLSCs.

Conclusions

Progerin accumulation during the aging process can lead to ER stress activation, which can suppress OPDLSC stemness via the ATF6/p53/p21 axis.

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来源期刊

Journal of Advanced Research Multidisciplinary-Multidisciplinary

CiteScore

21.60

自引率

0.90%

发文量

280

审稿时长

12 weeks

期刊介绍： Journal of Advanced Research (J. Adv. Res.) is an applied/natural sciences, peer-reviewed journal that focuses on interdisciplinary research. The journal aims to contribute to applied research and knowledge worldwide through the publication of original and high-quality research articles in the fields of Medicine, Pharmaceutical Sciences, Dentistry, Physical Therapy, Veterinary Medicine, and Basic and Biological Sciences. The following abstracting and indexing services cover the Journal of Advanced Research: PubMed/Medline, Essential Science Indicators, Web of Science, Scopus, PubMed Central, PubMed, Science Citation Index Expanded, Directory of Open Access Journals (DOAJ), and INSPEC.