Review articleHyaluronan: A critical regulator of endothelial-to-mesenchymal transition during cardiac valve formation
Introduction
The embryonic vertebrate heart initially forms as a linear heart tube displaying peristaltic contractions to push fluids forward. After the heart tube has looped into an S-shaped structure the cardiac chambers appear. The primitive peristaltic contraction pattern is replaced by sequential contraction of the chambers, due to the establishment of areas with fast and slow electrical conduction properties. At this stage valves appear in the atrioventricular canal and the outflow tract to prevent blood from flowing back into the chambers at diastole. Defects in cardiac valve formation lead to blood regurgitation resulting in a poor ejection fraction of the embryonic and newborn heart. Congenital heart defects such as mitral valve prolapse, Epstein's malformation or bicuspid valves have their origin during embryonic development and the underlying mechanisms causing the defects are still largely unknown. Therefore studying embryonic heart development and understanding the mechanisms regulating valve induction, growth and remodeling will contribute to a better understanding about the origin of these congenital heart defects.
Section snippets
Hyaluronan biosynthesis
During cardiac valve formation, endocardial cells within the endocardial cushions (ECs) undergo an endothelial-to-mesenchymal transition (Endo-MT). As a consequence, these endocardial cells lose contact with surrounding endocardial cells and migrate into the extracellular matrix between the endo- and myocardium, called cardiac jelly (Fig. 1a). This cardiac jelly is rich in collagen (Little et al., 1989) and the glycosaminoglycan hyaluronan (HA) (Camenisch et al., 2000). Biosynthesis of HA
Hyaluronan function
The chains of HA are negatively charged and therefore HA can be considered osmotically active, attracting large amounts of salt and consequently water (reviewed in Toole, 2004). Once deposited in the cardiac jelly, HA also binds to other extracellular molecules (Toole, 1990) resulting in a strong structural meshwork which is resistant to biomechanical pressure. In the adult heart HA is localized in aortic and mitral valve leaflets (Gupta et al., 2009). Alterations in HA content and localization
Hyaluronan degradation
Each tissue or developmental process requires a different extracellular makeup, depending on the necessity to resist pressure and allow permeability. To retain HA homeostasis in the extracellular matrix (ECM), the levels can be adjusted from two sides: regulated synthesis by Has enzymes and regulated HA chain hydrolysis in the lysosome by hyaluronidases. Currently, six hyaluronidase-like genes have been identified in human and mouse, each with distinct biological functions (reviewed in Csoka et
Mechanisms of hyaluronan regulation
Regulation of HA production is predominantly achieved by regulating the expression of the synthesizing genes. Genetic loss-of-function experiments in mouse embryos demonstrated that Has2 expression is induced by Bmp2, a TGF-β related growth factor, produced and secreted by the overlaying myocardium (Ma et al., 2005; Sugi et al., 2004). Negative regulators of Has2 expression have also been identified. In human osteosarcoma cells, renal proximal tubular epithelial cells, and skeletal muscle
Concluding remarks
The study by Lagendijk et al. (2011) has convincingly demonstrated that miR-23 is required for normal valve formation by tightly regulating the level of HA synthesis. Mathematical modeling confirms that HA homeostasis is achieved by the coordinated activity of both positive and negative feedback loops that control Has2 levels. Further work is needed to address whether miR-23 can be transported between cells as predicted by the model to provide robustness to the system. Since HA distribution and
Box I: Model description
In the model, cells are explicitly represented and can be in either endothelial or mesenchymal state. Cells are able to sense concentrations and secrete substances over their surface area and maintain an internal Has2 concentration level. These functions are governed by a signaling network, described below and in Fig. 2a.
Acknowledgments
This work was supported by EU FP7-NMP-2007-214539 (BioScent) and The Netherlands Consortium for Systems Biology (NCSB), which is a part of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research. The investigations were, in part, supported by the Division for Earth and Life Sciences (ALW) with financial aid from the Netherlands Organization for Scientific Research (NWO).
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