title: Endocardial-to-mesenchymal transformation and mesenchymal cell colonization at the onset of human cardiac valve development.
abstract: The elucidation of mechanisms in semilunar valve development might enable the development of new therapies for congenital heart disorders. Here, we found differences in proliferation-associated genes and genes repressed by VEGF between human semilunar valve leaflets from first and second trimester hearts. The proliferation of valve interstitial cells and ventricular valve endothelial cells (VECs) and cellular density declined from the first to the second trimester. Cytoplasmic expression of NFATC1 was detected in VECs (4 weeks) and, later, cells in the leaflet/annulus junction mesenchyme expressing inactive NFATC1 (5.5-9 weeks) were detected, indicative of endocardial-to-mesenchymal transformation (EndMT) in valvulogenesis. At this leaflet/annulus junction, CD44(+) cells clustered during elongation (11 weeks), extending toward the tip along the fibrosal layer in second trimester leaflets. Differing patterns of maturation in the fibrosa and ventricularis were detected via increased fibrosal periostin content, which tracked the presence of the CD44(+) cells in the second trimester. We revealed that spatiotemporal NFATC1 expression actively regulates EndMT during human valvulogenesis, as early as 4 weeks. Additionally, CD44(+) cells play a role in leaflet maturation toward the trilaminar structure, possibly via migration of VECs undergoing EndMT, which subsequently ascend from the leaflet/annulus junction.
authors.affiliation: Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University Tübingen, 72076 Tübingen, Germany Department of Cell and Tissue Engineering, Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB), 70569 Stuttgart, Germany.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Monaghan
authors.affiliation: Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Linneweh
authors.affiliation: Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Liebscher
authors.affiliation: Department of Medicine/Cardiology, Cardiovascular Research Laboratories (CVRL), University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Van Handel
authors.affiliation: Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University Tübingen, 72076 Tübingen, Germany Department of Cell and Tissue Engineering, Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB), 70569 Stuttgart, Germany.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Layland
authors.affiliation: Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University Tübingen, 72076 Tübingen, Germany Department of Cell and Tissue Engineering, Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB), 70569 Stuttgart, Germany Department of Medicine/Cardiology, Cardiovascular Research Laboratories (CVRL), University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA katja.schenke-layland@med.uni-tuebingen.de.
authors.forename: Katja
authors.initials: K
authors.lastname: Schenke-Layland
mesh_terms: D015815:Cell Adhesion Molecules / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation; D049109:Cell Proliferation; D004699:Endocardium / Q000196:embryology*; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006351:Heart Valves / Q000166:cytology* / Q000196:embryology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology* / Q000196:embryology*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D062211:Spatio-Temporal Analysis; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D018960:Hyaluronan Receptors; D050778:NFATC Transcription Factors; C512835:POSTN protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: EndMT; Extracellular matrix; Heart; NFATc-1; Periostin; Semilunar valves