Bilateral BBSRC-NSF/BIO: Asymmetric division and the temporal dynamics of cell motility

这项由美国(贝丝以色列女执事医学中心)和英国(曼彻斯特大学)的研究人员合作的项目旨在确定在器官发育过程中控制细胞迁移的基本机制。在生长组织中，细胞通常对称分裂，产生两个完全相同的子细胞。然而，在某些情况下，细胞分裂是不对称的，并产生本质上不同的子代，具有不同的特征，包括移动(或运动)的能力。该项目将探索细胞分裂后不对称在细胞运动中的分子和细胞基础，并确定不对称分裂在组织生长过程中控制细胞迁移的功能作用。这项研究不仅将产生适用于广泛应用的免费提供的新的计算方法和分析工具，而且这项工作的发现将对理解细胞在过多的细胞系统和生物体中迁移的控制具有广泛的影响。通过其更广泛的影响，该项目还将使本科生和高中生(重点是招收代表性不足的群体)接触综合的跨学科计算/实验科学方法，并在创建几个新的、有针对性的、互动的全球界面科学(GIS)讲习班后，提供国际合作研究技术的实践经验。此外，将通过在线媒体广泛传播关于在世界各地举办类似的地理信息系统讲习班的指导意见。不对称细胞分裂(ACD)决定了许多系统中不同的子细胞命运，但以前从未涉及到决定细胞运动的时间动力学。这个项目将定义ACD如何作为一种新的对称破坏机制来确保子代细胞在组织生长过程中获得不同的运动能力。将采取集成在计算机和体内的方法，创新一种新的多尺度混合时空代理模型(ABM)，该模型将为斑马鱼胚胎内皮细胞的单细胞实时成像实验提供信息。这些研究将探索运动细胞中的ACD，验证模型预测，并共同阐明有丝分裂在控制迁移中以前未被探索的作用。特别是，ACD与不同尺度的细胞信号、几何和机械运动信号的相互作用将通过以下任务进行研究：A)开发新的建模方法，以研究局部细胞内动力学在建立不对称有丝分裂后运动中的作用，并在功能上验证体内亚细胞分辨率的模型预测；B)预测ACD驱动的细胞结构差异对细胞运动动力学的影响，同时量化体内分裂过程中细胞结构的动态变化；C)在体内以单细胞分辨率量化有丝分裂前和有丝分裂后细胞张力的波动，并确定细胞张力与ACD的诱导和差异运动在硅胶和体内的相互作用。这项研究的产品将包括新的计算ABM模型和图像分析软件，这将独特地使细胞迁移的关键方面的研究成为可能，并将免费提供给更广泛的科学界。在其他更广泛的影响中，PIS将组织国际研讨会，提供一个平台，促进在不同细胞系统和组织的组织形态发生研究中广泛使用类似的集成在计算机/体内的方法。这一美英合作项目得到了美国国家科学基金会和英国生物技术和生物科学研究理事会的支持。在NSF内部，该奖项由分子和细胞生物科学部以及化学、生物工程、环境和运输系统部共同资助。

This collaborative project between researchers in the US (Beth Israel Deaconess Medical Center) and the UK (University of Manchester) aims to define the fundamental mechanisms controlling cell migration during organ development. In growing tissues, cells usually divide symmetrically to produce two identical daughter cells. However, in some instances cell divisions are asymmetric and give rise to intrinsically distinct daughters that have different characteristics including the ability to move (or motility). This project will explore the molecular and cellular basis of post-cell division asymmetry in cell motility and define the functional role of asymmetric divisions in the control of cell migration during tissue growth. Not only will this research generate freely available novel computational methods and analysis tools suitable for a wide array of applications, the findings of this work will have wide-reaching implications for understanding the control of cell migration across a plethora of cellular systems and organisms. Through its broader impacts, the project will additionally expose undergraduate and high school students (with emphasis on recruiting underrepresented groups) to integrated cross-disciplinary computational / experimental scientific approaches and provide hands-on experience of international collaborative research techniques upon the creation of several new, targeted, interactive Global Interface Science (GIS) workshops. Moreover, guidance on implementing similar GIS workshops anywhere worldwide will be widely disseminated via online media. Asymmetric cell division (ACD) specifies differential daughter cell fates in many systems, but has never before been implicated in determining the temporal dynamics of cell motility. This project will define how ACD acts as a novel symmetry-breaking mechanism to ensure daughter cells acquire distinct motilities during tissue growth. An integrated in silico and in vivo approach will be taken, innovating a novel multiscale hybrid, spatiotemporal agent-based model (ABM) that will inform single-cell live imaging experiments of endothelial cells in zebrafish embryos. These studies will probe ACD in motile cells, validate model predictions and altogether elucidate a previously unexplored role for mitosis in the control of migration. In particular, the interplay of ACD with cell signaling, geometry and mechanical motility cues across different scales, from the molecular to the cellular will be investigated through the following tasks: A) develop new modeling methodologies to investigate the role of localized intracellular dynamics in the establishment of asymmetric post-mitotic motility and functionally validate model predictions at sub-cellular resolution in vivo; B) Predict the effects of ACD-driven differences in cell architecture on motility dynamics in silico alongside quantification of dynamic alterations in cell architecture occurring during division in vivo; C) quantify pre- and post-mitotic fluctuations in cell tension at single-cell resolution in vivo and define the interplay of cell tension with the induction of ACD and differential motility in silico and in vivo. The products of this research will include novel computational ABM models and image analysis software, which will uniquely enable studies of key aspects of cell migration and will be made freely available to the wider scientific community. In additional broader impacts, the PIs will organize international workshops to provide a platform for promoting the widespread use of similar integrated in silico / in vivo approaches in studies of tissue morphogenesis across diverse cellular systems and organisms.This collaborative US/UK project is supported by the US National Science Foundation and the UK Biotechnology and Biological Sciences Research Council. Within NSF, the award is cofunded by the Division of Molecular And Cellular Biosciences and the Division of Chemical, Bioengineering, Environmental and Transport Systems.