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

项目摘要 由一个由细胞生物学家和生物物理学家组成的多PI团队领导的这个项目是我们 对伤口的细胞检测和反应的研究。对于我们的模型系统，我们 利用果蝇蛹，一种二倍体上皮单分子层，我们用激光将其缠绕 消融。虽然组织是二倍体，但伤口边缘及其附近的区域占主导地位。 由巨大的合胞体细胞。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，我们发现巨大的合胞体是通过细胞-细胞融合形成的 多个二倍体细胞。这些融合在受伤后约20分钟内发生，其结果是 合体细胞比二倍体细胞迁移更快，愈合伤口更快。到年底的时候 在组织修复过程中，这些巨大的合胞体大多从上皮细胞中消失。有趣的是，我们 已发现细胞融合和合胞体形成的数量取决于细胞融合的方式 伤人。我们将比较缺乏合胞体的伤口和那些 以研究这些巨细胞如何增加伤口闭合率(AIM 1)。在目标2中，我们将研究创伤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，它们似乎死于 随着伤口闭合的结束，细胞凋亡和排泄也即将结束。合体细胞和多倍体细胞已经 在其他生物和组织中观察到对创伤的反应，但我们的系统是第一个 使用LIVE详细分析它们的形成、贡献和可能的消除 成像。 参与伤口愈合的细胞通常与肿瘤细胞有共同的行为，而伤口- 诱导的巨型合体细胞可能代表巨型多倍体癌症的创伤等价物 细胞，一种在许多癌症中发现的合体细胞类型。巨大的多倍体癌细胞是恶性的， 对所有治疗方法都有抵抗力，并且似乎是肿瘤细胞促进转移和 旧病复发。我们预计，我们对创伤诱导的合胞体适应功能的研究将 对了解巨人适应不良的生物学、起源和潜在的治疗方法很重要 多倍体癌细胞。

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.