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

被引:63
作者
Neri, Tui [1 ,2 ]
Hiriart, Emilye [1 ]
van Vliet, Patrick P. [3 ,4 ,5 ,6 ]
Faure, Emilie [1 ]
Norris, Russell A. [7 ]
Farhat, Batoul [1 ,5 ,6 ]
Jagla, Bernd [8 ]
Lefrancois, Julie [1 ]
Sugi, Yukiko [7 ]
Moore-Morris, Thomas [1 ,5 ,6 ]
Zaffran, Stephane [1 ]
Faustino, Randolph S. [9 ]
Zambon, Alexander C. [10 ]
Desvignes, Jean-Pierre [1 ]
Salgado, David [1 ]
Levine, Robert A. [11 ]
de la Pompa, Jose Luis [12 ]
Terzic, Andre [9 ]
Evans, Sylvia M. [3 ]
Markwald, Roger [7 ]
Puceat, Michel [1 ,5 ,6 ]
机构
[1] Aix Marseille Univ, MMG, INSERM U1251, F-13885 Marseille, France
[2] CNR, UOS Milano, Ist Ric Genet & Biomed, I-20138 Rozzano, Italy
[3] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92092 USA
[4] CHU St Justine, Dept Pediat, Cardiovasc Genet, Montreal, PQ H7G 4W7, Canada
[5] INSERM, LIA Int Associated Lab, U1251, F-13885 Marseille, France
[6] St Justine Hosp, LIA Int Associated Lab, Montreal, PQ H7G 4W7, Canada
[7] Med Univ South Carolina, Dept Anat & Cell Biol, Charleston, SC 29401 USA
[8] Inst Pasteur, Cytometry & Biomarkers Unit Technol & Serv, Ctr Translat Sci & Bioinformat & Biostat Hub C3BI, USR,3756 IP CNRS, F-75015 Paris, France
[9] Mayo Clin, Ctr Regenerat Med, Rochester, MN 55901 USA
[10] Keck Grad Inst, Dept Biopharmaceut Sci, Claremont, CA 91711 USA
[11] Harvard Med Sch, Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02111 USA
[12] Ctr Nacl Invest Cardiovasc Carlos III CNIC, Intercellular Signaling Cardiovasc Dev & Dis Lab, E-28029 Madrid, Spain
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
MITRAL-VALVE-PROLAPSE; EPITHELIAL-MESENCHYMAL TRANSITION; PROGENITOR CELLS; HEART-DISEASE; EXPRESSION; FIELD; POPULATION; MUTATIONS; ARTERIAL; REVEALS;
D O I
10.1038/s41467-019-09459-5
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
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页数:14
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