A role for primary cilia in aortic valve development and disease

Abstract

Background Bicuspid aortic valve (BAV) disease is the most common congenital heart defect affecting 0.5–1.2% of the population and causes significant morbidity and mortality. Only a few genes have been identified in pedigrees and no single gene-model explains BAV inheritance, thus supporting a complex genetic network of interacting genes. However, patients with rare syndromic diseases that stem from alterations in the structure and function of primary cilia (“ciliopathies”) exhibit BAV as a frequent cardiovascular finding, suggesting primary cilia may factor broadly in disease etiology. Results Our data are the first to demonstrate that primary cilia are expressed on aortic valve mesenchymal cells during embryonic development and are lost as these cells differentiate into collagen-secreting fibroblastic-like cells. The function of primary cilia was tested by genetically ablating the critical ciliogenic gene, Ift88. Loss of Ift88 resulted in abrogation of primary cilia and increased fibrogenic ECM production. Consequentially, stratification of ECM boundaries normally present in the aortic valve were lost and a highly penetrant BAV phenotype was evident at birth. Conclusions Our data support cilia as a novel cellular mechanism for restraining ECM production during aortic valve development and broadly implicate these structures in the etiology of BAV disease in humans.

A human cell model of cardiac pathophysiological valvulogenesis

“…Valve endothelial cells and their human counterpart iPS cell-derived HPVCs expressing endocardial genes TBX2, TBX20, PITX2, GATA5, SMAD6 and MSX1 (Supplementary Fig. 4), expressed few cilia (data not shown) as recently reported in mouse 46 potentially because the high shear stress in the region of cardiac cushions as proposed in zebrafish 47 . EMT was thus induced by BMP2 treatment of HPVCs and cilia were scored in vimentin+ valvular interstitial cells (Fig.…”

“…Primary ciliary dyskinesia (PCD) without sinus invertus as well as other ciliopathies have been clinically associated with myxomatous mitral valve and other valve diseases 71,46 Interestingly, patients with autosomal dominant polycystic kidney disease (ADPKD), a disease in which cells feature a over-activation of SHH pathway 72 have an increased occurrence of mitral valve prolapse 73 . Dachsous is required for lymphatic valve development 45 .…”

Regulation of the Extracellular Matrix by Ciliary Machinery

“…Fibrosis in non-ciliopathies has also been linked to the primary cilium. In investigating the mechanisms underlying fibrosis after cardiac injury, Toomer et al found that conditional knockout of IFT88 in adult mouse heart leads to increased expression of ECM components, including the proteoglycan versican, and formation of immature collagen fibres, indicating involvement of a post-transcriptional defect [39]. Also, Villalobos et al found evidence of a relationship between TGFβ-SMAD2/3 signalling, collagen expression and cilia in the context of cardiac fibrosis [40].…”

Imbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesis

“…They possess sensory functions and serve as an important hub for signaling processes such as the Hedgehog (Hh) pathway (2). Activity of such signaling pathways is crucial during development (2) and is also needed for heart formation (3,4). Motile cilia, on the other hand, are typically found in multitudes, for instance on cells lining the surface of trachea, oviduct, and brain ventricles, and mainly serve to move fluids (1).…”