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A human cell model of cardiac pathophysiological valvulogenesis

Tui Neri, Emilye Hiriart, Patrick van Vliet, Emilie Faure, Russell A Norris, Batoul Farhat, Julie Lefrancois, Thomas Moore-Morris, Stéphane Zaffran, Randolph S. Faustino, Alexander C Zambon, Yukiko Sugi, Jean-Pierre Desvignes, David Salgado, Robert A. Levine, Jose Luis de la Pompa, André Terzic, Sylvia M. Evans, Roger Markwald, Michel Pucéat
doi: https://doi.org/10.1101/397422
Tui Neri
Université Aix-Marseille, INSERM U-1251, MMG, FranceInstituto di Ricerca Genetica e Biomedica, UOS di Milano, CNR, Italia
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Emilye Hiriart
Université Aix-Marseille, INSERM U-1251, MMG, France
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Patrick van Vliet
University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USACardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Montreal Canada
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Emilie Faure
Université Aix-Marseille, INSERM U-1251, MMG, France
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Russell A Norris
Medical University of South Carolina, Department of Anatomy and Cell Biology, Charleston, SC, USA
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Batoul Farhat
Université Aix-Marseille, INSERM U-1251, MMG, France
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Julie Lefrancois
Université Aix-Marseille, INSERM U-1251, MMG, France
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Thomas Moore-Morris
Université Aix-Marseille, INSERM U-1251, MMG, France
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Stéphane Zaffran
Université Aix-Marseille, INSERM U-1251, MMG, France
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Randolph S. Faustino
Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, US
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Alexander C Zambon
Keck Graduate Institute, Department of Biopharmaceutical Sciences, Claremont, CA, USA
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Yukiko Sugi
Medical University of South Carolina, Department of Anatomy and Cell Biology, Charleston, SC, USA
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Jean-Pierre Desvignes
Université Aix-Marseille, INSERM U-1251, MMG, France
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David Salgado
Université Aix-Marseille, INSERM U-1251, MMG, France
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Robert A. Levine
Cardiac Ultrasound Laboratory, Harvard Medical School, Massachusetts General Hospital, Boston
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Jose Luis de la Pompa
Intercellular Signaling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) Madrid, SPAIN
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André Terzic
Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, US
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Sylvia M. Evans
University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA
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Roger Markwald
Medical University of South Carolina, Department of Anatomy and Cell Biology, Charleston, SC, USA
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Michel Pucéat
Université Aix-Marseille, INSERM U-1251, MMG, France
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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.

Footnotes

  • ↵# both authors contributed to the same extent to this study

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Posted August 22, 2018.
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A human cell model of cardiac pathophysiological valvulogenesis
Tui Neri, Emilye Hiriart, Patrick van Vliet, Emilie Faure, Russell A Norris, Batoul Farhat, Julie Lefrancois, Thomas Moore-Morris, Stéphane Zaffran, Randolph S. Faustino, Alexander C Zambon, Yukiko Sugi, Jean-Pierre Desvignes, David Salgado, Robert A. Levine, Jose Luis de la Pompa, André Terzic, Sylvia M. Evans, Roger Markwald, Michel Pucéat
bioRxiv 397422; doi: https://doi.org/10.1101/397422
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A human cell model of cardiac pathophysiological valvulogenesis
Tui Neri, Emilye Hiriart, Patrick van Vliet, Emilie Faure, Russell A Norris, Batoul Farhat, Julie Lefrancois, Thomas Moore-Morris, Stéphane Zaffran, Randolph S. Faustino, Alexander C Zambon, Yukiko Sugi, Jean-Pierre Desvignes, David Salgado, Robert A. Levine, Jose Luis de la Pompa, André Terzic, Sylvia M. Evans, Roger Markwald, Michel Pucéat
bioRxiv 397422; doi: https://doi.org/10.1101/397422

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