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

Tui Neri (1) , Emilye Hiriart (2) , Patrick P. Van Vliet (3) , Emilie Faure (2) , Russell A. Norris (4) , Batoul Farhat (2) , Bernd Jagla (5) , Julie Lefrancois , Yukiko Sugi (4) , Thomas Moore-Morris (2) , Stéphane Zaffran (2) , Randolph S. Faustino (6) , Alexander C. Zambon (7) , Jean-Pierre Desvignes (2) , David Salgado (2) , Robert A. Levine (8) , Jose Luis de La Pompa (9, 10) , Andre Terzic (11) , Sylvia M. Evans (12, 13, 14) , Roger Markwald (4) , Michel Puceat (2)

1 I-STEM - Institut des cellules souches pour le traitement et l'étude des maladies monogéniques
2 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
3 UC San Diego - University of California [San Diego]
4 MUSC - Medical University of South Carolina [Charleston]
5 C3BI - Centre de Bioinformatique, Biostatistique et Biologie Intégrative
6 Mayo Clinic [Rochester]
7 KGI - Keck Graduate Institute [Claremont, Californie]
8 Massachusetts General Hospital [Boston]
9 CNIC - Centro Nacional de Investigaciones Cardiovasculares Carlos III [Madrid, Spain]
10 ISC - Instituto de Salud Carlos III [Madrid]
11 Division of Cardiovascular Diseases
12 Skaggs School of Pharmacy and Pharmaceutical Sciences [San Diego]
13 MED - UC San Diego - Department of Medicine [Univ California San Diego]
14 Department of Pharmacology [La Jolla, CA, USA]

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.

Keywords: Developmental biology; Disease model

Domains: Life Sciences [q-bio]; Genetics

Tui Neri, Emilye Hiriart, Patrick P. Van Vliet, Emilie Faure, Russell A. Norris, et al.. Human pre-valvular endocardial cells derived from pluripotent stem cells recapitulate cardiac pathophysiological valvulogenesis. Nature Communications, 2019, 10, pp.1929. ⟨10.1038/s41467-019-09459-5⟩. ⟨hal-02461454⟩