Glutathione dynamics determine the therapeutic efficacy of mesenchymal stem cells for graft-versus-host disease via CREB1-NRF2 pathway
- Authors
- Lim, Jisun; Heo, Jinbeom; Ju, Hyein; Shin, Ji-Woong; Kim, YongHwan; Lee, Seungun; Yu, Hwan Yeul; Ryu, Chae-Min; Yun, HongDuck; Song, Sujin; Hong, Ki-Sung; Chung, Hyung-Min; Kim, Hwa-Ryeon; Roe, Jae-Seok; Choi, Kihang; Kim, In-Gyu; Jeong, Eui Man; Shin, Dong-Myung
- Issue Date
- 4월-2020
- Publisher
- AMER ASSOC ADVANCEMENT SCIENCE
- Citation
- SCIENCE ADVANCES, v.6, no.16
- Indexed
- SCIE
SCOPUS
- Journal Title
- SCIENCE ADVANCES
- Volume
- 6
- Number
- 16
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/56720
- DOI
- 10.1126/sciadv.aba1334
- ISSN
- 2375-2548
- Abstract
- Glutathione (GSH), the most abundant nonprotein thiol functioning as an antioxidant, plays critical roles in maintaining the core functions of mesenchymal stem cells (MSCs), which are used as a cellular immunotherapy for graft-versus-host disease (GVHD). However, the role of GSH dynamics in MSCs remains elusive. Genome-wide gene expression profiling and high-throughput live-cell imaging assays revealed that CREB1 enforced the GSH-recovering capacity (GRC) of MSCs through NRF2 by directly up-regulating NRF2 target genes responsible for GSH synthesis and redox cycling. MSCs with enhanced GSH levels and GRC mediated by CREB1-NRF2 have improved self-renewal, migratory, anti-inflammatory, and T cell suppression capacities. Administration of MSCs overexpressing CREB1-NRF2 target genes alleviated GVHD in a humanized mouse model, resulting in improved survival, decreased weight loss, and reduced histopathologic damages in GVHD target organs. Collectively, these findings demonstrate the molecular and functional importance of the CREB1-NRF2 pathway in maintaining MSC GSH dynamics, determining therapeutic outcomes for GVHD treatment.
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Collections - College of Science > Department of Chemistry > 1. Journal Articles
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