TLR4 and IFN - γ Activated Mesenchymal Stem Cells Improve Schistosomiasis Liver Fibrosis by Regulating Macrophage Polarization
10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.2025.0306
- VernacularTitle:TLR4和IFN-γ激活的间充质干细胞通过调节巨噬细胞极化改善血吸虫病肝纤维化
- Author:
Yaojia REN
1
;
Fang CHEN
1
;
Wanxian HUANG
2
;
Zhongdao WU
2
;
Junxia LEI
1
Author Information
1. South China University of Technology School of Medicine， Guangzhou 510080， China
2. Key Laboratory of Tropical Disease Prevention and Control Research Designated by the Chinese Ministry of Education， Sun Yat-sen University， Guangzhou 510080， China
- Publication Type:Journal Article
- Keywords:
macrophages;
schistosomiasis;
hepatic fibrosis;
mesenchymal stem cells;
M2 macrophage polarization
- From:
Journal of Sun Yat-sen University(Medical Sciences)
2025;46(3):410-419
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveTo investigate whether co-activated mesenchymal stem cells（MSCs） exert therapeutic effects against schistosomiasis by modulating macrophage polarization. MethodsTwenty adult male Balb/c mice were randomly divided into four groups： uninfected， infected， MSC-treated， and MSCTLR4+IFN-γ-treated groups. The Schistosoma japonicum infection model was established via abdominal patch method with cercariae. At week 5 post-infection， praziquantel was administered orally for antiparasitic treatment. At week 6， mice received either MSCs treatments （with or without pre-activation） or no treatment. Body weight changes were monitored weekly. Hepatic pathological alterations were evaluated via HE and Masson staining. RT-qPCR was used to assess α-SMA and collagen （Col-I， Col-Ⅲ） mRNA levels to quantify fibrosis. The mRNA levels of hepatic inflammatory cytokines and matrix metalloproteinases（MMP） were analyzed to explore fibrotic mechanisms. The expressions of i-Nos and Arg-1 in liver tissues were detected by RT-qPCR， and the ratio of M1 or M2 macrophages was detected by immunofluorescence staining， aiming to analyze the correlation between MSCs treatment and macrophage polarization. An in vitro co-culture system validated direct MSC-macrophage interactions. ResultsCompared with the infected group， the MSCTLR4+IFN-γ group exhibited increased body weight gain （P< 0.01）， reduced hepatic granulomatous lesion area （P< 0.001）， and decreased α-SMA， Col-I， and Col-Ⅲ mRNA levels （P< 0.01）. Additionally， the MSCTLR4+IFN-γ group showed reduced TNF-α and IL-1β expression （P< 0.05）， as well as elevated MMP2， Mmp9， and MMP13 levels （P< 0.01）. The MSCTLR4+IFN-γ group showed higher expression of M2 marker Arg-1 mRNA compared with the infection group （P < 0.001） ， while the expression of M1 marker i-Nos decreased （P< 0.05）. Immunofluorescence confirmed a lower i-Nos+ cell ratio （P< 0.05） and higher F4/80+CD206+ cell ratio （P< 0.000 1） in the MSCTLR4+IFN-γ group compared with the infection group. In vitro co-culture experiments further demonstrated that MSCTLR4+IFN-γ promoted Arg-1 expression， suppressed pro-inflammatory cytokine i-Nos and TNF-α levels， consistent with ELISA results. ConclusionsThis study reveals that TLR4 and IFN-γ co-activated MSCs alleviate Schistosoma japonicum-induced hepatic fibrosis， potentially through modulating macrophage polarization toward the M2 phenotype. This mechanism may suppress inflammation and enhance extracellular matrix degradation， providing a therapeutic strategy for schistosomiasis-associated liver fibrosis.
