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

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 Adv

journal_title

Science advances

authors

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 DM

doi

10.1126/sciadv.aba1334

subject

Has Abstract

pub_date

2020-04-15 00:00:00

pages

eaba1334

issue

16

issn

2375-2548

pii

aba1334

journal_volume

6

pub_type

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