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.
journal_name
Sci Advjournal_title
Science advancesauthors
Lim J,Heo J,Ju H,Shin JW,Kim Y,Lee S,Yu HY,Ryu CM,Yun H,Song S,Hong KS,Chung HM,Kim HR,Roe JS,Choi K,Kim IG,Jeong EM,Shin DMdoi
10.1126/sciadv.aba1334subject
Has Abstractpub_date
2020-04-15 00:00:00pages
eaba1334issue
16issn
2375-2548pii
aba1334journal_volume
6pub_type
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