Cell fusion and the role of syncytia in the response to epithelial damage

细胞融合和合胞体在上皮损伤反应中的作用

• 批准号: 10680589
• 负责人: M. Shane Hutson
• 金额: $ 33.22万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680589
• 关键词: Ablation; Acceleration; Actins; Apoptosis; Attention; Basic Science; Behavior; Biological Models; Biology; Calcium; Carcinoma; Cell fusion; Cell membrane; Cells; Cessation of life; Detection; Development; Diploid Cells; Diploidy; Drosophila genus; Epithelium; Experimental Models; Foundations; Funding; Genes; Giant Cells; Image; Intercalated Cell; Investigation; Knowledge; Lasers; Malignant - descriptor; Malignant Neoplasms; Maps; Mediating; Membrane; Modeling; Mononuclear; Neoplasm Metastasis; Organism; Participant; Polyploid Cells; Polyploidy; Process; Recurrence; Relapse; Resistance; Role; Signal Transduction; Source; Stress; System; Testing; Tissues; Virus Diseases; cancer cell; cancer therapy; cancer type; cell injury; cell motility; cell type; clinically relevant; epithelial repair; innovation; live cell imaging; monolayer; multidisciplinary; neoplastic cell; repaired; response; seal; therapy resistant; tissue repair; tumor; wound; wound closure; wound healing; wound treatment

Project Summary Led by a multi-PI team of a cell biologist and a biophysicist, this project is a renewal of our investigation into the cellular detection of and responses to wounds. For our model system, we use the Drosophila pupal notum, a diploid epithelial monolayer, and we wound it by laser ablation. Although the tissue is diploid, the region at and near the wound margin is dominated by giant syncytial cells. The origin, function, and fate of these syncytial cells are all unknown. Using live imaging, we have found that the giant syncytia are formed via cell-cell fusion of multiple diploid cells. These fusions occur within ~20 minutes of wounding and the resulting syncytial cells migrate more quickly and close wounds faster than diploid cells. By the end of tissue repair, most of these giant syncytia are eliminated from the epithelium. Interestingly, we have found that the amount of cell fusion and syncytia formation depends on the mode of wounding. We will compare wound healing behaviors in wounds that lack syncytia and those that have syncytia to investigate how these giant cells increase the rate of wound closure (Aim 1). In Aim 2, we will investigate how wounds induce mononuclear diploid cells to fuse into syncytia. In Aim 3, we will analyze the long-term fate of these syncytia, which appear to die by apoptosis and extrusion as wound closure is ending. Syncytial and polyploid cells have been observed in other organisms and tissues in response to wounds, but our system is the first to make a detailed analysis of their formation, contribution, and elimination possible using live imaging. Cells involved in wound-healing generally share behaviors with tumor cells, and the wound- induced giant syncytial cells may represent the wound equivalent of Giant Polyploid Cancer Cells, a syncytial cell type found in many cancers. Giant Polyploid Cancer Cells are malignant, resistant to all therapies, and appear to be a major source of tumor cells fueling metastasis and relapse. We expect that our studies into the adaptive functions of wound-induced syncytia will be important for understanding the biology, origin, and potential therapies for maladaptive Giant Polyploid Cancer Cells.

项目摘要 由一个细胞生物学家和一个生物药理学家组成的多PI团队领导，这个项目是我们的一个更新。 对伤口的细胞检测和反应的研究。对于模型系统，我们 使用果蝇蛹背，一种二倍体上皮单层，我们用激光将其创伤， 消融术虽然组织是二倍体，但在伤口边缘和附近的区域占主导地位 巨大的合胞体细胞这些合胞体细胞的起源、功能和命运都是未知的。 利用活体成像，我们发现巨大的合胞体是通过细胞间融合形成的， 多个二倍体细胞这些融合发生在创伤后约20分钟内， 合胞体细胞比二倍体细胞迁移更快，伤口闭合更快。年底前 在组织修复过程中，这些巨大的合胞体中的大多数从上皮细胞中消除。有趣的是，我们 已经发现细胞融合和合胞体形成的数量取决于 伤人我们将比较缺乏合胞体的伤口和 研究这些巨细胞如何增加伤口闭合的速度（目的 1）。在目标2中，我们将研究伤口如何诱导单核二倍体细胞融合成 合体在目标3中，我们将分析这些合胞体的长期命运，它们似乎是通过以下方式死亡的： 随着伤口闭合结束，细胞凋亡和挤压。合胞体和多倍体细胞已经被 在其他生物体和组织中观察到对伤口的反应，但我们的系统是第一个 详细分析它们的形成、贡献和消除， 显像 参与伤口愈合的细胞通常与肿瘤细胞共享行为，并且伤口- 诱导的巨大合胞体细胞可能代表巨大多倍体癌的伤口等价物 细胞，在许多癌症中发现的合胞体细胞类型。巨多倍体癌细胞是恶性的， 对所有疗法都有抗性，似乎是肿瘤细胞的主要来源， 复发我们希望我们对创伤诱导的合胞体的适应功能的研究将 对于理解适应不良的巨人的生物学、起源和潜在的治疗方法是重要的。 多倍体癌细胞。

项目成果

Live imaging basement membrane assembly under the pupal notum epithelium.

蛹上皮下的实时成像基底膜组件。

• DOI: 10.17912/micropub.biology.001105
• 发表时间: 2024
• 期刊: microPublication biology
• 作者: Mehaffey,ThomasM;Hecht,ChloeA;White,JamesS;Hutson,MShane;Page-McCaw,Andrea
• 通讯作者: Page-McCaw,Andrea

Wounding increases nuclear ploidy in wound-proximal epidermal cells of the Drosophila pupal notum.

受伤会增加果蝇蛹的伤口近端表皮细胞的核倍性。

• DOI: 10.17912/micropub.biology.001067
• 发表时间: 2024
• 期刊: microPublication biology
• 作者: White,James;Hutson,MShane;Page-McCaw,Andrea
• 通讯作者: Page-McCaw,Andrea

After wounding, a G-protein coupled receptor promotes the restoration of tension in epithelial cells.

受伤后，G 蛋白偶联受体促进上皮细胞张力的恢复。

• DOI: 10.1101/2023.05.31.543122
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Han,Ivy;Hua,Junmin;White,JamesS;O'Connor,JamesT;Nassar,LilaS;Tro,KadenJ;Page-McCaw,Andrea;Hutson,MShane
• 通讯作者: Hutson,MShane