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Bioengineered 3D human heart valve tissues with enhanced maturational properties for disease modelling and therapeutic applications

ABSTRACT: 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 3-dimensional human heart valve tissues from pluripotent stem cells with enhanced maturational properties closely mirroring the valve interstitial cell, resident myeloid cells and protein expression profile of native heart valves. Importantly, bioengineered heart valves transplanted subcutaneously in rats did not calcify, highlighting potential clinical utility as a cellular therapy. In parallel, using a high-throughput 96-well platform, we demonstrate that bioengineered human heart valves can be used for modelling valve disease. Treatment with inflammatory cytokines augmented tissue passive tension and upregulated molecular markers associated with valve calcification and fibrosis. Thus, bioengineered human heart valve tissues provide a platform to understand human heart valve development, disease pathogenesis and offer a potential regenerative therapy for heart valve disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294124 | GEO | 2026/08/07

REPOSITORIES: GEO

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Project description:E12.5 AV cushion and E17.5 AV valve from wild-type FVB/N mice and in vitro cultured MC3T3 cells; In the study we demonstrated shared gene expression in embryonic heart valve development and Osteoblast progenitor cells. The atrioventricular (AV) valves of the heart develop from undifferentiated mesenchymal endocardial cushions, that later remodel into stratified valves with diversified extracellular matrix (ECM). Because the mature valves express genes associated with osteogenesis and exhibit disease-associated calcification, we hypothesized the existence of shared regulatory pathways active in the remodeling AV valves and in bone progenitor cells. In order to define gene regulatory programs of valvulogenesis relative to osteoblast progenitors, we undertook Affymetrix gene expression profiling analysis of murine embryonic day (E)12.5 AV cushions compared to E17.5 remodeled AV valves (mitral and tri-cuspid) and to pre-osteoblast MC3T3-E1 (subclone4) cells. Overall MC3T3 cells were significantly more similar to E17.5 valves than to E12.5 cushions, supporting the hypothesis that valve remodeling involves the expression of many genes also expressed in osteoblasts. Several transcription factors characteristic of mesenchymal and osteoblast precursor cells, including Twist1 are predominant in E12.5 cushion. Valve remodeling also includes differential regulation of matrix metalloproteinases and their inhibitors as well as characteristic collagen isoform switching. Among the most highly enriched genes during valvulogenesis were members of the small leucine-rich proteoglycan (SLRP) family including Asporin, a known negative regulator of osteoblast differentiation and mineralization. Together, these data support shared gene expression profiles of the remodeling valves and osteoblast bone precursor cells in normal valve development and homeostasis with potential functions in calcific valve disease. Experiment Overall Design: In the study, we hybridized RNA from E12.5 AV cushion and E17.5 AV valve from wild-type FVB/N mice and in vitro cultured MC3T3 cells to Affymetrix MOE430 2 GeneChipÂ® arrays.

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Bioengineered 3D human heart valve tissues with enhanced maturational properties for disease modelling and therapeutic applications

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