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

Author

Listed:
  • Tui Neri

    (Aix-Marseille University
    UOS di Milano, CNR)

  • Emilye Hiriart

    (Aix-Marseille University)

  • Patrick P. van Vliet

    (University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences
    CHU Sainte-Justine
    LIA (International Associated Laboratory) INSERM
    LIA (International Associated Laboratory) Ste Justine Hospital)

  • Emilie Faure

    (Aix-Marseille University)

  • Russell A. Norris

    (Medical University of South Carolina)

  • Batoul Farhat

    (Aix-Marseille University
    LIA (International Associated Laboratory) INSERM
    LIA (International Associated Laboratory) Ste Justine Hospital)

  • Bernd Jagla

    (Institut Pasteur - Cytometry and Biomarkers Unit of Technology and Service, Center for Translational Science and Bioinformatics and Biostatistics Hub – C3BI, USR, 3756 IP CNRS)

  • Julie Lefrancois

    (Aix-Marseille University)

  • Yukiko Sugi

    (Medical University of South Carolina)

  • Thomas Moore-Morris

    (Aix-Marseille University
    LIA (International Associated Laboratory) INSERM
    LIA (International Associated Laboratory) Ste Justine Hospital)

  • Stéphane Zaffran

    (Aix-Marseille University)

  • Randolph S. Faustino

    (Center for Regenerative Medicine, Mayo Clinic)

  • Alexander C. Zambon

    (Keck Graduate Institute)

  • Jean-Pierre Desvignes

    (Aix-Marseille University)

  • David Salgado

    (Aix-Marseille University)

  • Robert A. Levine

    (Harvard Medical School, Massachusetts General Hospital)

  • Jose Luis Pompa

    (Intercellular Signaling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC))

  • André Terzic

    (Center for Regenerative Medicine, Mayo Clinic)

  • Sylvia M. Evans

    (University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences)

  • Roger Markwald

    (Medical University of South Carolina)

  • Michel Pucéat

    (Aix-Marseille University
    LIA (International Associated Laboratory) INSERM
    LIA (International Associated Laboratory) Ste Justine Hospital)

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.

Suggested Citation

  • 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, 2019. "Human pre-valvular endocardial cells derived from pluripotent stem cells recapitulate cardiac pathophysiological valvulogenesis," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09459-5
    DOI: 10.1038/s41467-019-09459-5
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    Cited by:

    1. Dorota Zawada & Jessica Kornherr & Anna B. Meier & Gianluca Santamaria & Tatjana Dorn & Monika Nowak-Imialek & Daniel Ortmann & Fangfang Zhang & Mark Lachmann & Martina Dreßen & Mariaestela Ortiz & Vi, 2023. "Retinoic acid signaling modulation guides in vitro specification of human heart field-specific progenitor pools," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Jeremy Lotto & Rebecca Cullum & Sibyl Drissler & Martin Arostegui & Victoria C. Garside & Bettina M. Fuglerud & Makenna Clement-Ranney & Avinash Thakur & T. Michael Underhill & Pamela A. Hoodless, 2023. "Cell diversity and plasticity during atrioventricular heart valve EMTs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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