RT Journal Article
SR Electronic
T1 A human cell model of cardiac pathophysiological valvulogenesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 397422
DO 10.1101/397422
A1 Tui Neri
A1 Emilye Hiriart
A1 Patrick van Vliet
A1 Emilie Faure
A1 Russell A Norris
A1 Batoul Farhat
A1 Julie Lefrancois
A1 Thomas Moore-Morris
A1 Stéphane Zaffran
A1 Randolph S. Faustino
A1 Alexander C Zambon
A1 Yukiko Sugi
A1 Jean-Pierre Desvignes
A1 David Salgado
A1 Robert A. Levine
A1 Jose Luis de la Pompa
A1 André Terzic
A1 Sylvia M. Evans
A1 Roger Markwald
A1 Michel Pucéat
YR 2018
UL http://biorxiv.org/content/early/2018/08/22/397422.abstract
AB 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.