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

该奖项将研究活细胞如何在不同的物理环境中移动。细胞可以感知并对当前的周围环境做出反应。然而，目前尚不清楚细胞是否记得以前环境的物理属性，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人们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。这项研究的目标是将实验和计算模型结合在一起，将细胞迁移通过的两个机械上不同的环境结合在一起。这个项目将揭示细胞产生的力如何改变他们的环境，以及这些改变的记忆如何在新的环境中调节细胞的运动。更好地了解细胞及其机械记忆可以使癌症和纤维化得到更有效的治疗，这些疾病既能解释细胞现在和过去的物理环境，也能解释过去的物理环境。这项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。该项目将培训研究生进行多学科研究，为本科生提供培训和教育机会，并通过外展活动向更广泛的社会传播科学成果。细胞采用不同的机械传感和在不同力学环境中迁移的模式-例如，在坚硬表面上的快速运动，通过限制的阿米巴挤压，以及通过纤维性胶原蛋白基于力的间质迁移。此外，在干细胞中已经表明，细胞的命运可以通过存储的过去环境的机械记忆来重新编程。然而，在这些研究中，弹性水凝胶是机械线索的被动提供者。相比之下，纤维性胶原基质可以进行主动重塑。由于记忆负荷的细胞即使在离开启动环境后仍保持机械激活，该项目调查高强度启动的细胞是否会导致更大的胶原蛋白重塑，从而为后续细胞利用来进行侵袭编码“基质记忆”。这些问题是通过对植入胶原蛋白的启动细胞的时空侵袭测量来解决的，并在基于系统的记忆调节模型和基于晶格的细胞侵袭框架的电子建模中得到解决。这些发现将在细胞跨环境移动的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。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.