Facultad de Medicina, Departamento de Anatomía y Biología Celular and IDIVAL, Universidad de Cantabria, Santander, Spain.
J Anat. 2019 Jun;234(6):815-829. doi: 10.1111/joa.12972. Epub 2019 Mar 15.
During embryonic development, organ morphogenesis requires major tissue rearrangements that are tightly regulated at the genetic level. A large number of studies performed in recent decades assigned a central role to programmed cell death for such morphogenetic tissue rearrangements that often sculpt the shape of embryonic organs. However, accumulating evidence indicates that far from being the only factor responsible for sculpting organ morphology, programmed cell death is accompanied by other tissue remodeling events that ensure the outcome of morphogenesis. In this regard, cell senescence has been recently associated with morphogenetic degenerative embryonic processes as an early tissue remodeling event in development of the limbs, kidney and inner ear. Here, we have explored cell senescence by monitoring β-galactosidase activity during embryonic heart development where programmed cell death is believed to exert an important morphogenetic function. We report the occurrence of extensive cell senescence foci during heart morphogenesis. These foci overlap spatially and temporally with the areas of programmed cell death that are associated with remodeling of the outflow tract to build the roots of the great arteries and with the septation of cardiac cavities. qPCR analysis allowed us to identify a gene expression profile characteristic of the so-called senescence secretory associated phenotype in the remodeling outflow tract of the embryonic heart. In addition, we confirmed local upregulation of numerous tumor suppressor genes including p21, p53, p63, p73 and Btg2. Interestingly, the areas of cell senescence were also accompanied by intense lysosomal activation and non-apoptotic DNA damage revealed by γH2AX immunolabeling. Considering the importance of sustained DNA damage as a triggering factor for cell senescence and apoptosis, we propose the coordinated contribution of DNA damage, senescence and apoptotic cell death to assure tissue remodeling in the developing vertebrate heart.
在胚胎发育过程中，器官形态发生需要在遗传水平上进行的主要组织重排。在过去几十年中进行的大量研究将程序性细胞死亡分配给这种形态发生组织重排的核心作用，这种重排经常塑造胚胎器官的形状。然而，越来越多的证据表明，程序性细胞死亡远非负责塑造器官形态的唯一因素，而是伴随着其他组织重塑事件，这些事件确保了形态发生的结果。在这方面，细胞衰老最近与形态发生退行性胚胎过程相关联，作为肢体、肾脏和内耳发育过程中的早期组织重塑事件。在这里，我们通过监测胚胎心脏发育过程中β-半乳糖苷酶活性来探索细胞衰老，据信程序性细胞死亡在心脏形态发生中发挥重要的形态发生功能。我们报告了在心脏形态发生过程中广泛出现细胞衰老焦点。这些焦点在空间和时间上与程序性细胞死亡区域重叠，这些区域与流出道的重塑有关，以构建大动脉的根部，并与心脏腔室的分隔有关。qPCR 分析使我们能够确定与重塑流出道中所谓的衰老分泌相关表型相关的基因表达谱。此外，我们还证实了包括 p21、p53、p63、p73 和 Btg2 在内的许多肿瘤抑制基因的局部上调。有趣的是，细胞衰老区域也伴随着溶酶体激活和通过 γH2AX 免疫标记揭示的非凋亡性 DNA 损伤。考虑到持续 DNA 损伤作为细胞衰老和细胞凋亡的触发因素的重要性，我们提出了 DNA 损伤、衰老和凋亡细胞死亡的协调贡献，以确保发育中脊椎动物心脏的组织重塑。
