The Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
Key Laboratory of Experimental Teratology, Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Sci Rep. 2024 Oct 8;14(1):23410. doi: 10.1038/s41598-024-73684-2.
Muscle stem cells (MuSCs) are effective in treating inflammatory diseases driven by overactive innate immune responses, such as colitis and acute lung injury, due to their immunomodulatory properties. However, their potential in treating diseases driven by adaptive immune responses is still uncertain. When primed with inflammatory cytokines, MuSCs strongly suppressed T cell activation and proliferation in vitro in co-culture with activated splenocytes or peripheral blood mononuclear cells. Systemic administration of MuSCs from both mice and humans alleviated pathologies in mice with concanavalin A-induced acute liver injury, characterized by hyperactivated T lymphocytes. Importantly, MuSCs showed significant species-specific differences in their immunoregulatory functions. In mouse MuSCs (mMuSCs), deletion or inhibition of inducible nitric oxide synthase (iNOS) reduced their immunosuppressive activity, and absence of iNOS negated their therapeutic effects in liver injury. Conversely, in human MuSCs (hMuSCs), knockdown or inhibition of indoleamine 2,3-dioxygenase (IDO) eliminated their immunosuppressive effects, and loss of IDO function rendered hMuSCs ineffective in treating liver injury in mice. These results reveal significant species-specific differences in the mechanisms by which MuSCs mediate T cell immunosuppression. Mouse MuSCs rely on iNOS, while human MuSCs depend on IDO expression. This highlights the need to consider species-specific responses when evaluating MuSCs' therapeutic potential in immune-related disorders.
肌卫星细胞（MuSCs）因其免疫调节特性，在治疗由过度活跃的先天免疫反应驱动的炎症性疾病方面非常有效，例如结肠炎和急性肺损伤。然而，它们在治疗由适应性免疫反应驱动的疾病方面的潜力尚不确定。在与激活的脾细胞或外周血单核细胞共培养时，MuSCs 在受到炎症细胞因子刺激后，在体外强烈抑制 T 细胞的激活和增殖。来自小鼠和人类的 MuSCs 的系统给药减轻了伴刀豆球蛋白 A 诱导的急性肝损伤小鼠的病理，其特征为过度激活的 T 淋巴细胞。重要的是，MuSCs 在其免疫调节功能方面表现出明显的种属特异性差异。在小鼠 MuSCs（mMuSCs）中，诱导型一氧化氮合酶（iNOS）的缺失或抑制降低了其免疫抑制活性，而 iNOS 的缺失则否定了其在肝损伤中的治疗作用。相反，在人类 MuSCs（hMuSCs）中，吲哚胺 2,3-双加氧酶（IDO）的敲低或抑制消除了其免疫抑制作用，而 IDO 功能的丧失使 hMuSCs 在治疗小鼠肝损伤方面无效。这些结果揭示了 MuSCs 介导 T 细胞免疫抑制的机制在种属特异性方面存在显著差异。小鼠 MuSCs 依赖 iNOS，而人类 MuSCs 依赖 IDO 表达。这突出表明，在评估 MuSCs 在免疫相关疾病中的治疗潜力时，需要考虑种属特异性反应。
