Mesenchymal stem cells (MSCs) are a type of adult stem cells with immunomodulatory properties. Recently, due to their safety and efficacy, MSCs have become a potential cell therapy choice for pulmonary fibrosis. However, the mechanism by which MSCs treat pulmonary fibrosis remains unclear. Most studies suggest that MSCs exert their therapeutic effects mainly through paracrine mechanisms. However, it is difficult to clearly identify the main secreted proteins and the exact target cells and target sites of the paracrine effect. Neutrophils are key immune cells in the early stages of various tissue damage. It is currently unclear how MSCs regulate the function of neutrophils during pulmonary fibrosis. In this study, we focused on investigating the regulatory effect of MSCs on the function of neutrophils in the early stage of pulmonary fibrosis and its new molecular mechanism by constructing a bleomycin-induced mouse pulmonary fibrosis model and an MSC-neutrophil co-culture model.The results showed that the number of neutrophils and neutrophil extracellular traps (NETs) significantly increased in the early stage of pulmonary fibrosis induction, and NETs could promote the transformation of pulmonary fibroblasts into myofibroblasts. Early intervention with MSCs can treat pulmonary fibrosis by inhibiting the production of NETs. This effect is achieved by MSCs transferring their own mitochondria to neutrophils, inhibiting mitochondria autophagy in neutrophils, and thereby reducing the production of NETs. Further studies have found that the induction process of mitochondrial transfer is regulated by the Jak2-Stat3-Foxo1 pathway. Compared to normal MSCs, knockdown of either mitochondria or Foxo1 of MSCs have attenuated therapeutic effects on pulmonary fibrosis. Interestingly, in the co-culture system, the transfer of mitochondria by MSCs is only triggered when neutrophils produce NETs in response to stimulation. This study reveals the role and molecular mechanism of MSCs in regulating the function of neutrophils in the early stage of pulmonary fibrosis and proposes new strategies for the development of novel MSCs.

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2025
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