Human pre-valvular endocardial cells derived from pluripotent stem cells recapitulate cardiac pathophysiological valvulogenesis

Tui Neri, Emilye Hiriart, Patrick P. van Vliet, Emilie Faure, Russell A. Norris, Batoul Farhat, Bernd Jagla, Julie Lefrancois, Yukiko Sugi, Thomas Moore-Morris, Stéphane Zaffran, Randolph S. Faustino, Alexander C. Zambon, Jean Pierre Desvignes, David Salgado, Robert A. Levine, Jose Luis de la Pompa, André Terzic, Sylvia M. Evans, Roger MarkwaldMichel Pucéat

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Genetically modified mice have advanced our understanding of valve development and disease. Yet, human pathophysiological valvulogenesis remains poorly understood. Here we report that, by combining single cell sequencing and in vivo approaches, a population of human pre-valvular endocardial cells (HPVCs) can be derived from pluripotent stem cells. HPVCs express gene patterns conforming to the E9.0 mouse atrio-ventricular canal (AVC) endocardium signature. HPVCs treated with BMP2, cultured on mouse AVC cushions, or transplanted into the AVC of embryonic mouse hearts, undergo endothelial-to-mesenchymal transition and express markers of valve interstitial cells of different valvular layers, demonstrating cell specificity. Extending this model to patient-specific induced pluripotent stem cells recapitulates features of mitral valve prolapse and identified dysregulation of the SHH pathway. Concurrently increased ECM secretion can be rescued by SHH inhibition, thus providing a putative therapeutic target. In summary, we report a human cell model of valvulogenesis that faithfully recapitulates valve disease in a dish.

Original languageEnglish (US)
Article number1929
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Neri, T., Hiriart, E., van Vliet, P. P., Faure, E., Norris, R. A., Farhat, B., Jagla, B., Lefrancois, J., Sugi, Y., Moore-Morris, T., Zaffran, S., Faustino, R. S., Zambon, A. C., Desvignes, J. P., Salgado, D., Levine, R. A., de la Pompa, J. L., Terzic, A., Evans, S. M., ... Pucéat, M. (2019). Human pre-valvular endocardial cells derived from pluripotent stem cells recapitulate cardiac pathophysiological valvulogenesis. Nature communications, 10(1), [1929]. https://doi.org/10.1038/s41467-019-09459-5