Walls Gerard M, Ghita Mihaela, Queen Rachel, Edgar Kevin S, Gill Eleanor K, Kuburas Refik, Grieve David J, Watson Chris J, McWilliam Alan, Van Herk Marcel, Williams Kaye J, Cole Aidan J, Jain Suneil, Butterworth Karl T
Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Northern Ireland; Cancer Centre Belfast City Hospital, Belfast Health & Social Care Trust, Belfast, Northern Ireland.
Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Northern Ireland.
Int J Radiat Oncol Biol Phys. 2023 Feb 1;115(2):453-463. doi: 10.1016/j.ijrobp.2022.08.031. Epub 2022 Aug 17.
Radiation cardiotoxicity (RC) is a clinically significant adverse effect of treatment for patients with thoracic malignancies. Clinical studies in lung cancer have indicated that heart substructures are not uniformly radiosensitive, and that dose to the heart base drives RC. In this study, we aimed to characterize late changes in gene expression using spatial transcriptomics in a mouse model of base regional radiosensitivity.
An aged female C57BL/6 mouse was irradiated with 16 Gy delivered to the cranial third of the heart using a 6 × 9 mm parallel opposed beam geometry on a small animal radiation research platform, and a second mouse was sham-irradiated. After echocardiography, whole hearts were collected at 30 weeks for spatial transcriptomic analysis to map gene expression changes occurring in different regions of the partially irradiated heart. Cardiac regions were manually annotated on the capture slides and the gene expression profiles compared across different regions.
Ejection fraction was reduced at 30 weeks after a 16 Gy irradiation to the heart base, compared with the sham-irradiated controls. There were markedly more significant gene expression changes within the irradiated regions compared with nonirradiated regions. Variation was observed in the transcriptomic effects of radiation on different cardiac base structures (eg, between the right atrium [n = 86 dysregulated genes], left atrium [n = 96 dysregulated genes], and the vasculature [n = 129 dysregulated genes]). Disrupted biological processes spanned extracellular matrix as well as circulatory, neuronal, and contractility activities.
This is the first study to report spatially resolved gene expression changes in irradiated tissues. Examination of the regional radiation response in the heart can help to further our understanding of the cardiac base's radiosensitivity and support the development of actionable targets for pharmacologic intervention and biologically relevant dose constraints.
放射性心脏毒性（RC）是胸部恶性肿瘤患者治疗过程中具有临床意义的不良反应。肺癌的临床研究表明，心脏亚结构对辐射的敏感性并不一致，且心脏基部的剂量会引发RC。在本研究中，我们旨在利用空间转录组学在心脏基部区域放射敏感性小鼠模型中表征基因表达的晚期变化。
在小动物辐射研究平台上，使用6×9毫米平行相对射束几何形状，对一只老年雌性C57BL/6小鼠心脏的颅侧三分之一给予16 Gy照射，另一只小鼠进行假照射。超声心动图检查后，在30周时收集整个心脏进行空间转录组分析，以绘制部分照射心脏不同区域发生的基因表达变化。在捕获玻片上手动标注心脏区域，并比较不同区域的基因表达谱。
与假照射对照组相比，对心脏基部给予16 Gy照射后30周，射血分数降低。与未照射区域相比，照射区域内有明显更多的显著基因表达变化。观察到辐射对不同心脏基部结构的转录组学效应存在差异（例如，右心房[n = 86个失调基因]、左心房[n = 96个失调基因]和脉管系统[n = 129个失调基因]之间）。受到干扰的生物学过程包括细胞外基质以及循环、神经和收缩活动。
这是第一项报告照射组织中空间分辨基因表达变化的研究。对心脏区域辐射反应的研究有助于进一步了解心脏基部的放射敏感性，并支持开发可用于药物干预的可操作靶点和生物学相关的剂量限制。
