Biomechanical Regulation of Liver Progenitor Cell Functions

University Of Illinois At Urbana-Champaign, Urbana IL

Investigators

Abstract

Liver development occurs through a multistep process in which precursor cells, termed liver progenitor cells, proliferate extensively and then transition (differentiate) into the mature cell types found in the adult liver. This process is controlled by the microscopic local environment around the cells, termed the microenvironment; many diseases are suggested to arise due to abnormalities in liver microenvironments. Biomechanical signals represent an important component of cell microenvironments, however, it is currently unclear how biomechanical properties of liver tissue influence liver progenitor cell functions. One of the main issues that is limiting progress is that biomechanical cues often work together with other types of stimuli including a broad range of cell-secreted proteins. It is the complex combination of these signals that determines cell function. The goal of this project is to establish engineered tissue platforms that allow for the precise and independent tuning of biomechanical and interacting signals. This work will then leverage these platforms to study mechanisms of liver function that are not accessible with standard culture systems. A more complete understanding of the role of biomechanics in liver progenitor functions would provide an important picture of disease mechanisms. This project will also serve as a foundation for improving engineered liver tissue approaches currently being developed for drug testing or therapeutic applications. The research will be integrated with an educational program developing classroom and laboratory research modules for both high school students (via summer camp modules, where one camp is for girls) and science teachers. These activities have the potential to address societal concerns about encouraging broad participation in science and improving science education. This award will examine the combinatorial effects of biomechanical and biochemical signals using complementary two-dimensional and three-dimensional microfabricated platforms. Specifically, the project will investigate the cooperative influence of extracellular matrix composition and substrate mechanical stiffness on the hepatocyte and biliary differentiation of liver progenitor cells. These efforts will further utilize recently developed methods that integrate the capability to perturb extracellular matrix properties with the controlled modulation of multicellular geometries and traction force microscopy. Cell differentiation trajectories in parallel microenvironments will be quantitatively assessed using single-cell imaging cytometry. Mechanistic interconnections with biomechanical signaling will be investigated using a compendium of cell contractility mediators and small interfering RNA-based knockdown of candidate factors.