Glutathione dynamics determine the therapeutic efficacy of mesenchymal stem cells for graft-versus-host disease via CREB1-NRF2 pathway.
Jisun LimJinbeom HeoHyein JuJi-Woong ShinYongHwan KimSeungun LeeHwan Yeul YuChae-Min RyuHong Duck YunSujin SongHyung-Min ChungHwa-Ryeon KimJae-Seok RoeKihang ChoiIn-Gyu KimEui Man JeongDong-Myung ShinPublished in: Science advances (2020)
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.
Keyphrases
- mesenchymal stem cells
- genome wide
- oxidative stress
- umbilical cord
- fluorescent probe
- high throughput
- bone marrow
- allogeneic hematopoietic stem cell transplantation
- dna methylation
- weight loss
- anti inflammatory
- genome wide identification
- mouse model
- cell therapy
- single cell
- copy number
- gene expression
- stem cells
- type diabetes
- mass spectrometry
- acute lymphoblastic leukemia
- skeletal muscle
- transcription factor
- glycemic control
- gastric bypass
- fluorescence imaging