Heart valve (HV) morphogenesis relies on a coordinated interplay between transcription factors and mechanical forces generated by the blood flow. HVs ensure optimal blood circulation and avoid reverse blood. Industrialised countries have a prevalence of HV disease estimated at 2.5%, moreover HV replacement is one of the most common cardiac interventions. Valve diseases have their origin during embryogenesis, either as signs of abnormal developmental processes or the aberrant re-expression of foetal gene programs normally quiescent in adulthood.
The zebrafish is a good model organism to study heart development, despite having one atrium and one ventricle instead of two, it shares the same three cardiac tissue layers (endocardium, myocardium and epicardium) with the human heart. The atrium collects the deoxygenated blood and sends it to the ventricle through the atrioventricular valve (AVV). This valve is structurally similar to mammalian valves, suggesting conservation of the cellular and molecular events involved in its formation. The zebrafish AVV model has proven to be powerful in the study of the effect of mechanical forces on HV development. While mammals have a very limited regenerative capacity, zebrafish is one of the most widely used models for regeneration. However, it is unclear if HV have the ability to regenerate. Most importantly, the regenerative potential of valvulogenic endocardial cells (EdC) has never been explored, despite being crucial to the development of novel therapies. This project aimed to investigate the spatial and temporal nature of EdC behaviours necessary for HV morphogenesis in normal, pathological and regenerative contexts.
In the developing heart, the heartbeat and the blood flow signal to the EdCs through mechanosensitive proteins which in turn modulate the genetic program controlling valvulogenesis. However, the precise dynamics of the cellular events involved are difficult to describe owing to the location deep within the cardiac cavity and the constant motion of the beating heart. Dr. Vermot’s laboratory has recently demonstrated that oscillatory flow is essential for early valve morphogenesis and that the EdCs are able to discriminate between small changes in oscillatory flow, which leads to different cells responses. The flow-responsive transcription factor krüppel-like factor 2a (Klf2a), for example, is important during valvulogenesis. Removing klf2a expression is known to result in malformed valves. However, how mechanical forces influence key cellular processes underlying AVV morphogenesis and the full genetic network activated by oscillatory flow in EdCs is poorly understood. It is essential to determine how mechanical forces control pathway activation and morphogenesis in vivo because the mechanical stimuli experienced by EdCs are too complex to be faithfully reproduced in vitro.
