Key Laboratory of Biotechnology Shaanxi Province, College of Life Sciences, Northwest University, 229 Taibai North Road, 710069, Xi'an, People's Republic of China.
State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, 145 West Changle Road, Xi'an, 710032, People's Republic of China.
Mol Cell Biochem. 2024 Apr;479(4):993-1010. doi: 10.1007/s11010-023-04775-3. Epub 2023 Jun 3.
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.
放射治疗是癌症治疗的重要手段，但它不可避免地会损伤周围的正常组织，而骨骼组织是最常见的易受照射的部位之一。骨髓间充质干细胞（BMMSCs）对辐射敏感，BMMSCs 的辐射功能障碍可能与辐射诱导的骨损伤密切相关。巨噬细胞在调节干细胞功能、骨代谢平衡和辐射反应中发挥重要作用，但巨噬细胞对辐射 BMMSCs 的影响尚不清楚。本研究旨在探讨巨噬细胞和巨噬细胞衍生的外泌体在恢复辐射 BMMSCs 功能中的作用。检测了巨噬细胞条件培养基（CM）和巨噬细胞衍生的外泌体对辐射 BMMSCs 成骨和成纤维分化能力的影响。还确定了外泌体中的关键微小核糖核酸（miRNAs）和靶向蛋白。结果表明，照射显著抑制 BMMSCs 的增殖，并导致 BMMSCs 的分化失衡，成骨分化减少，成纤维分化增加。M2 巨噬细胞衍生的外泌体（M2D-exos）抑制成纤维分化，促进辐射 BMMSCs 的成骨分化。我们发现 M2D-exos 中 miR-142-3p 显著过表达，用 M2D-exos 处理的辐射 BMMSCs 中 miR-142-3p 也显著过表达。抑制 M2 巨噬细胞中的 miR-142-3p 后，M2D-exos 对辐射 BMMSCs 分化的作用被消除。此外，转化生长因子-β1（TGF-β1）作为 miR-142-3p 的直接靶标，在 M2D-exos 处理的辐射 BMMSCs 中显著降低。本研究表明，M2D-exos 可以通过靶向 TGF-β1 携带 miR-142-3p 来恢复辐射 BMMSCs 的分化平衡。这些发现为有前途的无细胞方法治疗辐射诱导的骨损伤开辟了新途径。
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