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Mesenchymal Stem Cells Attenuate Acute Lung Injury in Mice Partly by Suppressing Alveolar Macrophage Activation in a PGE2-Dependent Manner

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Abstract

Mesenchymal stem cells (MSCs) have been demonstrated to attenuate acute lung injury (ALI). We also found that they can suppress the activation of alveolar macrophages (AMs), which can partly account for their therapeutic effects. MSCs do not inherently own immunosuppressive effects, when co-cultured with inflammatory immune cells, MSCs can be activated by inflammatory cytokines and meanwhile exert immunosuppressive effects. In order to further research, RNA sequencing (RNA-seq) of MSCs cultured before and after co-culturing with activated macrophages was performed. The data suggested a total of 5268 differentially expressed genes (DEGs) along the process. We used the data of 2754 upregulated DEGs to develop a signaling network of genes and the transcription factors targeting them in order to predict the altered functions of MSCs after exposure to inflammatory stimuli. This constructed network revealed some critical target genes and potential roles of MSCs under inflammatory conditions. According to the network, Ptgs2 was assumed to be an important gene participating in the immunosuppressive effects of MSCs. We also identified significant increases in the expression of COX2 protein and the secretion of PGE2 from MSCs. The use of the COX2 inhibitor NS-398 restrained the secretion of PGE2 and reversed the suppression of macrophage activation by MSCs in vitro. In addition, a selective antagonist of PGE2 binding receptor (EP4 receptor), GW627368X, also reversed the inhibitory effects of MSCs on AMs and the protective effects in ALI mouse. In summary, the therapeutic effects of MSCs on ALI partly occur through suppressing AM activation via PGE2 binding to EP4 receptor.

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The data of this study are available from the corresponding author upon request.

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Acknowledgements

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Funding

This work was supported by National Natural Science Foundation of China (Grant numbers [8170080655]).

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Authors and Affiliations

  1. Department of Anesthesia, Sir Run Run Shaw Hospital, Zhejiang University, East Qinchun Rd, NO, Hangzhou, 310000, People’s Republic of China

    Gaojian Wang, Yaping Zhang, Nianqiang Hu, Qinxue Liu, Fengjie Ma & Junran Xie

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  1. Gaojian Wang
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  2. Yaping Zhang
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  3. Nianqiang Hu
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  4. Qinxue Liu
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  5. Fengjie Ma
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  6. Junran Xie
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Gaojian Wang, Yaping Zhang, Nianqiang Hu, Qinxue Liu, Fengjie Ma, and Junran Xie. The first draft of the manuscript was written by Gaojian Wang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Junran Xie.

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Wang, G., Zhang, Y., Hu, N. et al. Mesenchymal Stem Cells Attenuate Acute Lung Injury in Mice Partly by Suppressing Alveolar Macrophage Activation in a PGE2-Dependent Manner. Inflammation 45, 2000–2015 (2022). https://doi.org/10.1007/s10753-022-01670-9

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