Activating transcription factor-2 supports the antioxidant capacity and ability of human mesenchymal stem cells to prevent asthmatic airway inflammation

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. Asthma: Antioxidant-boosting protein improves stem cell treatment 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 invo