Cell-Matrix Memory and Remodeling in Cross-Environment Cell Invasion

跨环境细胞侵袭中的细胞基质记忆和重塑

• 批准号: 2209684
• 负责人: Amit Pathak
• 金额: $ 41.98万
• 依托单位: Washington University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2209684&HistoricalAwards=false
• 关键词: Cell; Matrix; Memory; Remodeling; Cross

This award will study how living cells move across dissimilar physical environments. Cells can sense and respond to their current surrounding environment. However, it is currently unclear whether cells remember the physical properties of their prior environment, and whether this mechanical memory dictates how they move through new environments. This gap in knowledge prevents understanding of whether cells that leave tumors or diseased tissues continue to retain those mechanical memories. The objective of this research is to integrate experiments and computational modeling that combines two mechanically different environments through which cells migrate. This project will reveal how forces generated by cells modify their surroundings, and how the memory of these modifications regulates cell movement through new environments. Better understanding of cells and their mechanical memory could enable more effective therapies for cancer and fibrosis that account for both the current and past physical environment of cells. This research project combines methodologies from mechanical engineering, biomaterials, physics-based modeling, and cell biology. This project will train graduate students in multidisciplinary research, provide training and education opportunities to undergraduate students, and disseminate scientific findings to broader society through outreach activities.Cells adopt different modes of mechano-sensing and migration through environments of varying mechanics – e.g., fast motility on stiff surfaces, amoeboid squeezing through confinement, and force-based mesenchymal migration through fibrous collagen. In addition, it has been shown in stem cells that cell fate can be reprogrammed using a stored mechanical memory of past environments. However, in these studies, elastic hydrogels are passive providers of mechanical cues. In contrast, fibrous collagen matrices can undergo active remodeling. Because memory-laden cells remain mechano-activated even after leaving their priming environment, this project investigates whether high forces of stiff-primed cells result in greater collagen remodeling, thus encoding a ‘matrix memory’ for follower cells to exploit for invasion. These questions are addressed through spatiotemporal invasion measurements of primed cells implanted in collagen and in silico modeling with a systems-based model for memory regulation combined with a lattice-based framework for cell invasion. Such findings would generate new knowledge in a variety of biological contexts – from tumor invasion, wound healing, regeneration, and development – in which cells move across environments.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该奖项将研究活细胞如何在不同的物理环境中移动。细胞可以感知并响应当前的周围环境。然而，目前尚不清楚细胞是否记得它们先前环境的物理特性，以及这种机械记忆是否决定了它们如何在新环境中移动。这种知识上的差距阻碍了对离开肿瘤或病变组织的细胞是否继续保留这些机械记忆的理解。这项研究的目的是整合实验和计算建模，结合两个机械不同的环境，通过细胞迁移。该项目将揭示细胞产生的力如何改变周围环境，以及这些改变的记忆如何调节细胞在新环境中的运动。更好地了解细胞及其机械记忆可以更有效地治疗癌症和纤维化，从而解释细胞当前和过去的物理环境。该研究项目结合了机械工程，生物材料，基于物理的建模和细胞生物学的方法。该项目将培养研究生进行多学科研究，为本科生提供培训和教育机会，并通过外联活动向更广泛的社会传播科学发现。细胞采用不同的力学传感模式和迁移模式，通过不同力学的环境-例如，在坚硬表面上的快速运动性、通过限制的变形挤压以及通过纤维胶原的基于力的间充质迁移。此外，在干细胞中已经表明，细胞命运可以使用过去环境的存储机械记忆重新编程。然而，在这些研究中，弹性水凝胶是机械线索的被动提供者。相反，纤维胶原基质可以经历主动重塑。由于记忆负载细胞即使在离开其启动环境后仍保持机械激活，因此该项目研究了刚性启动细胞的高作用力是否会导致更大的胶原蛋白重塑，从而为跟随细胞编码“基质记忆”以用于入侵。这些问题通过植入胶原蛋白中的致敏细胞的时空侵入测量和基于系统的记忆调节模型结合基于格子的细胞侵入框架的计算机建模来解决。这些发现将在各种生物学背景下产生新的知识-从肿瘤侵袭，伤口愈合，再生和发育-其中细胞在环境中移动。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。