Senescence-unrelated impediment of osteogenesis from Flk1+bone marrow mesenchymal stem cells induced by total body irradiation and its contribution to long-term bone and hematopoietic injury

Background and ObjectivesIonizing irradiation is a common treatment for cancer patients and can result in adverse side effects affecting the bone and hematopoietic systems. Although some studies have demonstrated that ionizing radiation can induce apoptosis and senescence in hematopoietic stem cells, little is known about the effects of total body irradiation (TBI) on bone marrow (BM) mesenchymal stem cells (MSC). The objectives of this study were to determine the response of BM MSC to irradiation stress, such as cellular senescence and differentiation potential, and the clinical significance of these changes caused by TBI.Design and MethodsAt different time points after TBI, FIk1(+) MSC were isolated from BM of male C57BL/6 mice and analyzed for colony forming units-fibroblast (CFU-F), cellular senescence-related indices and osteogenic potential. Bone histomorphometric analysis, immunohistochemical staining and bone mineral density (BMD) tests were performed to detect the effects of TBI on bone and the hematopoietic system.ResultsTBI reduced the pool of BM mesenchymal stem/progenitor cells, and altered osteoblast differentiation ability of BM MSC, evidenced by changes in TAZ expression. These alterations, sustained up to 28 days post-irradiation, were independent of cellular senescence in BM MSC. Irradiated mice showed obvious bone loss and destruction of the hematopoietic osteoblastic niche, which normally comprise of spindle-shaped N-cadherin-expressing osteoblasts.Interpretation and ConclusionsTBI treatment results in impairment in BM MSC, which might be responsible for bone loss and, at least partially, for impaired hematopoiesis.

背景与目的 电离辐射是癌症患者的一种常见治疗方法，可能会对骨骼和造血系统产生不良副作用。尽管一些研究表明电离辐射可诱导造血干细胞凋亡和衰老，但全身照射（TBI）对骨髓间充质干细胞（MSC）的影响知之甚少。本研究的目的是确定骨髓MSC对辐射应激的反应，如细胞衰老和分化潜能，以及TBI引起的这些变化的临床意义。 设计与方法 在TBI后的不同时间点，从雄性C57BL/6小鼠的骨髓中分离出Flk1（+）MSC，并分析其成纤维细胞集落形成单位（CFU - F）、细胞衰老相关指标和成骨潜能。进行骨组织形态计量分析、免疫组织化学染色和骨密度（BMD）测试，以检测TBI对骨骼和造血系统的影响。 结果 TBI减少了骨髓间充质干/祖细胞池，并改变了骨髓MSC的成骨细胞分化能力，这从TAZ表达的变化中可以看出。这些改变在辐射后持续长达28天，与骨髓MSC的细胞衰老无关。受辐射的小鼠出现明显的骨质流失以及造血成骨微环境的破坏，该微环境通常由表达N - 钙黏蛋白的梭形成骨细胞组成。 解释与结论 TBI治疗导致骨髓MSC受损，这可能是骨质流失的原因，并且至少部分是造血功能受损的原因。