Manganese Superoxide Dismutase Gene–Modified Mesenchymal Stem Cells Attenuate Acute Radiation-Induced Lung Injury

Abstract

Radiation-induced lung injury (RILI) is a major clinical complication for radiotherapy in thoracic tumors. An immediate effect of lung irradiation is the generation of reactive oxygen that can produce oxidative damage to DNA, lipids, and proteins resulting in lung cell injury or death. Currently, the medical management of RILI remains supportive. Therefore, there is an urgent need for the development of countermeasures. The present study aimed to evaluate the protective effect of manganese superoxide dismutase (MnSOD) gene-modified mesenchymal stem cells (MSCs) to facilitate the improved recovery of RILI. Here, nonobese diabetic/severe combined immunodeficiency mice received a 13 Gy dose of whole-thorax irradiation, and were then transfused intravenously with MnSOD-MSCs and monitored for 30 days. Lung histopathologic analysis, plasma levels of inflammatory cytokines (interleukin [IL]-1, IL-6, IL-10, and tumor necrosis factor-α), profibrotic factor transforming growth factor-β1, and the oxidative stress factor (hydroxyproline) were evaluated after MnSOD-MSC transplant. Apoptotic rates were evaluated by terminal deoxynucleotidyl transferase-mediated nick-end labeling immunohistochemical method. Colonization and differentiation of MnSOD-MSCs in the irradiated lung were analyzed by immunofluorescence staining. Consequently, systemic administration of MnSOD-MSCs significantly attenuated lung inflammation, ameliorated lung damage, and protected the lung cells from apoptosis. MnSOD-MSCs could differentiate into epithelial-like cells in vivo. MnSOD-MSCs were effective in modulating RILI in mice and had great potential for accelerating from bench to bedside.

Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia‐reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response

“…6A). In addition, the overexpression of MnSOD enhanced the protective effects of MSCs on damaged tissue (50,51). What's more, MSCs obtained from umbilical cord showed dramatically elevated MnSOD levels compared with BM MSCs (52).…”

Improved therapeutics of modified mesenchymal stem cells: an update

“…Among the several MSC therapy studies conducted in this field include a radiation induced lungs injury experiment, where Liu and colleagues noticed that, although the ordinary MSC decreases apoptosis and infiltration of lymphocyte, and as well increases epithelial cells proliferation and fibrosis inhibition in the later phase, the decorin-modified MSC produces a more enhanced therapeutic effect [118]. Similarly, manganese superoxide dismutase (MnSOD) gene modified MSCs significantly improve radiation induced lung damage, reduce inflammation and protect the cells from apoptosis [119]. In these experiments, the major markers analyzed include inflammatory cytokines levels in plasma, lung histopathology and Treg levels in the peripheral blood and spleen.…”

“…In these experiments, the major markers analyzed include inflammatory cytokines levels in plasma, lung histopathology and Treg levels in the peripheral blood and spleen. The MnSOD-modified MSCs could differentiate into epithelial-like cells post transplantation in the mice, while the decorin-modified MSCs effectively induce interferon-γ expression, decreased Tregs levels and inhibited collagen type III α1 expression within pulmonary tissues [118,119]. In other respiratory conditions, genetically modified MSC overexpressing angiotensin II type 2 receptor induce higher MSCs migration and accumulation at injured site, accompanied by substantial decrease in pulmonary vascular permeability as well as restored lung histopathology compared to the control group [120].…”

Concise Review: Therapeutic Potential of the Mesenchymal Stem Cell Derived Secretome and Extracellular Vesicles for Radiation-Induced Lung Injury: Progress and Hypotheses

“…It was reported that MSC‐secreted SOD1 protected lungs from radiation‐induced endothelial cell damage . Similarly, SOD3 or manganese superoxide dismutase‐modified MSCs also have more anti‐inflammatory and antifibrotic effects on RILI, compared with nongene‐modified MSCs . This effect of superoxide dismutase is probably based on their ability to catalyze the dismutation of the superoxide radical into oxygen and hydrogen peroxide, thereby protecting injured cells against ROS generated during RILI .…”