Infusion of Trx-1-Overexpressing hucMSC Prolongs the Survival of Acutely Irradiated NOD/SCID Mice by Decreasing Excessive Inflammatory Injury

Abstract

A protective reagent for ARI should have the ability to repair injured tissue caused by radiation and prevent continuous damage from secondary risk factors. Trx-1 was explored as a candidate therapy for ARI, as it scavenges reactive oxygen species, regulates cell growth and differentiation, participates in immune reactions, and inhibits apoptosis by acting inside and/or outside cells. Trx-1 can also decrease excessive inflammation in ARI by regulating the creation of inflamed media, by inhibiting the activation of complement, and by reducing the chemotaxis, adhesion, and migration of inflammatory cells. As effectively and stably expressing exogenous genes in the long term and regulating immune inflammation and tissue repair, MSC are a good choice for Trx-1 gene therapy. In this study, Trx-1-overexpressing hucMSC-Trx-1 were obtained by adenoviral vector-mediated infection. We first measured the redox capacity of hucMSC-Trx-1 with an antioxidant capacity (T-AOC) assay, a hydrogen peroxide (H2O2) content determination assay in vivo, a H2O2-induced oxidation hemolysis assay, and a lipid peroxidation assay in vitro. Then, we measured survival time, the protection of the hematopoietic system, and the regulation of inflammation in important organs in three treatment groups of NOD/SCID mice (treated with hucMSC-Trx-1, with hucMSC, and with saline) that were exposed to 4.5 Gy 60Co-γ-ray radiation. The hucMSC-Trx-1 group achieved superior antioxidation results, protecting bone marrow hematopoietic stem cells (Lin−CD117+: hucMSC-Trx-1 vs. hucMSC, P<0.05; hucMSC-Trx-1 vs. NS, P<0.01), promoting the formation of red blood cells and hemoglobin (hucMSC-Trx-1 vs. hucMSC or NS, P<0.05), reducing inflammation and damage in important organs (Bone marrow and lung: hucMSC-Trx-1 vs. NS, P<0.01; hucMSC-Trx-1 vs. hucMSC, P<0.05. Liver and intestine: hucMSC-Trx-1 vs. NS, P<0.05; hucMSC-Trx-1 vs. hucMSC, P<0.05), and prolonging survival (hucMSC-Trx-1 vs. hucMSC or NS, P<0.01). Therefore, hucMSC-Trx-1 combines the merits of gene and cell therapy as a multifunctional radioprotector for ARI.

Celastrol Alleviates Gamma Irradiation-Induced Damage by Modulating Diverse Inflammatory Mediators

“…Oxidative stress, lipid peroxidation, DNA breaks, and p53/ NF-κB activities have been previously studied in animal models after exposure to gamma radiation [82,83]. It has previously been demonstrated that death of mice occurred after 137 Cs [84] and 60 Co gamma radiation [82,85,86]. Our study also observed 80% animal death at 30 days after exposure to radiation of 6.4 Gy using 137 Cs as an irradiating source, and post-treatment with celastrol for 30 days significantly increased the mouse survival rate after whole-body gamma irradiation exposure.…”

Mesenchymal stem cells transplantation delays functional deteriorationby inhibiting neuroinflammation response in aged mice

“…that BM-MSCs significantly prolonged the graft survival time of other organs, such as the skin and heart (Hu et al, 2013;Wu et al, 2013;Zhang et al, 2013), but no reports showed higher lifetime in vivo. Our results also did not verify whether it can lengthen lifetime in vivo yet.…”

The potential of mesenchymal stem cells in the management of radiation enteropathy

“…In another study, Yang et al 80 reported that manganese superoxide dismutase (MSD) gene-modified MSCs were more effective than control MSCs in reducing mortality of irradiated mice, relieving gastrointestinal symptoms and restoring epithelial integrity with a spot of apoptotic cells in irradiated mice. Moreover, Hu et al 81 revealed that MSCs overexpressing Trx-1 gene were powerful in reducing oxidative stress in the irradiated intestine. Overall, the superior effectiveness of gene-modified MSCs over unmodified MSCs in healing RE can be attributed to the dual therapeutic effects of the high expression of ectopic genes and the intrinsic functions of MSCs.…”