Ling Xiao, Wang Teng, Han Chao, Wang Pin, Liu Xiaoli, Zheng Chengyun, Bi Jianzhong, Zhou Xiaoyan
Department of Gynaecology, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Digestive Internal Medicine, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Front Immunol. 2022 Mar 1;13:835345. doi: 10.3389/fimmu.2022.835345. eCollection 2022.
Our previous study showed that interferon gamma (IFN-γ) might enhance the immunosuppressive properties of mesenchymal stem cells (MSCs) by upregulating the expression of indoleamine 2,3-dioxygenease. Therefore, we treated experimental autoimmune encephalomyelitis (EAE) mice, an animal model of multiple sclerosis (MS), with IFN-γ-primed human umbilical cord MSCs (IFN-γ-hUCMSCs). This study aimed to investigate the potential therapeutic effects of IFN-γ-hUCMSCs transplantation and to identify the biological pathways involved in EAE mice. Firstly, the body weights and clinical scores of EAE mice were recorded before and after treatment. Then, the inflammatory cytokine levels in splenic cell supernatants were quantified by enzyme-linked immunosorbent assay. Finally, the mRNA expression levels of signal transducer and activator of transduction 3 (), retinoic acid-related orphan receptor gamma t (), and forkhead box P3 () were detected by quantitative reverse transcription polymerase chain reaction. We observed that IFN-γ-hUCMSCs transplantation significantly alleviated body weight loss and decreased the clinical scores of mice. Additionally, IFN-γ-hUCMSCs transplantation could regulate the production of inflammatory cytokines, interleukin (IL)-10 and IL-17, thereby showing more potent treatment efficacy than human umbilical cord MSCs (hUCMSCs) transplantation ( < 0.05). Compared with the EAE group, the expressions of and in the transplantation groups were significantly decreased, but the expression of was significantly upregulated in the IFN-γ-hUCMSCs transplantation group compared to that in the hUCMSCs transplantation group. We assumed that IFN-γ-hUCMSCs may affect the balance of T helper 17 (Th17) cells/regulatory T cells (Tregs) through the Foxp3/ROR-γt/STAT3 signaling pathway to reduce the inflammatory response, thereby improving the clinical symptoms of EAE mice. Our study demonstrated that transplantation of IFN-γ-hUCMSCs could reduce inflammation in EAE mice the Foxp3/ROR-γt/STAT3 signaling pathway, highlighting the therapeutic effects of IFN-γ-hUCMSCs in patients with MS.
我们之前的研究表明，γ干扰素（IFN-γ）可能通过上调吲哚胺2,3-双加氧酶的表达来增强间充质干细胞（MSCs）的免疫抑制特性。因此，我们用经IFN-γ预处理的人脐带间充质干细胞（IFN-γ-hUCMSCs）治疗实验性自身免疫性脑脊髓炎（EAE）小鼠，这是一种多发性硬化症（MS）的动物模型。本研究旨在探讨IFN-γ-hUCMSCs移植的潜在治疗效果，并确定EAE小鼠体内涉及的生物学途径。首先，记录治疗前后EAE小鼠的体重和临床评分。然后，通过酶联免疫吸附测定法定量脾细胞上清液中的炎性细胞因子水平。最后，通过定量逆转录聚合酶链反应检测信号转导子和转录激活子3（STAT3）、维甲酸相关孤儿受体γt（ROR-γt）和叉头框P3（Foxp3）的mRNA表达水平。我们观察到，IFN-γ-hUCMSCs移植显著减轻了小鼠的体重减轻，并降低了其临床评分。此外，IFN-γ-hUCMSCs移植可调节炎性细胞因子白细胞介素（IL）-10和IL-17的产生，从而显示出比人脐带间充质干细胞（hUCMSCs）移植更有效的治疗效果（P<0.05）。与EAE组相比，移植组中STAT3和ROR-γt的表达显著降低，但与hUCMSCs移植组相比，IFN-γ-hUCMSCs移植组中Foxp3的表达显著上调。我们推测，IFN-γ-hUCMSCs可能通过Foxp3/ROR-γt/STAT3信号通路影响辅助性T细胞17（Th17）/调节性T细胞（Tregs）的平衡，以减轻炎症反应，从而改善EAE小鼠的临床症状。我们的研究表明，IFN-γ-hUCMSCs移植可通过Foxp3/ROR-γt/STAT3信号通路减轻EAE小鼠的炎症，突出了IFN-γ-hUCMSCs对MS患者的治疗效果。
