Irradiation-induced senescence of bone marrow mesenchymal stem cells aggravates osteogenic differentiation dysfunction via paracrine signaling.
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 β-galactosidase (SA-β-gal) staining-positive cells, and upregulated senescence-related genes p53/p21, whereas no changes happened to p16. Additionally, DNA damage γ-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 μM 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.
['Bai|Jiangtao|J|0000-0002-5999-6282', 'Wang|Yuyang|Y|', 'Wang|Jianping|J|', 'Zhai|Jianglong|J|', 'He|Feilong|F|', 'Zhu|Guoying|G|']
D001862:Bone Resorption D059447:Cell Cycle Checkpoints D002454:Cell Differentiation D049109:Cell Proliferation D016922:Cellular Senescence D004249:DNA Damage D018507:Gene Expression Regulation, Developmental D006657:Histones D006801:Humans D053613:Janus Kinase 1 D059630:Mesenchymal Stem Cells D008928:Mitochondria D010012:Osteogenesis D019899:Paracrine Communication D011827:Radiation D017382:Reactive Oxygen Species D050796:STAT3 Transcription Factor D015398:Signal Transduction
bone marrow mesenchymal stem cells osteogenic differentiation cellular senescence SASP irradiation