Implementing the nascent ECM into the dynamic reciprocity of cell-ECM interactions

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

A core goal in biomedical research is to understand signaling pathways that regulate cellular decisions in complex three-dimensional environments such as cells in developing or regenerating tissue. Directly manipulating these signaling patterns in vivo is often complicated or provides little control. This is especially the case for questions including the complex and heterogeneous extracellular matrix. Excitingly, recent advances in engineered in vitro systems have made complex three-dimensional environments – including organoids and organ-on-chip systems – more controlled. However, while these systems are powerful, they have largely ignored the dynamic reciprocity between a cell and its newly deposited (nascent) environment. The key challenge is to implement this dynamic nascent extracellular matrix into the existing model of cell-matrix dynamic reciprocity – the Bissell model – to identify the mechanisms of cellular decisions within complex tissue environments. If successful, this improved model will unlock the potential of engineered model systems to better represent target tissue environments and as a testing bed for novel drug testing. The overarching theme of my research group is to develop and apply engineering tools to drive the understanding of cell-cell and cell-ECM interactions. Developed tools in my group include dynamic chemistries and engineering approaches to mimic and manipulate organoids and their nascent matrix, and magnetic actuation to induce dynamic changes in a cell’s environment. We apply these tools to further develop complex cellular systems that implement dynamic changes of the nascent matrix to better guide translatable discoveries. Project one: Manipulating the local nascent environment to guide cellular decisions in complex cellular systems. Controlled modulation of matrix components and their physical properties enables spatiotemporal control over stem/progenitor cell differentiation pathways and their decision making, and towards controlling complex tissue development. We will develop new chemistries to directly manipulate the physical properties of the nascent matrix in situ and within engineered nascent matrix hydrogels. Our goal is to develop improved in vitro models of dynamic reciprocity, including cell-nascent matrix interactions that will be extendable to other cellular systems and disease models. Project two: Remote control of cell-cell and cell-matrix interactions in complex cellular systems. To better control and manipulate cellular systems dynamically, we will take advantage of magnetic actuation of cell-cell contacts, including cadherins, and cell-matrix contacts, including integrins. We propose to develop cadherin- mimetic magnetic microgels to exert forces onto cells within organoids and matrix-binding magnetics to introduce forces to the nascent matrix. These models will enable characterizing how physical forces exerted onto cells and their nascent matrix guide cellular decisions within complex three-dimension environments.