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Method Article

A human cell model of valvulogenesis

michel PUCEAT, Tui Neri, Emilye Hiriart, Piet Van vliet

Abstract

Genetically modified mice have advanced our understanding of valve development and related pathologies. Yet, little is known regarding human valvulogenesis in health and diseases. Genuine human in vitro models that reproduce valvular (patho)biology are thus needed. We here developed a human pluripotent stem cell-derived model fit to decode the early steps of human valvulogenesis and to recapitulate valve disease traits in a dish.

Using cellular based, single cell omics-informed and in vivo-validated approaches, we derived a population of pre-valvular endocardial cells from a pluripotent stem cell source. These human prevalvular cells (HPVCs) expressed gene patterns conforming to the atrio-ventricular canal (AVC) endocardium signature originally established in E9.0 mouse embryos. In fact, HPVC treated with BMP2, cultured onto mouse AVC cushions, or transplanted into the AVC of embryonic mouse hearts, underwent endothelial-to-mesenchymal transition and expressed markers of valve interstitial cells of different valvular layers demonstrating tissue functionality. HPVCs also differentiated into tendinous/chondrogenic cells in line with the valvular repertoire. Extending this valvulogenic model to patient specific iPS cells, we recapitulated features of mitral valve prolapse and uncovered that dysregulation of the SHH pathway is likely to be at the origin of the disease thus providing a putative therapeutic target.

Human pluripotent stem cells recapitulate early valvulogenesis and provide a powerful model to systematically decipher the origin and lineage contribution of different valvular cell types in humans as well as to study valve diseases in a dish.

Keywords
embryonic stem cell, valve, iPS cells, heart

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Introduction

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Anticipated Results

References

Acknowledgements

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Preprint: Please note that this article has not completed peer review.
Method Article

A human cell model of valvulogenesis

michel PUCEAT, Tui Neri, Emilye Hiriart, Piet Van vliet

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Abstract

Genetically modified mice have advanced our understanding of valve development and related pathologies. Yet, little is known regarding human valvulogenesis in health and diseases. Genuine human in vitro models that reproduce valvular (patho)biology are thus needed. We here developed a human pluripotent stem cell-derived model fit to decode the early steps of human valvulogenesis and to recapitulate valve disease traits in a dish.

Using cellular based, single cell omics-informed and in vivo-validated approaches, we derived a population of pre-valvular endocardial cells from a pluripotent stem cell source. These human prevalvular cells (HPVCs) expressed gene patterns conforming to the atrio-ventricular canal (AVC) endocardium signature originally established in E9.0 mouse embryos. In fact, HPVC treated with BMP2, cultured onto mouse AVC cushions, or transplanted into the AVC of embryonic mouse hearts, underwent endothelial-to-mesenchymal transition and expressed markers of valve interstitial cells of different valvular layers demonstrating tissue functionality. HPVCs also differentiated into tendinous/chondrogenic cells in line with the valvular repertoire. Extending this valvulogenic model to patient specific iPS cells, we recapitulated features of mitral valve prolapse and uncovered that dysregulation of the SHH pathway is likely to be at the origin of the disease thus providing a putative therapeutic target.

Human pluripotent stem cells recapitulate early valvulogenesis and provide a powerful model to systematically decipher the origin and lineage contribution of different valvular cell types in humans as well as to study valve diseases in a dish.

Figures

Introduction

Reagents

Equipment

Procedure

Timing

Anticipated Results

References

Acknowledgements

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