Activation of eIF2α-ATF4 by endoplasmic reticulum-mitochondria coupling stress enhances COX2 expression and MSC-based therapeutic efficacy for rheumatoid arthritis

作者：Jiaqing Liu, Xing Zhang, Xiangge Zhao, Jinyi Ren, Huina Huang, Cheng Zhang, Xianmei Chen, Weiping Li, Jing Wei, Xia Li · 发表于：Stem Cell Research & Therapy · 年份：2025 · DOI：10.1186/s13287-025-04362-x · 被引用次数：8 · 研究领域：Endoplasmic Reticulum Stress and Disease、Autophagy in Disease and Therapy、Extracellular vesicles in disease

BACKGROUND: Mesenchymal stem/stromal cell (MSC) therapy holds promise as a therapeutic strategy for rheumatoid arthritis (RA). However, the loss of secretory function following cell delivery has significantly restricted its clinical application. Our preliminary studies confirmed that endoplasmic reticulum stress (ERS)-MSCs greatly inhibited RA follicular helper T cells (Tfh) through cyclooxygenase-2 (COX2)/prostaglandin E2 (PGE2) pathway activation via an unknown molecular mechanism, demonstrating the therapeutic effects of ERS-modified MSCs on RA. METHODS: To compare their therapeutic efficacy, thapsigargin (TG)-stimulated or unstimulated MSCs were transplanted into collagen-induced arthritis (CIA) mice. Joint inflammation was evaluated from both general and histological aspects. Splenocytes were isolated, and flow cytometry was performed to assess the proportions of T helper 1 (Th1), Th17, and Tfh subsets. Additionally, the levels of TNF-α in mouse serum were measured using ELISA. For mechanistic exploration, the TRRUST and Cistrome Data Browser databases were used to analyse transcription factors related to COX2 regulation, as well as target genes regulated by activating transcription factor 4 (ATF4). To identify the most effective treatment concentration and duration for inducing ERS, we conducted a concentration and time gradient analysis for TG treatment via qRT‒PCR and a CCK‒8 assay. Then, western blotting and qRT‒PCR were employed to determine the level of ATF4 in ERS...