Development of the heart (L17) Flashcards
What is the prevalence of cardiovascular disease?
Cardiovascular disease is the leading cause of death worldwide - 31% - 150,000 per year in the UK. Congenital heart disease affects around 1% - to do with structural malformations due to abnormal development. PRoblems with the heart are the most common birth defect. It affects about 1% of live births. Heart disease cost to the UK economy is around £19 billion per year
How do different model organisms vary in their uses for study cardiogenesis and why?
High vertebrates have a 4-chambered heart, separated by a septum and valves - gives us 2 separate circulatory systems. (mice and chicks). Organisms with 2 and 3 chambered hearts are also sued to study the earlier development. Xenopus have a 3 chambered heaty - common to many amphibians. 2 atria and one ventricle Its still 2 separate circulatory systems - the ventricle manages to keep blood relatively separated. Zebrafish have a 2 chambered heart, 1 ventricle and 1 atrium. Blood enters the atria and gets transferred to ventricles - it then goes to gills (where it is oxygenated) and then travels to rest of the body. Drosophila has a tubular heart - its basically a fancy vessel lined with valves that promote the flow in one direction. Its a very simple system but is good for looking at very early signalling.
What is the general morphological heart development?
- Cardiac precursor cells are found as bilateral populations of cells around the midline (the cardiac crescent)
- The 2 populations migrate to the midline and fuse to form the heart tube
- The heart tube undergoes an asymmetrical bending (heart lopping) - the asymmetric bending makes sure future chambers are aligned
- The heart undergoes maturation resulting in the formation of structures required for proper function. Valves, septa, trabeculae etc.
What are the different timings of heart development in different organisms?
In humans, the heart is fully formed by about 50 days and is about 15 days in mice. Slightly different in zebrafish - happens a lot quicker due to not as much maturation. Still starts with 2 groups of cells but they migrate to form a disc. The disc then undergoes an extension to form a tube and then loops - after around 48hrs the heart is nearly formed.
How do the 2 populations of cardiac cells form?
The 2 populations of cells are specified early during development and exhibit distinct spatiotemporal differentiation into the heart. The first heart field (FHF) form the left ventricle and left and right atria. The second heart field (SHF) forms the right ventricle, left and right atria and outflow tracts. So FHF males tube first, then as the heart develops, the SHF takes over the majority of the heart. Cardiac cells are specified from mesodermal tissue along the primitive streak (mouse) or embryonic margin (fish) - this is controlled by combinatorial morphogen signalling. Cardiac mesoderm receives non-canonical Wnt signalling, then if they receive BMP signalling, they become FHF progenitors. If they receive beta-catenin or FGF instead of BMP, they become SHF progenitors. The morphogen signals turn on different TFs which are cardiac cell markers and cause them to develop (E.g. Tbx5 in FHF and ISL1 in SHF). Once specified, the cells migrate anteriorly to form the primitive heart tube (FHF) and SHF in adjacent mesoderm. NKX2.5 is expressed in both FHF and SHF, so if you’re lacking this you get some serious problems
What decisions does the heart tissue need to make to allow for functionality?
Different parts of the heart tube are differentiated to become different things. The heart needs to make decisions on how it is patterned to allow for its function. The first patterning it undergoes is chamber Vs non-chamber. (e.g. contractile Vs non-contractile tissue). The tissue in the heart needs to decide whether it is going to be contractile muscle or things like connective tissue. The contractile tissue then needs to decide whether to be atrial or ventricular (to allow for directional conduction). Ventricles also have to undergo trabeculation. So, the different chambers do different things. Regional levels of the specification also have to be patterned into the heart tube. E.g. inflow (pacemaker/SA node), AV canal (AV valve/node), and outflow (valves). This is all controlled by a very complex interplay of activating and inhibitory factor interactions.
What are the main signals involved in the regional specification of the heart tube?
