Biomaterials Directed Cell Polarity and Migration

描述（由申请人提供）： 细胞运动性在组织形态发生、胚胎发育、血管生成和伤口愈合中起核心作用。用于诱导体外定向细胞迁移、用于组织图案的自下而上组装、伤口愈合和芯片上细胞装置的主要技术依赖于外部梯度、趋化性。然而，由于细胞响应的梯度范围有限，独立地引导大量细胞在长距离上的迁移仍然是一个挑战。在过去的资助期间，我们报告了使用2D表面微图案（MANDIP -自然方向持久性的微阵列扩增）和3D微通道（TANDIP -自然方向持久性的地形放大）引导细胞迁移的创新技术。没有梯度，MANDIP和TANDIP是高度可扩展的，并且可以并行操作，以在复杂路径上的无限距离上引导大量细胞。这种能力的已证明的应用包括MANDIP指导的不同细胞群在空间上的自组装。 通过细胞的内在运动性来确定细胞的结构和分类。使用MANDIP，TANDIP，和一种新的技术，用于制造基板与光开关细胞贴壁，我们现在可以探测机械细胞如何感觉到他们周围的细胞外基质（ECM）的贴壁和迁移方向无论是沿着或对他们的初始形态极化。我们也 与加州大学医学院和儿童医院的4名合作者合作，他们专门研究迁移信号通路和细胞极性。在这第一个竞争性更新应用中，我们将通过解决以下具体问题，重点了解细胞极化和迁移过程中发生的关键事件的顺序和相互依赖性：目标1。板状伪足附着的局部变化如何改变形态学极化？ 目标2.几何细胞基质相互作用如何指导高尔基体极化？ 目标3.不同类型的细胞对生物力学信号的反应有何不同？

DESCRIPTION (provided by applicant): Cell motility plays a central role in tissue morphogenesis, embryonic development, angiogenesis, and wound healing. The primary techniques for inducing directional cell migration in vitro, for bottom-up assembly of tissue patterns, wound healing, and cell- on-chip devices, rely on external gradients, chemotaxis. However, due to the finite range of gradients that cells respond to, steering the migration of large population of cells independently over long distances remains a challenge. Over the past funding period, we reported innovative techniques for guiding cell migration using: 2D surface micropatterns (MANDIP - Microarray Amplification of Natural Directional Persistence) and 3D microchannels (TANDIP - Topographical Amplification of Natural Directional Persistence). Free from gradients, MANDIP and TANDIP are highly scalable and can operate in parallel to direct large number of cells over unlimited distances on complex paths. Demonstrated applications of this capability include MANDIP directed self- assembly of different cell populations into spatially defined structures and sorting of cells by their intrinsic motility. Using MANDIP, TANDIP, and a new technique for fabricating substrates with light-switchable cell adhesiveness, we can now probe mechanistically how cells sense their surrounding extracellular matrix (ECM) to polarize and migrate directionally either along or against their initial morphological polarization. We also partnered with 4 collaborators at UC Medical School and Childrens Hospital who specialize in migration signaling pathways and cell polarity. In this first competitive renewal application, we will focus on understanding the sequence and interdependency of key events that occur during cell polarization and migration by addressing the following specific questions: Aim 1. How do local changes in attachment of lamellipodia alter morphological polarization? Aim 2. How do geometric cell-substrate interactions direct Golgi polarization? Aim 3. How do different cell types differ in their response to biomechanical cues?