Inflammatory cytokines-stimulated human muscle stem cells ameliorate ulcerative colitis via the IDO-TSG6 axis

Shengchao Zhang,Ying Wang,Gerry Melino,Qianwen Shang,Guan Wang,Pengbo Hou,Lijuan Cao,Rui Liu,Changshun Shao,Yongjing Chen,Chao Feng,Yanan Li,Zhanhong Liu,Yufang Shi,Yuyan Zhang,Jiankai Fang

doi:10.1186/s13287-020-02118-3

Abstract

BackgroundMuscle stem cells (MuSCs) are absolutely required for the formation, repair, and regeneration of skeletal muscle tissue. Increasing evidence demonstrated that tissue stem cells, especially mesenchymal stem cells (MSCs), can exert therapeutic effects on various degenerative and inflammatory disorders based on their immunoregulatory properties. Human mesenchymal stem cells (hMSCs) treated with interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) were reported to possess anti-inflammatory functions by producing TNF-stimulated gene 6 (TSG-6). However, whether human muscle stem cells (hMuSCs) also possess TSG-6 mediated anti-inflammatory functions has not been explored.MethodsThe ulcerative colitis mouse model was established by subjecting mice to dextran sulfate sodium (DSS) in drinking water for 7 days. hMuSCs were pretreated with IFN-γ and TNF-α for 48 h and were then transplanted intravenously at day 2 of DSS administration. Body weights were monitored daily. Indoleamine 2,3-dioxygenase (IDO) and TSG-6 in hMuSCs were knocked down with short hairpin RNA (shRNA) and small interfering RNA (siRNA), respectively. Colon tissues were collected for length measurement and histopathological examination. The serum level of IL-6 in mice was measured by enzyme-linked immunosorbent assay (ELISA). Real-time PCR and Western blot analysis were performed to evaluate gene expression.ResultshMuSCs treated with inflammatory factors significantly ameliorated inflammatory bowel disease (IBD) symptoms. IDO and TSG-6 were greatly upregulated and required for the beneficial effects of hMuSCs on IBD. Mechanistically, the tryptophan metabolites, kynurenine (KYN) or kynurenic acid (KYNA) produced by IDO, augmented the expression of TSG-6 through activating their common receptor aryl hydrocarbon receptor (AHR).ConclusionInflammatory cytokines-treated hMuSCs can alleviate DSS-induced colitis through IDO-mediated TSG-6 production.

Highlights

Muscle stem cells (MuSCs) are absolutely required for the formation, repair, and regeneration of skeletal muscle tissue
IDO is vital for the anti-inflammatory effects of human muscle stem cells (hMuSCs) on dextran sulfate sodium (DSS)-induced inflammatory bowel disease (IBD) To investigate the immunoregulatory functions of hMuSCs in inflammatory diseases, we injected intravenously hMuSCs, untreated or stimulated with IFN-γ and tumor necrosis factor-α (TNF-α) (I+T), into mice during IBD induction by DSS
The level of IL-6 in serum, an important indicator for inflammatory progression, was lowest in the I+T hMuSC group (Fig. S2d). These results indicated that while hMuSCs could exert antiinflammatory effects on IBD, those stimulated by inflammatory cytokines acquired augmented potency

Summary

Introduction

Muscle stem cells (MuSCs) are absolutely required for the formation, repair, and regeneration of skeletal muscle tissue. As the most abundant tissue of the human body, skeletal muscle comprises approximately 40% of total body mass It fulfills multiple functions in the body such as postural support, voluntary locomotion, breathing, and endocrine and paracrine production, and regulates thermogenesis and systemic metabolism [1, 2]. MuSCs are activated to enter the cell cycle, proliferate, differentiate, and fuse to form new muscle fibers, which replace damaged and necrotic muscle tissues [4]. This process is termed as “cell replacement”

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