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.

项目概要 该项目由细胞生物学家和生物物理学家组成的多 PI 团队领导，是我们的更新 研究伤口的细胞检测和反应。对于我们的模型系统，我们 使用果蝇蛹，一种二倍体上皮单层，我们用激光缠绕它 消融。尽管组织是二倍体，但伤口边缘及其附近的区域占主导地位 由巨型合胞体细胞。这些合体细胞的起源、功能和命运都是未知的。 使用实时成像，我们发现巨型合胞体是通过细胞与细胞融合形成的 多个二倍体细胞。这些融合发生在受伤后约 20 分钟内，并且由此产生的 合胞体细胞比二倍体细胞迁移更快，伤口愈合也更快。到年底 组织修复后，这些巨大合胞体大部分从上皮中消除。有趣的是，我们 发现细胞融合和合胞体形成的量取决于融合的模式 伤人。我们将比较缺乏合胞体和那些缺乏合胞体的伤口的伤口愈合行为 具有合胞体来研究这些巨细胞如何提高伤口闭合速度（目标 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 合胞体。在目标 3 中，我们将分析这些合胞体的长期命运，这些合胞体的死亡似乎是由于 当伤口闭合结束时细胞凋亡和挤压。合体细胞和多倍体细胞已被 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 使用实时数据对它们的形成、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具有相同的行为，并且伤口愈合 诱导的巨型合胞体细胞可能相当于巨型多倍体癌的伤口 细胞，一种在许多癌症中发现的合体细胞类型。巨型多倍体癌细胞是恶性的， 对所有疗法都有抵抗力，并且似乎是促进转移和肿瘤细胞的主要来源 复发。我们期望我们对伤口诱导合胞体适应性功能的研究将 对于了解适应不良巨人的生物学、起源和潜在疗法很重要 多倍体癌细胞。

项目成果

After wounding, a G-protein coupled receptor restores tension to epithelial cells in a dynamic inward-traveling wave

受伤后，G蛋白偶联受体以动态向内行进波恢复上皮细胞的张力

• 发表时间: 2024-09-14
• 作者: Ivy Han;Lila S. Nassar;A. Page;M. S. Hutson
• 通讯作者: M. S. Hutson

Live imaging basement membrane assembly under the pupal notum epithelium.

蛹上皮下的实时成像基底膜组件。

• 发表时间: 2024
• 作者: Mehaffey, Thomas M;Hecht, Chloe A;White, James S;Hutson, M Shane;Page
• 通讯作者: Page

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。

• 发表时间: 2024-05-01
• 影响因子: 3.3
• 作者: Han, Ivy S;Hua, Junmin;White, James S;O'Connor, James T;Nassar, Lila S;Tro, Kaden J;Page;Hutson, M Shane
• 通讯作者: Hutson, M Shane

Multiple Mechanisms Drive Calcium Signal Dynamics around Laser-Induced Epithelial Wounds.

多种机制驱动激光诱导上皮伤口周围的钙信号动态。

• 发表时间: 2017-10-03
• 影响因子: 3.4
• 作者: Shannon, Erica K;Stevens, Aaron;Edrington, Westin;Zhao, Yunhua;Jayasinghe, Aroshan K;Page;Hutson, M Shane
• 通讯作者: Hutson, M Shane

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。

• 发表时间: 2024
• 作者: White, James;Hutson, M Shane;Page
• 通讯作者: Page