经训练的人骨髓间充质干细胞可恢复暴发性肝衰竭小鼠的组织免疫微环境。

Trained human bone marrow mesenchymal stem cells restore tissue immuno-microenvironment in fulminant hepatic failure mice.

作者信息

Li Bingqi, Zeng Xiaofei, Jiang Jing, Zhou Qian, Tong Li, Liang Xi, Xin Jiaojiao, Chen Xi, Wu Xiao, Kong Yuheng, Ma Shiwen, Luo Jinjin, Qiang Wei, Zhu Bing, Luo Xinhua, Li Jun, Shi Dongyan

机构信息

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug Development, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China.

Zunyi Medical University, Zunyi, 563000, China.

出版信息

Stem Cell Res Ther. 2025 Aug 10;16(1):440. doi: 10.1186/s13287-025-04540-x.

DOI:10.1186/s13287-025-04540-x

PMID:40784876

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12337527/

Abstract

BACKGROUND

Trained immunity with human bone marrow mesenchymal stem cells (hBMSC) is a promising approach to liver regeneration. This study aimed to clarify the trained-hBMSC (T-hBMSC) in restoring tissue immuno-microenvironment in fulminant hepatic failure (FHF) mice.

METHODS

hBMSC trained with tumor necrosis factor-α and interferon-γ were phenotypically characterized in vitro. FHF mouse models were established in male Balb/c mice via tail vein injection of concanavalin A. The therapeutic potential of T-hBMSC was evaluated through transplantation into FHF mice. Transcriptomic analysis was performed to elucidate the mechanism of liver regeneration post-transplantation of T-hBMSC.

RESULTS

T-hBMSC with the characteristics of trilineage differentiation potential showed that pro-inflammatory (IL1β, IL8, both p < 0.0001) and immunoregulatory genes (PDL1, IDO1, both p < 0.0001) were significantly upregulated compared to untrained-hBMSC (UT-hBMSC). Time-trajectory analysis revealed downregulation of pro-inflammatory genes (IL6, IL8, and IL1α) and upregulation of immunomodulatory genes (IDO1) in T-hBMSC upon mimic-stimulation, characterized by distinct transcriptional programs. The liver function (ALT, AST) and inflammatory cytokines (IL6, MCP1, both p < 0.01) levels were significantly improved in the T-hBMSC-treated mice. The survival status of the T-hBMSC group was superior to the UT-hBMSC group, although there was no statistical significance. Histological analysis confirmed reduced necrosis and fewer infiltrating CD45 immune cells in the T-hBMSC-treated mice. Significant downregulation of immune response (TNF & IL-17 signaling pathways and neutrophil chemotaxis) and upregulation of metabolic pathways were observed in the T-hBMSC group, associated with enhanced liver regeneration. The proportion of anti-inflammatory F4/80CD163 macrophages was increased in the liver of T-hBMSC group.

CONCLUSION

T-hBMSC exhibited enhanced immunomodulation, effectively rescuing liver failure and reducing inflammation via restoring the immune-microenvironment. These findings highlighted the potential of trained immunity as a novel strategy for the treatment of liver failure.

摘要

背景

用人骨髓间充质干细胞（hBMSC）进行训练免疫是一种很有前景的肝脏再生方法。本研究旨在阐明训练后的hBMSC（T-hBMSC）在恢复暴发性肝衰竭（FHF）小鼠组织免疫微环境中的作用。

方法

对用肿瘤坏死因子-α和干扰素-γ训练的hBMSC进行体外表型鉴定。通过尾静脉注射刀豆蛋白A在雄性Balb/c小鼠中建立FHF小鼠模型。通过将T-hBMSC移植到FHF小鼠中来评估其治疗潜力。进行转录组分析以阐明T-hBMSC移植后肝脏再生的机制。

结果

具有三系分化潜能特征的T-hBMSC显示，与未训练的hBMSC（UT-hBMSC）相比，促炎基因（IL1β、IL8，均p<0.0001）和免疫调节基因（PDL1、IDO1，均p<0.0001）显著上调。时间轨迹分析显示，在模拟刺激后，T-hBMSC中促炎基因（IL6、IL8和IL1α）下调，免疫调节基因（IDO1）上调，其特征是具有独特的转录程序。T-hBMSC治疗的小鼠肝功能（ALT、AST）和炎性细胞因子（IL6、MCP1，均p<0.01）水平显著改善。T-hBMSC组的生存状况优于UT-hBMSC组，尽管无统计学意义。组织学分析证实，T-hBMSC治疗的小鼠坏死减少，浸润的CD45免疫细胞减少。在T-hBMSC组中观察到免疫反应（TNF和IL-17信号通路以及中性粒细胞趋化性）显著下调，代谢通路上调，这与肝脏再生增强有关。T-hBMSC组肝脏中抗炎性F4/80CD163巨噬细胞的比例增加。