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Nat Commun. 2019 Apr 26;10(1):1929. doi: 10.1038/s41467-019-09459-5.

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

Author information

1
INSERM U-1251, MMG, Aix-Marseille University, Marseille, 13885, France.
2
Istituto di Ricerca Genetica e Biomedica, UOS di Milano, CNR, Rozzano, 20138, Italy.
3
University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, 92092 92093, USA.
4
Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Montreal, H7G 4W7, QC, Canada.
5
LIA (International Associated Laboratory) INSERM, Marseille, U1251-13885, France.
6
LIA (International Associated Laboratory) Ste Justine Hospital, Montreal, H7G 4W7, Canada.
7
Department of Anatomy and Cell Biology, Medical University of South Carolina, Charleston, SC, 29401-5703, USA.
8
Institut Pasteur - Cytometry and Biomarkers Unit of Technology and Service, Center for Translational Science and Bioinformatics and Biostatistics Hub - C3BI, USR, 3756 IP CNRS, 75015, Paris, France.
9
Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, 55901, USA.
10
Department of Biopharmaceutical Sciences, Keck Graduate Institute, Claremont, CA, 91711, USA.
11
Cardiac Ultrasound Laboratory, Harvard Medical School, Massachusetts General Hospital, Boston, MA, 02111, USA.
12
Intercellular Signaling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, E-28029, Spain.
13
INSERM U-1251, MMG, Aix-Marseille University, Marseille, 13885, France. michel.puceat@inserm.fr.
14
LIA (International Associated Laboratory) INSERM, Marseille, U1251-13885, France. michel.puceat@inserm.fr.
15
LIA (International Associated Laboratory) Ste Justine Hospital, Montreal, H7G 4W7, Canada. michel.puceat@inserm.fr.

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.

PMID:
31028265
PMCID:
PMC6486645
DOI:
10.1038/s41467-019-09459-5
[Indexed for MEDLINE]
Free PMC Article

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