Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China.
Cell-Gene Therapy Translational Medicine Research Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Stem Cell Res Ther. 2021 Sep 9;12(1):496. doi: 10.1186/s13287-021-02560-x.
Fulminant hepatitis is a severe life-threatening clinical condition with rapid progressive loss of liver function. It is characterized by massive activation and infiltration of immune cells into the liver and disturbance of inflammatory cytokine production. Mesenchymal stem cells (MSCs) showed potent immunomodulatory properties. Transplantation of MSCs is suggested as a promising therapeutic approach for a host of inflammatory conditions.
In the current study, a well-established concanavalin A (Con A)-induced fulminant hepatitis mouse model was used to investigate the effects of transplanting human umbilical cord Wharton's jelly-derived MSCs (hWJ-MSCs) on fulminant hepatitis.
We showed that hWJ-MSCs effectively alleviate fulminant hepatitis in mouse models, primarily through inhibiting T cell immunity. RNA sequencing of liver tissues and human T cells co-cultured with hWJ-MSCs showed that NF-κB signaling and glycolysis are two main pathways mediating the protective role of hWJ-MSCs on both Con A-induced hepatitis in vivo and T cell activation in vitro.
In summary, our data confirmed the potent therapeutic role of MSCs-derived from Wharton's jelly of human umbilical cord on Con A-induced fulminant hepatitis, and uncovered new mechanisms that glycolysis metabolic shift mediates suppression of T cell immunity by hWJ-MSCs.
暴发性肝炎是一种严重的危及生命的临床病症，其特征是肝功能迅速恶化，大量免疫细胞浸润肝脏，并扰乱炎症细胞因子的产生。间充质干细胞（MSCs）具有强大的免疫调节特性。MSC 的移植被认为是治疗多种炎症疾病的一种很有前途的方法。
在本研究中，我们使用了已建立的伴刀豆球蛋白 A（Con A）诱导的暴发性肝炎小鼠模型，来研究人脐带华通氏胶来源的间充质干细胞（hWJ-MSCs）移植对暴发性肝炎的影响。
我们表明，hWJ-MSCs 通过抑制 T 细胞免疫，有效地缓解了小鼠模型中的暴发性肝炎。对肝组织和与人 hWJ-MSCs 共培养的人 T 细胞进行 RNA 测序显示，NF-κB 信号通路和糖酵解是 hWJ-MSCs 对体内 Con A 诱导的肝炎和体外 T 细胞活化的保护作用的两个主要介导途径。
综上所述，我们的数据证实了人脐带华通氏胶来源的 MSC 对 Con A 诱导的暴发性肝炎具有强大的治疗作用，并揭示了糖酵解代谢转换通过 hWJ-MSCs 抑制 T 细胞免疫的新机制。
