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 在一个由细胞生物学家和生物物理学家组成的多P-PI团队的领导下，该项目是我们的续签 研究对伤口的细胞检测和反应。对于我们的模型系统，我们 使用果蝇p​​upal notum，二倍上皮单层，我们通过激光损伤了它 消融。尽管组织是二倍体，但伤口缘和附近的区域占主导地位 通过巨型合胞细胞。这些综合细胞的起源，功能和命运都是未知的。 使用实时成像，我们发现巨型合胞菌是通过细胞细胞融合形成的 多个二倍体细胞。这些融合发生在受伤后约20分钟内，由此产生 合胞细胞比二倍体细胞更快地迁移伤口。到结束 组织修复，大多数这些巨型合成症都从上皮中消除。有趣的是，我们 已经发现细胞融合和合胞体的形成量取决于 受伤。我们将比较缺乏合成症的伤口的伤口愈合行为 具有合成症来研究这些巨细胞如何增加伤口闭合率（AIM 1）。在AIM 2中，我们将研究伤口如何诱导单核二倍体细胞融合 合成。在AIM 3中，我们将分析这些合成的长期命运，这些命运似乎死于 伤口闭合时的凋亡和挤压结束。合成细胞和多倍体细胞已经 在其他生物体和组织中观察到的伤口，但我们的系统是第一个 对他们的形成，贡献和消除进行详细分析 成像。 参与伤口愈合的细胞通常与肿瘤细胞共享行为，伤口 - 诱导的巨型合胞细胞可能代表巨型多倍体癌的伤口 细胞，一种在许多癌症中发现的合胞细胞类型。巨型多倍体癌细胞是恶性的， 对所有疗法有抵抗力，并且似乎是肿瘤细胞燃烧转移和的主要来源 复发。我们期望我们对伤口诱导的合成症的适应功能的研究将 对于理解适应不良巨人的生物学，起源和潜在疗法至关重要 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