Immuno-mechanical regulation of monocytes in fibrotic niches

Project summary – This project investigates the role of mechanical cues of extracellular matrix in regulating monocyte inflammation. Monocytes are recruited from the bone marrow to diverse tissues, where they shape the local inflammatory response and regulate tissue repair, regeneration, cancer, and infection. Tissues of inflammation and injury exhibit not only solid-like elasticity, but also fluid-like dissipation of stress by multiple length-scales of physical interactions. We previously developed biomaterial systems for modeling innate immune cell-matrix interaction with an interpenetrating hydrogel of polysaccharide and fibrillar type I collagen that mimics tissue architecture with tunable ionic and covalent crosslinking. These dual-network hydrogels allow one to independently control the elasticity and stress relaxation for mechanobiological studies. Our recent studies showed that viscoelasticity of stiff fibrotic hydrogels controls a mechanical checkpoint of monocyte fate. Stiff, elastic gels increased differentiation of naïve monocytes into inflammatory monocytes and activated dendritic cells. Stiff, viscous gels suppressed inflammatory signaling and maintained immature monocytes. There remains a significant gap in knowledge of how mechanical cues regulate innate inflammation of monocytes. Further, monocytes pose significant challenges for mechanobiology, due lack in overlap of human and mouse markers, lack of relevant naïve immature cell lines, limited half-life of primary isolated cells, and difficulty in transducing/transfecting primary naïve monocytes cells. Here, we apply multiple strategies to overcome these challenges to investigate the overall question of how immature monocytes are regulated by stiffness and viscoelasticity of ECM. We develop human stem cell-based culture systems for studying monocyte mechanobiology. We investigate the mechanical regulation of non-canonical NF-kappa-B in vitro and in vivo. We determine the role of nuclear mechanotransduction and epigenetics on monocyte fate. Together these studies will build fundamental understanding of physical regulation of innate immunity and will launch further highly impact research in the future.