The role of dendritic cells in heart valve extracellular matrix remodeling, homeostasis, and disease

项目总结/文摘

Project Summary/Abstract Normal heart valve structure and composition development during valve remodeling, starting at late embryonic stages and continues to mature postnatally. Valve remodeling results in a stratified extracellular matrix (ECM), decreased cell density and reduction in cell proliferation. Congenital valve malformations include abnormalities in valve remodeling such as ECM disruption and disorganization. Congenital heart valve abnormalities due to ECM gene mutations and defects, often lead to myxomatous valve disease (MVD). Progressive MVD is characterized by collagen fiber fragmentation, replacement of mucopolysaccharides and proteoglycans, leaflet thickening, and insufficiency, but the mechanisms mediating progressive valve degeneration remain unknown and there are no therapies to prevent or reverse MVD. Recently, our group identified immune cell populations in normal aortic and mitral valves composed of predominantly dendritic cells and myeloid cells. We found that in a murine model of Marfan Syndrome, Fbn1C1039G/+, with MVD that the mitral valve undergoes abnormal postnatal maturation of the ECM accompanied by an increase in immune cells near regions of collagen breakdown and proteoglycan expansion. It was found that deficiency of infiltrating CCR2+ monocytes inhibited the progression of myxomatous generation in MFS mice, with decreased numbers of macrophages and reduced valve thickening, suggesting that immunogenic ECM components and immune cells may be key drivers of MVD progression. Based on RNA sequencing of normal murine valves at postnatal days 7 and 30, dendritic cells (DCs) are the only CCR2+ immune cell subpopulation as a gene signature of top 20 correlated genes [6], suggesting a potential role of DCs in valvular ECM remodeling. Therefore, we hypothesize that immature Xcr1 DCs mediate homeostasis during mitral valve postnatal ECM remodeling and maturation but lead to MVD progression in MFS when activated. We propose two aims to elucidate the role of DCs in ECM remodeling, maturation and disease. In Aim 1, we will determine if activated monocytes are sufficient to drive ECM remodeling, maturation and MVD progression in MFS mitral valves in a murine model injected with Lipopolysaccharide (LPS). The localization and activate of DCs will be determined by assessing DC activation, morphometric ECM changes, inflammatory response in DC knock-in mice models. In Aim 2, we will determine if Xcr1 DCs in the mitral valves are required for ECM remodeling and MVD progression in MFS by accessing DC activation, morphometric ECM changes, inflammatory response and functional and biomechanical changes in DC knock-in and DC knockout mice crossed with fibrillin 1 mutant mice. Understanding DC contributions to MVD in MFS and disease progression will advance therapeutic strategies aimed at preventing or reversing MVD.