Abstract
Radiotherapy is essential to cancer treatment, while it inevitably injures surrounding normal tissues, and bone tissue is one of the most common sites prone to irradiation. Bone marrow mesenchymal stem cells (BMMSCs) are sensitive to irradiation and the irradiated dysfunction of BMMSCs may be closely related to irradiation-induced bone damage. Macropahges play important role in regulating stem cell function, bone metabolic balance and irradiation response, but the effects of macrophages on irradiated BMMSCs are still unclear. This study aimed to investigate the role of macrophages and macrophage-derived exosomes in restoring irradiated BMMSCs function. The effects of macrophage conditioned medium (CM) and macrophage-derived exosomes on osteogenic and fibrogenic differentiation capacities of irradiated BMMSCs were detected. The key microribonucleic acids (miRNAs) and targeted proteins in exosomes were also determined. The results showed that irradiation significantly inhibited the proliferation of BMMSCs, and caused differentiation imbalance of BMMSCs, with decreased osteogenic differentiation and increased fibrogenic differentiation. M2 macrophage-derived exosomes (M2D-exos) inhibited the fibrogenic differentiation and promoted the osteogenic differentiation of irradiated BMMSCs. We identified that miR-142-3p was significantly overexpressed in M2D-exos and irradiated BMMSCs treated with M2D-exos. After inhibition of miR-142-3p in M2 macrophage, the effects of M2D-exos on irradiated BMMSCs differentiation were eliminated. Furthermore, transforming growth factor beta 1 (TGF-β1), as a direct target of miR-142-3p, was significantly decreased in irradiated BMMSCs treated with M2D-exos. This study indicated that M2D-exos could carry miR-142-3p to restore the differentiation balance of irradiated BMMSCs by targeting TGF-β1. These findings pave a new way for promising and cell-free method to treat irradiation-induced bone damage.
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The data that support the findings of this study are available from the corresponding author, LT, as well as CZ, upon reasonable request.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (81903249) and Shaanxi Provincial Natural Science Basic Research Program project (2022JZ-50).
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This work was supported by the National Natural Science Foundation of China (81903249) and Shaanxi Provincial Natural Science Basic Research Program project (2022JZ-50).
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All authors contributed to the general study conception and design. The material preparation and data collection were performed by CH, LZ, YX, ZT, LJ and KG. The data analysis and visualization were performed by Chong Huang, Lu Zhao, and CZ. The first draft of the manuscript was written by CH and LZ. The manuscript was revised by LT and CZ. All authors commented on previous versions of the manuscript, gave valuable suggestions for corrections, and approved the final manuscript. LT and CZ supervised the research project.
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Huang, C., Zhao, L., Xiao, Y. et al. M2 macrophage-derived exosomes carry miR-142-3p to restore the differentiation balance of irradiated BMMSCs by targeting TGF-β1. Mol Cell Biochem 479, 993–1010 (2024). https://doi.org/10.1007/s11010-023-04775-3
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DOI: https://doi.org/10.1007/s11010-023-04775-3