Bone Marrow Mesenchymal Stem Cell-Derived Exosomal miR-451a Inhibits Macrophage M1 Polarization Through the TLR4/PI3K/AKT Signaling Pathway to Alleviate Acute Lung Injury.
- 1Department of Pulmonary and Critical Care Medicine Kunming Children's Hospital (Children's Hospital Affiliated to Kunming Medical University) Kunming 650100 Yunnan China kmmc.cn.
Abstract
Background
Abnormal polarization of macrophages toward the M1 phenotype is a key pathogenic mechanism in acute lung injury (ALI). Bone marrow mesenchymal stem cell (MSC)-derived exosomes (BMSC-Exos) represent a promising therapeutic approach to inhibit macrophage M1 polarization and alleviate ALI, but the molecular mediators involved are incompletely defined. This study aimed to identify the responsible exosomal mediator and to define its downstream signaling.Methods
An ALI mouse model was established via intratracheal LPS instillation, and a cell injury model was constructed using LPS-stimulated RAW264.7 cells. Exos were isolated from human BMSCs. Lung injury was assessed through HE staining, lung wet/dry weight ratio, bronchoalveolar lavage fluid (BALF) protein concentration, and total BALF cell count. The expression levels of related genes and proteins were assessed using RT-qPCR, western blotting, ELISA, and immunofluorescence.Results
Treatment with BMSC-Exos significantly ameliorated lung damage in ALI mice and reduced the lung wet/dry weight ratio, BALF protein concentration, and total inflammatory cell count. Additionally, BMSC-Exos reduced the expression of M1 macrophage markers (iNOS, CD80, and CD86) and proinflammatory cytokines (IL-1β, IL-6, and TNF-α), thereby inhibiting macrophage M1 polarization. Mechanistically, BMSC-Exos suppressed the LPS-induced activation of the PI3K/AKT signaling pathway, whereas the PI3K/AKT activator 740 Y-P weakened the inhibitory effect of BMSC-Exos on M1 polarization. The expression of miR-451a was significantly downregulated in ALI and enriched in BMSC-Exos. miR-451a inhibits the PI3K/AKT signaling pathway by targeting and suppressing TLR4 expression. miR-451a knockdown or TLR4 overexpression attenuated the therapeutic effects of BMSC-Exos on ALI.Conclusion
BMSC-Exos-derived miR-451a inhibited the PI3K/AKT signaling pathway by downregulating TLR4 expression, thereby suppressing macrophage M1 polarization and alleviating ALI.
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BibTeX
@article{yang2026bone,
title = {{Bone Marrow Mesenchymal Stem Cell-Derived Exosomal miR-451a Inhibits Macrophage M1 Polarization Through the TLR4/PI3K/AKT Signaling Pathway to Alleviate Acute Lung Injury.}},
author = {Jiawu Yang and Yongze Liu and Qinglang Dai and Yuan Liao and Liang Zhao and Zhu Tian and Feng Li},
journal = {Stem cells international},
year = {2026},
month = oct,
doi = {10.1155/sci/5080421},
url = {https://europepmc.org/article/MED/42947947},
note = {CC BY},
}
RIS
TY - JOUR
TI - Bone Marrow Mesenchymal Stem Cell-Derived Exosomal miR-451a Inhibits Macrophage M1 Polarization Through the TLR4/PI3K/AKT Signaling Pathway to Alleviate Acute Lung Injury.
AU - Jiawu Yang
AU - Yongze Liu
AU - Qinglang Dai
AU - Yuan Liao
AU - Liang Zhao
AU - Zhu Tian
AU - Feng Li
PY - 2026
DA - 2026/10/26
JO - Stem cells international
DO - 10.1155/sci/5080421
UR - https://europepmc.org/article/MED/42947947
AB - Background Abnormal polarization of macrophages toward the M1 phenotype is a key pathogenic mechanism in acute lung injury (ALI). Bone marrow mesenchymal stem cell (MSC)-derived exosomes (BMSC-Exos) represent a promising therapeutic approach to inhibit macrophage M1 polarization and alleviate ALI, but the molecular mediators involved are incompletely defined. This study aimed to identify the responsible exosomal mediator and to define its downstream signaling.Methods An ALI mouse model was established via intratracheal LPS instillation, and a cell injury model was constructed using LPS-stimulated RAW264.7 cells. Exos were isolated from human BMSCs. Lung injury was assessed through HE staining, lung wet/dry weight ratio, bronchoalveolar lavage fluid (BALF) protein concentration, and total BALF cell count. The expression levels of related genes and proteins were assessed using RT-qPCR, western blotting, ELISA, and immunofluorescence.Results Treatment with BMSC-Exos significantly ameliorated lung damage in ALI mice and reduced the lung wet/dry weight ratio, BALF protein concentration, and total inflammatory cell count. Additionally, BMSC-Exos reduced the expression of M1 macrophage markers (iNOS, CD80, and CD86) and proinflammatory cytokines (IL-1β, IL-6, and TNF-α), thereby inhibiting macrophage M1 polarization. Mechanistically, BMSC-Exos suppressed the LPS-induced activation of the PI3K/AKT signaling pathway, whereas the PI3K/AKT activator 740 Y-P weakened the inhibitory effect of BMSC-Exos on M1 polarization. The expression of miR-451a was significantly downregulated in ALI and enriched in BMSC-Exos. miR-451a inhibits the PI3K/AKT signaling pathway by targeting and suppressing TLR4 expression. miR-451a knockdown or TLR4 overexpression attenuated the therapeutic effects of BMSC-Exos on ALI.Conclusion BMSC-Exos-derived miR-451a inhibited the PI3K/AKT signaling pathway by downregulating TLR4 expression, thereby suppressing macrophage M1 polarization and alleviating ALI.
SN - 1687-966X
SN - 1687-9678
ER -