Enhanced therapeutic effects of human mesenchymal stem cells transduced with superoxide dismutase 3 in a murine atopic dermatitis‐like skin inflammation model. Issue 12 (11th October 2018)

• Record Type: Journal Article
• Authors: Sah, Shyam Kishor; Agrahari, Gaurav; Nguyen, Cuong Thach; Kim, Yeon‐Soo; Kang, Kyung‐Sun; Kim, Tae‐Yoon
• Is Part Of: Allergy. Volume 73:Issue 12(2018)
• Page Start: 2364
• Page End: 2376
• Publication Date: 2018-10-11
• Subjects: atopic dermatitis -- histamine 4 receptor -- mesenchymal stem cells -- oxidative stress -- superoxide dismutase 3; Allergy -- Periodicals; 616.97
• DOI: 10.1111/all.13594
• Languages: English
• ISSNs: 0105-4538

Abstract

Abstract: Background: The use of mesenchymal stem cells (MSCs) has been proposed to treat various autoimmune diseases. However, effective strategies for treating atopic dermatitis (AD) are still lacking, and the mechanisms underlying stem cell therapy remain largely unknown. In this study, we sought to explore potential clinical application of superoxide dismutase 3‐transduced MSCs (SOD3‐MSCs) to experimental AD‐like skin inflammation in in vitro and in vivo and its underlying anti‐inflammatory mechanisms. Methods: SOD3‐MSCs were administered subcutaneously to mice with AD, and associated symptoms and biologic changes were evaluated. Human keratinocytes, mast cells, and murine T helper (Th) 2 cells were cocultured in vitro with SOD3‐MSCs to investigate potential therapeutic effects of SOD3‐MSCs. Results: In mice with AD, SOD3‐MSCs ameliorated AD pathology and enhanced the efficacy of MSC therapy by controlling activated immune cells, by reducing expression levels of proinflammatory mediators in the skin, and by inhibiting the histamine H4 receptor (H4R)‐mediated inflammatory cascade and activation of Janus kinase signal transducer and activator of transcription pathways. Similarly, coculture of SOD3‐MSCs with mast cells, keratinocytes, and Th2 cells effectively dampened H4R‐dependent persistent inflammatory responses by multiple mechanisms. Moreover, we also showed that SOD3 interacts with H4R and IL‐4 receptor α. The functional significance of this interaction could be a markedly reduced inflammatory response in keratinocytes and overall AD pathogenesis, representing a novel mechanism for SOD3's anti‐inflammatory effects. Conclusion: SOD3‐MSCs can be potentially used as an effective and clinically relevant therapy for AD and other autoimmune disorders. Abstract : (A and B) Proposed mechanism by which SOD3‐MSCs control inflammatory pathways in the skin through regulation of keratinocytes, Th2 cells, and mast cell function. In this study, we demonstrated that SOD3‐MSCs suppress skin inflammation via H4R/IL‐4R‐dependent mechanism, with suppression of multiple proximal pathways in mast cells, keratinocytes, and Th2 cells.