Glutathione dynamics determine the therapeutic efficacy of mesenchymal stem cells for graft-versus-host disease via CREB1-NRF2 pathway

Jisun Lim, Jinbeom Heo, Hyein Ju, Ji Woong Shin, Yong Hwan Kim, Seungun Lee, Hwan Yeul Yu, Chae Min Ryu, Hong Duck Yun, Sujin Song, Ki Sung Hong, Hyung Min Chung, Hwa Ryeon Kim, Jae Seok Roe, Kihang Choi, In Gyu Kim, Eui Man Jeong, Dong Myung Shin

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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.

Original languageEnglish
Article numbereaba1334
JournalScience Advances
Volume6
Issue number16
DOIs
Publication statusPublished - 2020 Apr

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    Lim, J., Heo, J., Ju, H., Shin, J. W., Kim, Y. H., Lee, S., Yu, H. Y., Ryu, C. M., Yun, H. D., Song, S., Hong, K. S., Chung, H. M., Kim, H. R., Roe, J. S., Choi, K., Kim, I. G., Jeong, E. M., & Shin, D. M. (2020). Glutathione dynamics determine the therapeutic efficacy of mesenchymal stem cells for graft-versus-host disease via CREB1-NRF2 pathway. Science Advances, 6(16), [eaba1334]. https://doi.org/10.1126/sciadv.aba1334