Thioredoxin‐1 Protects Bone Marrow‐Derived Mesenchymal Stromal Cells from Hyperoxia‐Induced Injury In Vitro

Abstract

Background The poor survival rate of mesenchymal stromal cells (MSC) transplanted into recipient lungs greatly limits their therapeutic efficacy for diseases like bronchopulmonary dysplasia (BPD). The aim of this study is to evaluate the effect of thioredoxin-1 (Trx-1) overexpression on improving the potential for bone marrow-derived mesenchymal stromal cells (BMSCs) to confer resistance against hyperoxia-induced cell injury. Methods 80% O2 was used to imitate the microenvironment surrounding-transplanted cells in the hyperoxia-induced lung injury in vitro. BMSC proliferation and apoptotic rates and the levels of reactive oxygen species (ROS) were measured. The effects of Trx-1 overexpression on the level of antioxidants and growth factors were investigated. We also investigated the activation of apoptosis-regulating kinase-1 (ASK1) and p38 mitogen-activated protein kinases (MAPK). Result Trx-1 overexpression significantly reduced hyperoxia-induced BMSC apoptosis and increased cell proliferation. We demonstrated that Trx-1 overexpression upregulated the levels of superoxide dismutase and glutathione peroxidase as well as downregulated the production of ROS. Furthermore, we illustrated that Trx-1 protected BMSCs against hyperoxic injury via decreasing the ASK1/P38 MAPK activation rate. Conclusion These results demonstrate that Trx-1 overexpression improved the ability of BMSCs to counteract hyperoxia-induced injury, thus increasing their potential to treat hyperoxia-induced lung diseases such as BPD.

Edaravone prevents high glucose-induced injury in retinal Müller cells through thioredoxin1 and the PGC-1α/NRF1/TFAM pathway

“…Zhang et al. ( 2018 ) reported that high glucose caused a time-dependent decrease in the expression of PGC-1α, NRF1 and TFAM in mouse podocytes, and an increase in ROS levels in cells and mitochondria. The study by Nanjaiah and Vallikannan ( 2019 ) revealed that hyperglycaemia affected mitochondria in the retina, and diminished mitochondrial biogenesis by downregulation of PGC-1α and TFAM.…”

“…Hyperglycaemia causes overexpression of TXNIP, which interacts with TRX1 and inhibits its nuclear translocation, thus blocking TRX1-dependent gene transcription and the expression of genes associated with cell death and survival (Dunn et al 2010). Zhang et al (2018) reported that high glucose caused a time-dependent decrease in the expression of PGC-1a, NRF1 and TFAM in mouse podocytes, and an increase in ROS levels in cells and mitochondria. The study by Nanjaiah and Vallikannan (2019) revealed that hyperglycaemia affected mitochondria in the retina, and diminished mitochondrial biogenesis by downregulation of PGC-1a and TFAM.…”

“…TRX1 overexpression and small-interfering RNA (siRNA) For TRX1 overexpression, the method used was similar to that described in the study by Zhang et al (2018), employing a lentiviral vector encoding TRX1. M€ uller cells were transfected with lentiviral vectors carrying TRX1 (TRX1 þ/þ ) or an empty lentiviral vector (EmptyV) using Lipofectamine 2000 transfection reagent (Invitrogen, Thermo Fisher Scientific, Inc., MA, USA).…”

Effects of Antioxidants in Human Milk on Bronchopulmonary Dysplasia Prevention and Treatment: A Review

“…To minimize lung injury in the BPD model, the antioxidant capacity of the TXN system is dependent on the activation of Nrf2 and an increase in lung epithelial HO-1 expression ( 69 ). According to Zhang et al, TXN1 overexpression reduced apoptosis and increased MSC proliferation in lung MSCs transplanted into recipients, SOD levels, and GPX levels ( 70 ). TXN1 is a new target for BPD treatment in neonatal lung disorders as it is resistant to hyperoxic lung injury.…”

An NRF2 Perspective on Stem Cells and Ageing

“…On a similar note, many of the critical enzymes involved in glutathione synthesis, as well as phase, I, II, and III xenobiotic/drug metabolism are regulated by NRF2 ( Dodson et al, 2019 ). Accordingly, high levels of glutathione have been shown to be required for MSC function, and increased expression of the catalytic and modulatory subunits of glutamate cysteine ligase (GCLC/GCLM), glutathione reductase (GR), and thioredoxin-1 (TXN1) have all been associated with the increased ability of MSCs to self-renew, migrate, and mitigate the effects of pro-inflammatory stimuli/oxidative insult, particularly when transplanted as a form of immunotherapy ( Jeong et al, 2018 ; Zhang et al, 2018 ; Lim et al, 2020 ). High glutathione and glutathione peroxidase 2 (GPX2) levels have also been reported in iPSCs, with depletion of GPX2 resulting in increased ROS-dependent DNA damage ( Dannenmann et al, 2015 ).…”