Infusion of Trx-1-overexpressing hucMSC prolongs the survival of acutely irradiated NOD/SCID mice by decreasing excessive inflammatory injury.
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 (60)Co-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.
Department of Hematopoietic Stem Cell Transplantation and Gene Therapy Center, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China.
JiangWei
J
Hu
ZaiLiang
Z
Yang
Jun
J
Wang
YongYong
Y
Tang
Hao
H
Liu
Bin
B
Zhang
Hu
H
Chen
D054508:Acute Radiation Syndrome / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010084:Oxidation-Reduction; D016019:Survival Analysis; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes; D014916:Whole-Body Irradiation
D000975:Antioxidants; C515559:Txn1 protein, mouse; D013879:Thioredoxins