Irradiation-induced senescence of bone marrow mesenchymal stem cells aggravates osteogenic differentiation dysfunction via paracrine signaling
Irradiation-induced senescence of bone marrow mesenchymal stem cells aggravates osteogenic differentiation dysfunction via paracrine signaling
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DOI：
10.1152/ajpcell.00520.2019
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发表时间：
2020-05-01
影响因子：
5.5
通讯作者：
Zhu, Guoying
中科院分区：
文献类型：
--
作者：
Bai, Jiangtao;Wang, Yuyang;Zhu, Guoying
辐射诱导的细胞衰老在骨丢失中的作用引起了人们的广泛关注。放射性骨退化是肿瘤放疗常见的并发症之一，具有临床意义，但其病理机制尚未阐明。本研究旨在探讨辐射诱导骨髓间充质干细胞（BMSCs）细胞衰老和衰老相关分泌表型（SASP）的变化及其在成骨分化障碍中的作用。结果发现，照射后BMSCs失去了典型的成纤维细胞样形态，表现出活力和分化潜能受到抑制，并伴有衰老表型，包括衰老相关的β-半乳糖苷酶（SA-β-gal）染色阳性细胞增多，衰老相关基因p53/p21上调，而p16无变化。此外，DNA损伤γ-H2 AX灶，细胞周期停滞的G 0/G1期，细胞和线粒体活性氧（ROS）以辐射剂量依赖性方式增加。同时，JAK 1/STAT 3通路被激活并伴随SASP分泌的增加，如IL-6、IL-8和基质金属蛋白酶9（MMP 9），而0.8 μ M JAK 1抑制剂（JAKi）处理有效地抑制JAK通路和SASP的产生。此外，辐射诱导衰老（IRIS）BMSCs的条件培养基（CM）表现出成骨细胞的成骨分化和标志基因表达的能力显着降低，而JAKi干预CM可以有效地改善这些恶化的影响。结论：辐射可通过旁分泌信号途径诱导BMSC衰老和SASP分泌，进一步加重成骨分化障碍，而SASP靶向治疗可能是减轻辐射诱导骨丢失的一种可能的干预策略。
The role of cellular senescence induced by radiation in bone loss has attracted much attention. As one of the common complications of anticancer radiotherapy, irradiation-induced bone deterioration is common and clinically significant, but the pathological mechanism has not been elucidated. This study was performed to explore the cellular senescence and senescence-associated secretory phenotype (SASP) induction of bone marrow-derived mesenchymal stem cells (BMSCs) by irradiation and its role in osteogenic differentiation dysfunction. It was observed that irradiated BMSCs lost typical fibroblast-like morphology, exhibited suppressed viability and differentiation potential accompanied with senescence phenotypes, including an increase in senescence-associated beta-galactosidase (SA-beta-gal) staining-positive cells, and upregulated senescence-related genes p53/p21, whereas no changes happened to p16. Additionally, DNA damage gamma-H2AX foci, G0/G1 phase of cell cycle arrest, and cellular and mitochondrial reactive oxygen species (ROS) increased in an irradiation dose-dependent manner. Meanwhile, the JAK1/STAT3 pathway was activated and accompanied by an increase in SASP secretion, such as IL-6, IL-8, and matrix metalloproteinase-9 (MMP9), whereas 0.8 mu M JAK1 inhibitor (JAKi) treatment effectively inhibited the JAK pathway and SASP production. Furthermore, conditioned medium (CM) from irradiation-induced senescent (IRIS) BMSCs exhibited a markedly reduced ability in osteogenic differentiation and marker gene expression of osteoblasts, whereas CM with JAKi intervention may effectively improve these deterioration effects. In conclusion, irradiation could provoke BMSC senescence and SASP secretion and further aggravate osteogenic differentiation dysfunction via paracrine signaling, whereas SASP targeting may be a possible intervention strategy for alleviating irradiation-induced bone loss.