Journal Article

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

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

2025

Overview

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 F4/80 + CD163 + 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. Graphical Abstract

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Animal models / Animals / Anopheles / BCG / BCG vaccines / Biological response modifiers / Biomedical and Life Sciences / Biomedical Engineering and Bioengineering / Bone marrow / Bone Marrow Cells - cytology / Bone marrow mesenchymal stem cells / CD163 antigen / CD45 antigen / Cell Biology / Cell Differentiation / Cellular Microenvironment / Chemotaxis / Concanavalin A / Cytokines / Disease Models, Animal / DNA methylation / Down-regulation / Epigenetics / Flow cytometry / Fulminant hepatic failure / Genes / Growth factors / Health aspects / Hepatitis / Humans / Immune microenvironment / Immune response / Immunity / Immunity (Disease) / Immunology / Immunomodulation / Immunoregulation / Inflammation / Interferon / Kinases / Laboratory animals / Leukocytes (neutrophilic) / Life Sciences / Liver / Liver failure / Liver Failure, Acute - immunology / Liver Failure, Acute - pathology / Liver Failure, Acute - therapy / Liver Regeneration / Liver transplantation / Macrophages / Male / Medical research / Mesenchymal Stem Cell (MSCs) and MSC-Derived Extracellular Vesicles: Roles in Regenerative Medicine and Beyond / Mesenchymal Stem Cell Transplantation - methods / Mesenchymal stem cells / Mesenchymal Stem Cells - cytology / Mesenchymal Stem Cells - immunology / Mesenchymal Stem Cells - metabolism / Metabolic pathways / Metabolism / Mice / Mice, Inbred BALB C / Microenvironments / Oxidative stress / Regeneration / Regenerative Medicine/Tissue Engineering / Stem Cells / Trained immunity / Trainers / Transcriptomics / Transplantation / Tumor necrosis factor / Tumor necrosis factor-TNF / Up-regulation / Viral infections / γ-Interferon