Key Takeaways & Executive Findings
- •• Trained hBMSC (T-hBMSC) exhibit enhanced immunomodulatory and anti-inflammatory properties, with upregulation of PDL1 and IDO1, and downregulation of pro-inflammatory cytokines upon stimulation. • T-hBMSC transplantation significantly improves liver function (ALT, AST) and reduces inflammatory cytokines (IL6, MCP1) in fulminant hepatic failure (FHF) mice, leading to reduced necrosis and immune cell infiltration. • Transcriptomic analysis reveals that T-hBMSC shift the liver microenvironment from pro-inflammatory to regenerative, with downregulation of TNF/IL-17 signaling and upregulation of metabolic pathways. • T-hBMSC increase the proportion of anti-inflammatory F4/80+CD163+ macrophages in the liver, contributing to tissue immuno-microenvironment restoration and enhanced liver regeneration.
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 F4/80+CD163+ macrophages was increased in the liver of T-hBMSC group.
1. Introduction
Fulminant hepatic failure (FHF) is a rapid deterioration of liver function with a high short-term mortality rate, caused by chemical toxins, drugs, hepatotropic or non-hepatotropic viral infections (e.g., hepatitis A and E), and autoimmune hepatitis [1]. The main characteristics of FHF are massive liver tissue necrosis and an inflammatory factor storm [2]. Liver transplantation is an effective treatment strategy for FHF; nonetheless, two major challenges must be overcome: donor shortage and immunological rejection. Mesenchymal stem cells (MSC) exhibit promising prospects in liver regeneration, owing to their differentiating into hepatocytes or other parenchymal cells to replace necrotic cells and regulating the intrahepatic lesion microenvironment via paracrine effects [3, 4]. Our previous studies have revealed that human bone marrow mesenchymal stem cells (hBMSC) rescued FHF pigs via immunoregulation [5, 6]. Clinical studies have demonstrated that hBMSC significantly improved liver function and the short-term survival rate of patients with acute-on-chronic liver failure (ACLF) [7]. However, a severe lesion microenvironment in vivo, characterized by sustained inflammatory responses, oxidative stress, and abnormal immune activation, impairs the survival and homing of stem cells, posing obstacles to their consistent efficiency [8].
The term “trained immunity” was initially proposed by Netea to describe the inflammatory memory of innate immune cells [9]. This phenomenon indicates how innate immune cells undergo adaptive modifications following initial exposure to inflammatory stimuli, enabling them to mount a more robust immunological response or sustain immune tolerance upon subsequent encounters with the same or different stimuli [10]. The Bacillus Calmette-Guerin (BCG) vaccination diminishes the risk of infection beyond tuberculosis and amplifies the anti-tumor and antiviral capacities of immune cells, which is closely related to the enhanced non-specific immunological response of the organism [11]. Well-known "trainers"
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Bingqi Li, Xiaofei Zeng, Jing Jiang, Qian Zhou, Li Tong, Xi Liang, Jiaojiao Xin, Xi Chen, Xiao Wu, Yuheng Kong, Shiwen Ma, Jinjin Luo, Wei Qiang, Bing Zhu, Xinhua Luo, Jun Li, Dongyan Shi (2026). Trained human bone marrow mesenchymal stem cells restore tissue immuno-microenvironment in fulminant hepatic failure mice. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-025-04540-x
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Frequently Asked Questions
What is trained immunity in the context of mesenchymal stem cells?
Trained immunity refers to the memory-like behavior of innate immune cells after initial exposure to a stimulus, leading to enhanced or altered responses upon subsequent challenges. In this study, human bone marrow mesenchymal stem cells (hBMSC) were trained with TNF-α and IFN-γ to enhance their immunomodulatory properties, making them more effective in restoring the tissue immuno-microenvironment in fulminant hepatic failure.
How does T-hBMSC transplantation improve liver function in FHF mice?
T-hBMSC transplantation significantly reduced liver enzyme levels (ALT, AST) and inflammatory cytokines (IL6, MCP1), decreased necrosis and immune cell infiltration, and increased anti-inflammatory macrophages (F4/80+CD163+), thereby restoring the liver immuno-microenvironment and promoting regeneration.
What are the key molecular changes induced by T-hBMSC in the liver?
Transcriptomic analysis showed downregulation of pro-inflammatory pathways (TNF and IL-17 signaling, neutrophil chemotaxis) and upregulation of metabolic pathways, indicating a shift from inflammation to regeneration. Additionally, T-hBMSC exhibited upregulation of immunoregulatory genes (PDL1, IDO1) and downregulation of pro-inflammatory genes upon stimulation.
What is the significance of the increased F4/80+CD163+ macrophages in T-hBMSC-treated mice?
F4/80+CD163+ macrophages are anti-inflammatory (M2-like) macrophages that help resolve inflammation and promote tissue repair. Their increased proportion in the liver of T-hBMSC-treated mice indicates a shift towards an anti-inflammatory microenvironment, which is crucial for liver regeneration.
What are the potential clinical implications of this study?
This study suggests that trained hBMSC could be a promising cell therapy for fulminant hepatic failure, potentially improving outcomes by modulating the immune microenvironment and enhancing liver regeneration. It provides a basis for future clinical applications in liver diseases.
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