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Updated: Oct 17, 2025
Mesenchymal Stem Cell Regulation of Macrophage Phagocytosis; Quantitation and Imaging
Published on: July 16, 2021
SPION-MSCs enhance therapeutic efficacy in sepsis by regulating MSC-expressed TRAF1-dependent macrophage polarization
Yujun Xu1, Xinghan Liu1, Yi Li1
1The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, 22 Hankou Road, Nanjing, 210093, China.
Background:
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The liver has a crucial role in sepsis and is also a target for sepsis-related injury. Macrophage polarization between the M1 and M2 types is involved in the progression and resolution of both inflammation and liver injury. Iron oxide-based synthetic nanoparticles (SPIONs) can be used as antibacterial agents to regulate the inflammatory response. Mesenchymal stromal/stem cells (MSCs) have been widely used in the treatment of autoimmune diseases, sepsis, and other diseases. However, to date, both the effects of SPIONs on MSCs and the fate of SPION-labelled MSCs in sepsis and other diseases are still unclear.
Methods:
Mice were subjected to caecal ligation and puncture (CLP) or lipopolysaccharide (LPS) induction to develop sepsis models. The CLP or LPS models were treated with MSCs or SPION-labelled/pretreated MSCs (SPION-MSCs). Bone marrow (BM)-derived macrophages and RAW 264.7 cells were cocultured with MSCs or SPION-MSCs under different conditions. Flow cytometry, transmission electron microscopy, western blotting, quantitative real-time PCR, and immunohistochemical analysis were performed.
Results:
We found that SPIONs did not affect the basic characteristics of MSCs. SPIONs promoted the survival of MSCs by upregulating HO-1 expression under inflammatory conditions. SPION-MSCs enhanced the therapeutic efficacy of liver injury in both the CLP- and LPS-induced mouse models of sepsis. Moreover, the protective effect of SPION-MSCs against sepsis-induced liver injury was related to macrophages. Systemic depletion of macrophages reduced the efficacy of SPION-MSC therapy. Furthermore, SPION-MSCs promoted macrophages to polarize towards the M2 phenotype under sepsis-induced liver injury in mice. The enhanced polarization towards M2 macrophages was attributed to their phagocytosis of SPION-MSCs. SPION-MSC-expressed TRAF1 was critical for promotion of macrophage polarization and alleviation of sepsis in mice.
Conclusion:
MSCs labelled/pretreated with SPIONs may be a novel therapeutic strategy to prevent or treat sepsis and sepsis-induced liver injury.
Highlights:
1. SPIONs enhance the viability of MSCs by promoting HO-1 expression. 2. SPION-labelled/pretreated MSCs effectively improve sepsis by regulating macrophage polarization to M2 macrophages. 3. SPION-labelled/pretreated MSCs regulate macrophage polarization in a manner dependent on MSC-expressed TRAF1 protein.
Insights
Synthetic nanoparticles (SPIONs) combined with mesenchymal stromal/stem cells (MSCs) show promise in treating sepsis-induced liver injury by reprogramming macrophages. This novel therapeutic strategy enhances MSC survival and promotes M2 macrophage polarization for improved outcomes.
Area of Science:
- Biomedical Engineering
- Immunology
- Regenerative Medicine
Background:
- Sepsis is a life-threatening condition characterized by organ dysfunction due to a dysregulated host response to infection.
- The liver is a key organ affected by sepsis, and macrophage polarization (M1/M2) influences inflammation and injury.
- Synthetic polymeric nanoparticles (SPIONs) and mesenchymal stromal/stem cells (MSCs) are being explored for therapeutic applications, but their combined effects in sepsis are unclear.
Purpose of the Study:
- To investigate the effects of SPIONs on MSCs and the therapeutic potential of SPION-labeled MSCs (SPION-MSCs) in sepsis-induced liver injury.
- To elucidate the role of SPION-MSCs in modulating macrophage polarization and their impact on sepsis outcomes.
Main Methods:
- Sepsis models were established in mice using caecal ligation and puncture (CLP) or lipopolysaccharide (LPS) induction.
- Mice were treated with MSCs or SPION-MSCs, and outcomes were assessed using flow cytometry, microscopy, western blotting, qPCR, and immunohistochemistry.
- Bone marrow-derived macrophages and RAW 264.7 cells were co-cultured with MSCs or SPION-MSCs to study cellular interactions.
Main Results:
- SPIONs did not alter basic MSC characteristics and promoted MSC survival under inflammation by upregulating HO-1 expression.
- SPION-MSCs significantly enhanced therapeutic efficacy in sepsis-induced liver injury models, with effects mediated by macrophages.
- SPION-MSCs promoted M2 macrophage polarization, dependent on SPION-MSC-expressed TRAF1, leading to reduced sepsis severity.
Conclusions:
- SPION-labeled/pretreated MSCs represent a novel therapeutic strategy for sepsis and associated liver injury.
- The therapeutic benefits are linked to enhanced MSC viability and the modulation of macrophage polarization towards an anti-inflammatory M2 phenotype.
- TRAF1 expression in SPION-MSCs is crucial for their ability to promote macrophage polarization and alleviate sepsis.
