Activating transcription factor-2 supports the antioxidant capacity and ability of human mesenchymal stem cells to prevent asthmatic airway inflammation.
Activating transcription factor-2 supports the antioxidant capacity and ability of human mesenchymal stem cells to prevent asthmatic airway inflammation.
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DOI：
10.1038/s12276-023-00943-z
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发表时间：
2023-02
影响因子：
12.8
通讯作者：
Shin, Dong-Myung
中科院分区：
文献类型：
--
作者：
Ju, Hyein;Yun, HongDuck;Kim, YongHwan;Nam, Yun Ji;Lee, Seungun;Lee, Jinwon;Jeong, Seon Min;Heo, Jinbeom;Kwon, Hyungu;Cho, You Sook;Jeong, Gowun;Ryu, Chae-Min;Shin, Dong-Myung
谷胱甘肽（GSH）是一种丰富的非蛋白巯基抗氧化剂，参与多种生物学过程并决定干细胞的功能。对介导GSH动力学的分子网络的详细了解仍然缺乏。在这里，我们表明，激活转录因子-2（ATF 2），cAMP反应元件结合蛋白（CREB），在维持人类间充质干细胞（MSC）中的GSH水平和活性的关键作用，通过与核因子红细胞样-2（NRF 2），一个众所周知的主调节细胞氧化还原稳态crosstalk。抗坏血酸2-葡萄糖苷（AA 2G），一种稳定的维生素C衍生物，引发增加ATF 2在人胚胎干细胞和脐带来源的MSC中的表达和活性。随后，激活的ATF 2与CREB 1-NRF 2通路交叉，通过诱导参与GSH合成（GCLC和GCLM）和氧化还原循环（GSR和PRDX 1）的基因来保持MSC的GSH动力学。因此，shRNA介导的ATF 2沉默显著损害了MSC的自我更新、迁移、促血管生成和抗炎能力，并且这些缺陷通过补充GSH来挽救。此外，在卵清蛋白诱导的过敏性哮喘小鼠模型中，沉默ATF 2减弱了MSC减轻气道炎症反应的能力。一致地，通过过表达或基于AA 2G的引发程序激活ATF 2增强了MSC的核心功能，提高了MSC治疗哮喘的体内治疗功效。总的来说，我们的研究结果表明，ATF 2是一种新的GSH动力学调节剂，决定了用于治疗过敏性哮喘的MSC的核心功能和治疗效力。一种促进关键抗氧化剂的细胞蛋白质将成为过敏性哮喘干细胞疗法的重要组成部分。来自脐带的干细胞已被提议作为治疗不可治愈的过敏性哮喘的方法，因为它们具有对抗炎症和再生受损细胞的能力。现在，韩国首尔蔚山大学医学院的Dong-Myung Shin和同事已经证明，转录激活因子2（ATF 2）可以维持抗氧化剂谷胱甘肽的健康水平，这对于干细胞治疗的有效性至关重要。具体而言，ATF 2与特定的核蛋白相互作用，以激活参与谷胱甘肽合成的基因。研究人员表明，MSC治疗减轻哮喘小鼠模型气道炎症的能力通过沉默ATF 2而大大降低，并通过其过度表达而增强。
Glutathione (GSH), an abundant nonprotein thiol antioxidant, participates in several biological processes and determines the functionality of stem cells. A detailed understanding of the molecular network mediating GSH dynamics is still lacking. Here, we show that activating transcription factor-2 (ATF2), a cAMP-response element binding protein (CREB), plays a crucial role in maintaining the level and activity of GSH in human mesenchymal stem cells (MSCs) by crosstalking with nuclear factor erythroid-2 like-2 (NRF2), a well-known master regulator of cellular redox homeostasis. Priming with ascorbic acid 2-glucoside (AA2G), a stable vitamin C derivative, increased the expression and activity of ATF2 in MSCs derived from human embryonic stem cells and umbilical cord. Subsequently, activated ATF2 crosstalked with the CREB1-NRF2 pathway to preserve the GSH dynamics of MSCs through the induction of genes involved in GSH synthesis (GCLC and GCLM) and redox cycling (GSR and PRDX1). Accordingly, shRNA-mediated silencing of ATF2 significantly impaired the self-renewal, migratory, proangiogenic, and anti-inflammatory capacities of MSCs, and these defects were rescued by supplementation of the cells with GSH. In addition, silencing ATF2 attenuated the ability of MSCs to alleviate airway inflammatory responses in an ovalbumin-induced mouse model of allergic asthma. Consistently, activation of ATF2 by overexpression or the AA2G-based priming procedure enhanced the core functions of MSCs, improving the in vivo therapeutic efficacy of MSCs for treating asthma. Collectively, our findings suggest that ATF2 is a novel modulator of GSH dynamics that determines the core functionality and therapeutic potency of MSCs used to treat allergic asthma. A cellular protein that promotes a key antioxidant will be a crucial component in stem cell therapies for allergic asthma. Stem cells derived from umbilical cords have been proposed as treatments for incurable allergic asthma, due to their ability to combat inflammation and regenerate damaged cells. Now, Dong-Myung Shin at University of Ulsan College of Medicine in Seoul, South Korea, and co-workers have shown that the activating transcription factor 2 (ATF2) acts to maintain healthy levels of the antioxidant glutathione, which is essential for the effectiveness of stem cell therapy. Specifically, ATF2 interplays with a specific nuclear protein to activate genes involved in glutathione synthesis. The researchers showed that the ability of MSC treatments to reduce airway inflammation in asthmatic mouse models was greatly reduced by silencing ATF2, and enhanced by its over-expression.
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影响因子：
3.7
作者：
Cerrada A;de la Torre P;Grande J;Haller T;Flores AI;Pérez-Gil J
通讯作者：
Pérez-Gil J
影响因子：
5.2
作者：
Kassmer, Susannah H.;Bruscia, Emanuela M.;Zhang, Ping-Xia;Krause, Diane S.
通讯作者：
Krause, Diane S.
影响因子：
14.2
作者：
Ha, Eun Hee;Choi, Jun-Pyo;Cho, You Sook
通讯作者：
Cho, You Sook
影响因子：
12.8
作者：
Heo, Jinbeom;Lee, Jinyoung;Nam, Yun Ji;Kim, YongHwan;Yun, HongDuck;Lee, Seungun;Ju, Hyein;Ryu, Chae-Min;Jeong, Seon Min;Lee, Jinwon;Lim, Jisun;Cho, Yong Mee;Jeong, Eui Man;Hong, Bumsik;Son, Jaekyoung;Shin, Dong-Myung
通讯作者：
Shin, Dong-Myung
影响因子：
6.6
作者：
Jin, Hye Jin;Lee, Hyang Ju;Kim, Seong Who
通讯作者：
Kim, Seong Who