Background Radiation ulcers are a common and severe injury after uncontrolled exposure to ionizing radiation. The most important feature of radiation ulcers is progressive ulceration, which results in the expansion of radiation injury to the nonirradiated area and refractory wounds. Current theories cannot explain the progression of radiation ulcers. Cellular senescence refers to as irreversible growth arrest that occurs after exposure to stress, which contributes to tissue dysfunction by inducing paracrine senescence, stem cell dysfunction and chronic inflammation. However, it is not yet clear how cellular senescence facilitates the continuous progression of radiation ulcers. Here, we aim to investigate the role of cellular senescence in promoting progressive radiation ulcers and indicate a potential therapeutic strategy for radiation ulcers. Methods Radiation ulcer animal models were established by local exposure to 40 Gy X-ray radiation and continuously evaluated for >260 days. The roles of cellular senescence in the progression of radiation ulcers were assessed using pathological analysis, molecular detection and RNA sequencing. Then, the therapeutic effects of conditioned medium from human umbilical cord mesenchymal stem cells (uMSC-CM) were investigated in radiation ulcer models. Results Radiation ulcer animal models with features of clinical patients were established to investigate the primary mechanisms responsible for the progression of radiation ulcers. We have characterized cellular senescence as being closely associated with the progression of radiation ulcers and found that exogenous transplantation of senescent cells significantly aggravated them. Mechanistic studies and RNA sequencing suggested that radiation-induced senescent cell secretions were responsible for facilitating paracrine senescence and promoting the progression of radiation ulcers. Finally, we found that uMSC-CM was effective in mitigating the progression of radiation ulcers by inhibiting cellular senescence. Conclusions Our findings not only characterize the roles of cellular senescence in the progression of radiation ulcers but also indicate the therapeutic potential of senescent cells in their treatment.

中文翻译：

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放射性溃疡细胞衰老的特征和间充质干细胞来源的条件培养基的治疗效果。

背景 辐射性溃疡是不受控制地暴露于电离辐射后的一种常见且严重的损伤。放射性溃疡最重要的特征是进行性溃疡，导致放射损伤向非照射区和难治性创面扩展。目前的理论无法解释放射性溃疡的进展。细胞衰老是指在暴露于压力后发生的不可逆的生长停滞，它通过诱导旁分泌衰老、干细胞功能障碍和慢性炎症导致组织功能障碍。然而，目前尚不清楚细胞衰老如何促进放射性溃疡的持续进展。在这里，我们旨在研究细胞衰老在促进进行性放射性溃疡中的作用，并指出一种潜在的放射性溃疡治疗策略。方法采用40 Gy X射线局部照射建立放射性溃疡动物模型，连续评价>260 d。使用病理分析、分子检测和 RNA 测序评估细胞衰老在放射性溃疡进展中的作用。然后，研究了人脐带间充质干细胞 (uMSC-CM) 条件培养基在放射性溃疡模型中的治疗效果。结果建立了具有临床患者特征的放射性溃疡动物模型，探讨了放射性溃疡进展的主要机制。我们将细胞衰老描述为与放射性溃疡的进展密切相关，并发现衰老细胞的外源移植显着加重了它们。机制研究和 RNA 测序表明，辐射诱导的衰老细胞分泌物是促进旁分泌衰老和促进放射性溃疡进展的原因。最后，我们发现 uMSC-CM 通过抑制细胞衰老有效减轻放射性溃疡的进展。结论 我们的研究结果不仅描述了细胞衰老在放射性溃疡进展中的作用，还表明了衰老细胞在其治疗中的治疗潜力。