The Notch -Tbx20 pathway is important in specifying chambers. And the BMP-Tbx2 pathway is important in the AV canal. What happens if you have no Tbx2 - you get abnormal valve morphology and increases Nppa (chamber marker) expression in the AV canal. - Tbx2 usually helps in inhibiting Nppa in the AV canal. If you lose Tbx20, you get a loss of chamber identity and an expansion of valve markers (Tbx2).
The heart needs to be the right shape to allow blood to flow through it in the right direction. Blood flow is important for gene expression E.g. formation of valves. This occurs through flow responsive genes such as Klf2.
Explain heart looping morphogenesis
Involves a carefully coordinated interplay of several responses:
- changes in cell shape - as the looping occurs, the cells grow slightly in size and also change shape in different ways in different parts of the heart tube. Cells on the inner curvature are cuboidal in shape, cells on the outer curvature undergo a very significant change (because this is the bit that moves the most) and become elongated and change their orientation.
- Growth of the heart tube - The SHF cells add into the heart tube as it grows to help the heart shape changes as well.
-Asymmetric cell movements at the poles of the heaty - the tube sort of twists and buckles.
- Regional changes in ECM composition - e.g. at AV canal where the valves are going to form, you get extra ECM to help valves emerge and also change the stiffness of the tube. E.g. a stiff part won’t move are much during the looping.
Lateralised cell signalling from the embryo helps make sure it bends in the right direction. Rightward helical looping to allow for aligning of the chambers.
How do SHF cells contribute to the heart morphogenesis?
Growth of the heart from the second heart field: Cells from SHF migrate and become added to the poles of the heart. SHF cells express islet1 (you can use this as a marker) and can see that they’re expressed in the mesoderm adjacent to the heart. If you use a lacz reporter to see where the cells end up (after they’re finished expressing islet1) you can see that the cells end up in the heart - this proves they become incorporated. Analysis of my17 in Islet-1 mutant mice shows the heart is reduced in size and is incompletely looped. Shows that SHF cells are important in the growth and looping of the heart.
What is heterotaxia?
L/R asymmetry abnormalities - often lead to congenital heart defects
E.g. situs inversus - effects approx 1/10000 of the general population, usually asymptomatic (because they still work together properly). Complete reversal of all organs.
- Situs ambiguous/heterotaxia - causes a reversal of some organs, causes them to not work together properly - unknown prevalence, usually associated with significant pathology. Abnormal cardiac development and function are common in heterotaxia patients. Someone with heterotaxia usually has 1+ group of congenital heart defects which include septal defects (holes in the heart), inflow/outflow problems, swapping of great vessels.
What is organ asymmetry regulated by?
Asymmetrical expression of Nodal - It is expressed asymmetrically in the left lateral plate mesoderm of embryos prior to organ formation. Loss of nodal function results in disrupted organ asymmetry.
How does Nodal become expressed asymmetrically?
Spaw is a nodal homolog in zebrafish. In the early stages of somitogenesis, you get the formation of the node (Knopper’s vesicle in zebrafish) which is a transient cup-shaped organ at posterior of the embryo. It’s lined with motile cilia, which beat in a clockwise movement. This creates a directional fluid flow which results in elevated extracellular calcium on the left of the embryo. This results in asymmetric expression of spaw/nodal in the left lateral plate mesoderm. It also moves its expression more anteriorly. When it reaches the anterior, nodal target genes are expressed in the left half of the cardiac disc (lefty2) and other areas where organs are going to form e.g. primordial gut/cells and brain
The cardiac disc then undergoes rotation and involution to form a tube - and also helps dictate looping direction
If you lose nodal flow (the node doesn’t secrete nodal) you get randomisation of lateralised gene expression (e,g, random spaw expression. This leads to a directional heaty displacement. In humans, individuals with mutations in ciliary genes (causes primary ciliary dyskinesis - they move the wrong way) you get heterotaxia because they can’t move the calcium so you get random gene expression. The same happens with a loss of nodal as well. Except in humans you also get isolated cardiovascular malformations.
