Review article
Hyaluronan: A critical regulator of endothelial-to-mesenchymal transition during cardiac valve formation

https://doi.org/10.1016/j.tcm.2012.10.002Get rights and content

Abstract

During embryonic development, cardiac valves arise at specific regions in the cardiac endothelium that swell up due to enhanced extracellular matrix production (so-called endocardial cushions). An important extracellular matrix component that is produced by the endocardial cells is the glycosaminoglycan hyaluronan. A deficiency in hyaluronan synthesis results in a failure to form endocardial cushions and a loss of their cellularization by a process called endothelial-to-mesenchymal transformation. Expression of the major hyaluronan synthase Has2 is under the influence of both positive and negative regulators. MicroRNA-dependent degradation of Has2 is required to control extracellular hyaluronan levels and thereby the size of the endocardial cushions. In this article, we review the current literature on hyaluronan synthesis during cardiac valve formation and propose that a balanced activity of both positive and negative regulators is required to maintain the critical homeostasis of hyaluronan levels in the extracellular matrix and thereby the size of the endocardial cushions. The activating and inhibitory interactions between microRNA-23, Has2, and hyaluronan are reminiscent of a reaction–diffusion system. Using a mathematical modeling approach we show that the system can produce a confined expression of hyaluronan, but only if the inhibitory signal is transferred to adjacent cells in exosomes.

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).

References (52)

  • V. Gupta et al.

    Abundance and location of proteoglycans and hyaluronan within normal and myxomatous mitral valves

    Cardiovascular Pathology

    (2009)
  • D.R. Michael et al.

    The human hyaluronan synthase 2 (HAS2) gene and its natural antisense RNA exhibit coordinated expression in the renal proximal tubular epithelial cell

    Journal of Biological Chemistry

    (2011)
  • K.J. Rodriguez et al.

    Regulation of valvular interstitial cell phenotype and function by hyaluronic acid in 2-D and 3-D culture environments

    Matrix Biology

    (2011)
  • Y. Sugi et al.

    Bone morphogenetic protein-2 can mediate myocardial regulation of atrioventricular cushion mesenchymal cell formation in mice

    Developmental Biology

    (2004)
  • M.H. Swat et al.

    Multiscale modeling of tissues using CompuCell3D

    Methods in Cell Biology

    (2012)
  • B.P. Toole

    Hyaluronan and its binding proteins, the hyaladherins

    Current Opinion in Cell Biology

    (1990)
  • P.H. Weigel et al.

    Hyaluronan synthases: a decade-plus of novel glycosyltransferases

    Journal of Biological Chemistry

    (2007)
  • J. Bakkers et al.

    Has2 is required upstream of Rac1 to govern dorsal migration of lateral cells during zebrafish gastrulation

    Development

    (2004)
  • S. Banerji et al.

    LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan

    Journal of Cell Biology

    (1999)
  • A. Belle et al.

    Quantification of protein half-lives in the budding yeast proteome

    Proceedings of the National Academy of Sciences of the United States of America

    (2006)
  • T.D. Camenisch et al.

    Regulation of cardiac cushion development by hyaluronan

    Experimental and Clinical Cardiology

    (2001)
  • T.D. Camenisch et al.

    Heart-valve mesenchyme formation is dependent on hyaluronan-augmented activation of ErbB2–ErbB3 receptors

    Nature Medicine

    (2002)
  • T.D. Camenisch et al.

    Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme

    Journal of Clinical Investigation

    (2000)
  • T. Cickovski et al.

    From genes to organisms via the cell: a problem-solving environment for multicellular development

    Computing in Science and Engineering

    (2007)
  • F. Collino et al.

    Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs

    PLoS One

    (2010)
  • E.G. Contreras et al.

    Early requirement of hyaluronan for tail regeneration in Xenopus tadpoles

    Development

    (2009)

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