Human heart valve-like tissues from pluripotent stem cells with enhanced maturation recapitulate inflammatory valve disease

Therapeutic management of heart valve disease is currently hampered by a lack of mechanistic understanding of human valve development and pathobiology. Here, we develop a protocol to generate three-dimensional human heart valve-like tissues from pluripotent stem cells with enhanced maturational properties that partially recapitulate key molecular features of native valves. This includes an abundance of valve interstitial cells, resident macrophage cells, and the transcriptional profile of native heart valves. Importantly, we define a heart valve maturation signature from proteomic analysis and show that maturation of stem cell-derived valve cells is enhanced under 3D culture. We demonstrate that bioengineered valve-like microtissues can be used for modeling valve disease. Namely, treatment with inflammatory cytokines augmented tissue passive tension and induced molecular hallmarks of valve calcification, consistent with the pathological signature of clinical samples from diseased valves. Thus, bioengineered human heart valve-like tissues provide a platform to understand human heart valve development, maturation, and disease pathogenesis.