Biomechanical Mechanisms Underlying Pathologic Hepatic Stellate Cell Behavior in Liver Fibrosis

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PROJECT SUMMARY The unregulated activation of hepatic stellate cells is a key step in the pathogenesis of liver fibrosis, a condition which arises from multiple etiologies including viral infections, autoimmune diseases, metabolic disorders, and toxic insults. When activated, stellate cells become myofibroblastic and adopt wound healing functions. Cirrhosis, the most advanced stage of fibrosis, is associated with severe extrahepatic complications and a lifetime increased risk for hepatocellular carcinoma. Fibrosis was once thought to be a unidirectional, irreversible condition, but recent advances in curative treatment for hepatitis B and C have demonstrated that fibrosis is able to regress. Therefore, effective antifibrotic therapies are in high demand to treat all stages of fibrosis from any etiology. A promising approach is to inhibit the many functions of the activated stellate cell, or the activation process itself, since these steps are central to driving disease pathogenesis. Like all cells, activated stellate cells respond to cues delivered by their surrounding extracellular matrix (ECM). Some of these cues are biochemical in nature. However, the mechanical properties of the ECM are also instructive and provide signals that have profound effects on cell differentiation, migration, remodeling, and tissue organization. The liver possesses two mechanical properties of notable interest: stiffness, the extent to which an object resists deformation to an applied force, and stress relaxation, the ability to dissipate energy from an applied force. An understanding of how stiffness and stress relaxation act independently and synergistically to affect activated hepatic stellate cells may reveal previously unexplored opportunities for therapeutic development. The objectives of the proposed research are therefore to modulate the behavior of hepatic stellate cells by tuning matrix mechanical properties in a spatiotemporally precise manner. We have developed photoresponsive poly(ethylene glycol)/liver ECM hybrid hydrogels with tunable stress relaxation that can be reversibly stiffened with visible light. The Specific Aims of the proposed research are to (1) elucidate the independent role of stress relaxation on hepatic stellate cell mechanical memory and (2) assess hepatic stellate cell durotactic migratory capacity as a function of stress relaxation. In addition to functional readouts of healthy and diseased cell phenotypes, we will use established metrics for cellular mechanosensing, such as YAP nuclear translocation, to develop clear structure-function relationships between ECM mechanics, mechanosensing, and cell behavior. The anticipated product of this research is a causal understanding of the response of stellate cells to mechanical signals. This research will be a collaborative effort between Northwestern University’s Department of Chemistry, Northwestern Memorial Hospital, and external collaborators. In carrying out the proposed Aims and associated training activities, I will develop a unique skillset that allows me to address biomedical problems using materials chemistry as a means of accelerating translational scientific discovery.