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Updated: Aug 6, 2026
Isolation of Human Primary Valve Cells for In vitro Disease Modeling
Published on: April 16, 2021
Modeling calcific aortic valve disease with engineered human valve tissues identifies SAMHD1 as a therapeutic target
Xiangfu Meng1, Qian Zhou1, Zijin Zhu1
1Stem Cells and Tissue Engineering Manufacture Center, College of Life Sciences, Hubei University, Wuhan, 430062, China; National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan, 430062, China.
Insights
Engineered heart valve tissues (EVTs) from human stem cells mimic calcific aortic valve disease (CAVD). A novel composite model revealed SAMHD1 as a key therapeutic target for CAVD, offering new treatment possibilities.
Area of Science:
- Biomedical Engineering
- Regenerative Medicine
- Cardiovascular Research
Background:
- Valvular heart disease (VHD), particularly calcific aortic valve disease (CAVD), affects millions globally with no effective drug treatments.
- Current animal and cellular models for CAVD lack physiological relevance and scalability.
- There is a critical need for advanced in vitro models to study CAVD pathogenesis and develop therapies.
Purpose of the Study:
- To develop a novel engineered valvular tissue (EVT) model using human induced pluripotent stem cells (hiPSCs) to mimic CAVD.
- To create a biomechanically active composite tissue by integrating EVTs with hiPSC-derived cardiomyocytes.
- To identify and validate therapeutic targets for CAVD using this innovative model.
Main Methods:
- Fabrication of EVTs from hiPSC-derived valvular interstitial cells (VICs) within a 3D hydrogel system for anisotropic alignment.
- Assembly of EVTs with hiPSC-derived cardiomyocytes to create a self-stimulating composite tissue model.
- Induction of calcification in EVTs under static and dynamic mechanical loading, followed by transcriptomic analysis and pharmacological intervention.
Main Results:
- The EVT model accurately recapitulated key features of CAVD, including matrix remodeling, fibrosis, and hydroxyapatite deposition.
- The composite model demonstrated that mechanical stress significantly exacerbates valve calcification.
- Transcriptomic analysis identified SAMHD1 as a core regulator of CAVD, and its inhibition reduced calcification and improved tissue function.
Conclusions:
- Engineered valvular tissues (EVTs) provide a physiologically relevant and scalable model for studying calcific aortic valve disease (CAVD).
- The self-stimulating myocardium-valve composite model elucidates the role of mechanical stress in CAVD progression.
- SAMHD1 is validated as a promising therapeutic target for developing pharmacotherapies against CAVD.
Abstract:
Valvular heart disease (VHD) affects over 209 million people worldwide, with calcific aortic valve disease (CAVD) playing an increasingly dominant role. However, no effective pharmacotherapies are currently available. Existing animal or cellular models are limited by insufficient physiological relevance or lack of scalability. Here, we report for the first time engineered valvular tissues (EVTs) constructed from human induced pluripotent stem cell (hiPSC)-derived valvular interstitial cells (VICs). This model was fabricated using a three-dimension (3D) hydrogel system (fibrinogen/Matrigel/collagen I), enabling anisotropic alignment of VICs with high tissue integrity that closely mimics native valve architecture and supports tissue-level biomechanical testing. Uniquely, we engineered hiPSC-derived cardiomyocytes into myocardial tissues and assembled them with EVTs to create a biomechanically active composite tissue. This design cleverly leverages the spontaneous contraction of cardiomyocytes to provide cyclic mechanical stimulation to the engineered valve, thereby validating that mechanical stress significantly exacerbates calcification. Under calcification-inducing conditions, EVTs robustly mimic key features of CAVD, including matrix remodeling, fibrosis, RUNX2 upregulation, and hydroxyapatite deposition. Biomechanical testing confirmed increased stiffness and reduced extensibility in calcified tissues, consistent with clinical observations. Furthermore, we performed time-series transcriptomic analysis throughout the in vitro culture and calcification induction process. This analysis not only confirmed a high degree of similarity between EVTs and native valves (R > 0.8) but also revealed that EVT calcification follows an osteogenic differentiation trajectory comparable to native valve calcification. Weighted gene co-expression network analysis (WGCNA) identified six potential central regulators of calcification; through subsequent small-molecule inhibition and pharmacological intervention, we definitively validated SAMHD1 as the core regulator through inflammatory signal pathway. Recombinant SAMHD1 protein significantly reduced calcification, improved tissue elasticity, and attenuated dysfunction in both static and mechanically loaded models. Our work establishes an innovative EVTs model with quantifiable tissue mechanical properties; pioneers the integration of myocardium-valve engineered tissues to construct a self-driven, cyclically stressed myocardium-valve composite model; and identifies SAMHD1 as a highly promising therapeutic target for CAVD.
