Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

Abstract

Aims: Radiation-induced normal tissue toxicity is closely linked to endothelial cell (EC) damage and dysfunction (acute effects). However, the underlying mechanisms of radiation-induced adverse late effects with respect to the vascular compartment remain elusive, and no causative radioprotective treatment is available to date. Results: The importance of injury to EC for radiation-induced late toxicity in lungs after whole thorax irradiation (WTI) was investigated using a mouse model of radiation-induced pneumopathy. We show that WTI induces EC loss as long-term complication, which is accompanied by the development of fibrosis. Adoptive transfer of mesenchymal stem cells (MSCs) either derived from bone marrow or aorta (vascular wall-resident MSCs) in the early phase after irradiation limited the radiation-induced EC loss and fibrosis progression. Furthermore, MSC-derived culture supernatants rescued the radiation-induced reduction in viability and longterm survival of cultured lung EC. We further identified the antioxidant enzyme superoxide dismutase 1 (SOD1) as a MSC-secreted factor. Importantly, MSC treatment restored the radiation-induced reduction of SOD1 levels after WTI. A similar protective effect was achieved by using the SOD-mimetic EUK134, suggesting that MSCderived SOD1 is involved in the protective action of MSC, presumably through paracrine signaling. Innovation: In this study, we explored the therapeutic potential of MSC therapy to prevent radiation-induced EC loss (late effect) and identified the protective mechanisms of MSC action. Conclusions: Adoptive transfer of MSCs early after irradiation counteracts radiation-induced vascular damage and EC loss as late adverse effects. The high activity of vascular wall-derived MSCs for radioprotection may be due to their tissue-specific action. Antioxid. Redox Signal. 26, 563-582.

The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung

“…In our hands, adoptively transferred MSC normalized certain aspects of radiation-induced immune deviation in the lung tissue, normalized vascular function, and attenuated radiation-induced pulmonary fibrosis (36, 37). We and others showed that the anti-inflammatory and anti-fibrotic action of MSC is mediated by the inhibition of TNF-a, IL-1alpha, and interleukin 1 receptor antagonist (249, 251), stimulating the secretion of hepatocyte growth factor (HGF) and PGE2 (250, 252) and restoration of the superoxide dismutase 1 expression (37). …”

“…Several reports including own studies revealed that MSC show anti-fibrotic and protective effects in the irradiated lung, and current reviews highlight a potential therapeutic benefit of MSC therapy for the treatment of radiation-induced and BLM-induced tissue damage (36, 37, 248, 263). In our hands, adoptively transferred MSC normalized certain aspects of radiation-induced immune deviation in the lung tissue, normalized vascular function, and attenuated radiation-induced pulmonary fibrosis (36, 37).…”

“…The radiation-induced oxidative injury in the lung and the release of DAMPs induce resident cells to secrete inflammatory and chemotactic cytokines. Human and murine studies revealed that DAMPs in the injured lung include among others extracellular heat shock proteins, S100 proteins, defensins, high-mobility group box-1 (146), extracellular nucleotides and nucleosides (35), as well as extracellular matrix (ECM) components like fibronectin, hyaluronan, uric acid, and surfactant proteins (37, 147). This is in line with findings from other studies dealing with lung injury, induced, for example, by smoke (148) or mechanical ventilation (149).…”

“…This approach is based on the initial observation that healthy resident MSC are important to lung homeostasis and protect the lungs after injury among others by immunomodulation mostly through paracrine mechanisms (253–256). However, when resident-specific endogenous MSC are damaged or lost, e.g., by differentiation into myofibroblasts, this cell population contributes to TGF-β production, tissue remodeling, and fibrosis in various models, including thoracic irradiation, exposure to BLM, and IPF (37, 257–262). In this context, impaired regulation of effector T cell proliferation upon loss of resident pulmonary MSC has been implicated in the development of BLM-induced fibrosis (257).…”

“…Major symptoms of lung fibrosis are breathing difficulties and subsequent volume loss of the lung (25). Studies from various groups using rodent models and patient samples helped to reveal a complex response of the lung tissue toward irradiation with multiple interactions between resident lung cells including lung-resident mesenchymal stem cells (MSC), locally generated or recruited fibroblasts, and infiltrating immune cells, respectively (26–37). We speculate that a sophisticated network between damaged resident cells (epithelial cells, endothelial cells, and lung-resident MSC), recruited immune cells, and soluble mediators (cytokines, chemokines, growth factors, and proteases) and the resulting environmental changes participate in shaping the observed inflammatory and fibrotic alterations of the lung tissue (Figures 1 and 2).…”