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

• Published in: Antioxidants & redox signaling Vol. 26; no. 11; p. 563
• Main Authors: Klein, Diana, Steens, Jennifer, Wiesemann, Alina, Schulz, Florian, Kaschani, Farnusch, Röck, Katharina, Yamaguchi, Masahiro, Wirsdörfer, Florian, Kaiser, Markus, Fischer, Jens W, Stuschke, Martin, Jendrossek, Verena
• Format: Journal Article
• Language: English
• Published: United States 10.04.2017
• Subjects: Animals; Disease Models, Animal; Endothelial Cells - metabolism; Endothelial Cells - pathology; Endothelial Cells - radiation effects; Endothelial Cells - ultrastructure; Fibroblasts - metabolism; Fibroblasts - radiation effects; Fibrosis; Gene Expression; Lung - metabolism; Lung - pathology; Lung - radiation effects; Mesenchymal Stem Cell Transplantation; Mesenchymal Stromal Cells - cytology; Mice; Organometallic Compounds - pharmacology; Phenotype; Radiation Injuries - genetics; Radiation Injuries - metabolism; Radiation Injuries - pathology; Radiation Injuries - therapy; Radiation Injuries, Experimental; Salicylates - pharmacology; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism; radiotherapy; radioprotection; mesenchymal stem cell therapy; vascular dysfunction
• ISSN: 1557-7716
• DOI: 10.1089/ars.2016.6748

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. 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 long-term 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 MSC-derived SOD1 is involved in the protective action of MSC, presumably through paracrine signaling. 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. 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.