한빛사논문
Hyein Ju1,2,6, HongDuck Yun1,2,6, YongHwan Kim1,2, Yun Ji Nam1,2, Seungun Lee1,2, Jinwon Lee1,2, Seon Min Jeong1,2, Jinbeom Heo1,2, Hyungu Kwon1,2, You Sook Cho3, Gowun Jeong4, Chae-Min Ryu5 and Dong-Myung Shin1,2
1Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea.
2Department of Physiology, University of Ulsan College of Medicine, Seoul 05505, South Korea.
3Division of Allergy and Clinical Immunology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea.
4AI Recommendation, T3K, SK Telecom, Seoul 04539, South Korea.
5Center for Cell Therapy, Asan Medical Center, Seoul 05505, South Korea.
6These authors contributed equally: Hyein Ju, HongDuck Yun
Corresponding authors : Correspondence to Chae-Min Ryu or Dong-Myung Shin.
Abstract
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.
논문정보
관련 링크
연구자 ID
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기