한빛사논문
Jisun Lim1,2,*, Jinbeom Heo1,2,*, Hyein Ju1,2, Ji-Woong Shin3,4, YongHwan Kim1,2,4, Seungun Lee1,2, Hwan Yeul Yu1,2, Chae-Min Ryu1,2, HongDuck Yun1,2, Sujin Song1,2, Ki-Sung Hong5, Hyung-Min Chung5, Hwa-Ryeon Kim6, Jae-Seok Roe6, Kihang Choi7, In-Gyu Kim3, Eui Man Jeong3,† and Dong-Myung Shin1,2,†
1Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
2Department of Physiology, University of Ulsan College of Medicine, Seoul 05505, Korea.
3Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea.
4Biomedical Research Institute, Cell2in Co. Ltd., Seoul 03080, Korea.
5Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul 05029, Korea.
6Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
7Department of Chemistry, Korea University, Seoul 02841, Korea.
†Corresponding author.
* These authors equally contributed to this work.
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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