Endocardial-to-mesenchymal transformation and mesenchymal cell colonization at the onset of human cardiac valve development.

Michael G Monaghan,Shannon L Layland,Simone Liebscher,Ben Van Handel,Miriam Linneweh,Katja Schenke-Layland

doi:10.1242/dev.133843

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.

Highlights

Congenital heart disorders, which include aortic and pulmonary valve disease, are one of the most prevalent birth defects in humans (Roger et al, 2012)
It should be noted that there were significantly fewer KI67+ valve endothelial cells (VECs) on the ventricularis when compared with the fibrosa, a trend that persisted from 7-8 weeks of development (Fig. 1E)
We have identified that human leaflet cell density and proliferation decrease significantly from the first to the second trimester

Summary

Introduction

Congenital heart disorders, which include aortic and pulmonary valve disease, are one of the most prevalent birth defects in humans (Roger et al, 2012). Most developmental studies define mechanisms of valvulogenesis in zebrafish, mouse or chicken. Received 3 December 2015; Accepted 9 December 2015 models (Butcher and Markwald, 2007; de Vlaming et al, 2012; Lin et al, 2012) Such investigations have identified key mechanisms and regulatory pathways; these data have yet to be corroborated in humans

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Conclusion