Development of the Heart Flashcards
When do progenitor heart cells appear?
What cell type are they derived from?
- the vascular system begins to develop in the middle of the 3rd week (day 16-18) when the embryo can no longer satisfy its requirements from diffusion alone
- progenitor heart cells are derived from the epiblast, immediately adjacent to the cranial end of the primitive streak
Where do the progenitor heart cells migrate to and what do they form?
- progenitor heart cells (epiblast) invaginate through the primitive streak
- they migrate to the splanchnic layer of the lateral plate mesoderm between days 16-18
- some of the PHCs will form horseshoe-shaped clusters of cells called the primary heart field (PHF)
- these are located cranial to the neural folds
What do the cells of the primary heart field give rise to?
- the atria
- left ventricle
- part of the right ventricle
- the remainder of the right ventricle and outflow tract (conus cordis & truncus arteriosus) are formed from the secondary heart field
How are progenitor heart cells “fate-mapped” as they migrate through the primitive streak?
- as the PHCs migrate through the primitive streak, they are specified on both sides from lateral to medial to become the different parts of the heart
- this process occurs around the same time that laterality is being established
When does the secondary heart field develop?
Where is this located?
- the secondary heart field (blue) forms in the region cranial to the primary heart field
- this still resides in the splanchnic mesoderm but ventral to the pharynx
What is the “master gene” for heart development?
Where is this secreted?
NKX2.5
- signals from the anterior (cranial) endoderm induce a heart-forming region in the overlying splanchnic mesoderm by inducing NKX2.5
What must be secreted and inhibited before the anterior endoderm can secrete NKX2.5?
- these signals require secretion of bone morphogenic proteins (BMPs) 2 & 4 secreted by the endoderm and lateral plate mesoderm
- there must also be inhibition of WNT proteins (3a & 8) secreted by the neural tube as these inhibit heart development
How is inhibition of WNT proteins acheived?
- there is WNT inhibition by CRESCENT*** and ***CERBERUS
- these are produced by endoderm cells immediately adjacent to heart-forming mesoderm in the anterior half of the embryo
What combination of factors lead to expression of NKX2.5?
- inhibition of WNT proteins by CERBERUS & CRESCENT
- upregulation of BMP 2 & 4 activity
- BMP expression also upregulates activity of FGF8 that is needed for expression of cardiac specfic proteins
- the product of development of the primary heart fied is an endocardial tube surrounded by myoblasts (cardiogenic region)
How is the cardiogenic region established following formation of the PHF?
- the underlying pharyngeal endoderm signals for cells to form cardiac myoblasts and angiogenic cell clusters / blood islands (will form blood cells / vessels)
- the blood islands unite to form a horseshoe-shaped endothelial-lined tube surrounded by myoblasts
- this is the cardiogenic region - an endocardial tube surrounded by myoblasts
How does the heart tube form following formation of the cardiogenic region?
Which regions of this tube receive and pump out blood?
- as a result of embryonic folding, the caudal regions of the paired cardiac tube merge (except at their caudalmost ends)
- the central part of the tube expands to form the future outflow tract and ventricular regions
- the heart tube is an expanding tube that consists of an inner endothelial lining** and an **outer myocardial layer
- it receives venous drainage at its caudal pole and begins to pump blood out of the first aortic arch into the dorsal aorta at the cranial pole
How is development of the secondary heart field regulated?
How can outflow tract defects arise?
- development of the secondary heart field is regulated by neural crest cells (NCCs)
- NCCs proliferate and differentiate to allow the SHF to lengthen and form the outflow tract** and **part of the RV
- disruption to NCCs can result in outflow tract defects
How is the SHF involved in lengthening of the heart tube and why is this important?
- the heart tube continues to elongate as cells from the SHF are added
- addition of these cells is regulated by NCCs, which are essential for formation of part of the right ventricle and the outflow tract region
What is the bulbus cordis and what is it formed from?
- the bulbus cordis consists of the truncus arteriosus and the conus arteriosus
- together these form the outflow tract of the heart, which is derived from NCCs
What is the purpose of cardiac looping?
When does it start and end?
- cardiac looping begins on day 23 as the outflow tract lengthens
- it is complete by day 28
- it occurs in preparation for the heart dividing into 4 chambers
How do the bulbus cordis, primitive ventricle and primitive atrium move during cardiac looping?
Bulbus cordis:
- moves caudally, ventrally and to the right
Primitive ventricle:
- is displaced before moving back to the midline
Primitive atrium:
- moves cranially, dorsally and to the left
- all the primitive chambers are connected, so if one moves caudally then it will push the other side cranially
Which transcription factor of the laterality pathway is important for cardiac looping?
- cardiac looping is dependent on several factors, including expression of *PITX2* in lateral plate mesoderm on the left side
- PITX2 plays a role in the deposition and function of extracellular matrix molecules that assist in looping
How is NKX2.5 involved in cardiac looping?
- NKX2.5 upregulates expression of HAND1 and HAND2
- these transcription factors are expressed in the primitive heart tube before later becoming restricted to the future left (HAND1) and right (HAND2) ventricles
- downstream effectors of these genes participate in looping
- HAND1 & HAND2, under the regulation of NKX2.5, also contribute to expansion and differentiation of the ventricles
What transcription factor is important in lengthening of the outflow tract by the SHF?
SHH
- lengthening of the outflow tract by the SHF is in part regulated by SHH
- SHH is expressed by the pharyngeal arch endoderm and acts through its receptor patched (PTC) to stimulate proliferation of cells in the SHF
- PTC is expressed by SHF cells
How is retionic acid involved in cardiac development?
- the venous portion of the cardiac tube is specified by retinoic acid (RA)
- RA is produced by mesoderm adjacent to the sinus venosus and atria
- after exposure to RA, these structures are able to make their own RA and are committed to becoming caudal cardiac structures
- lower concentrations of RA in the ventricles and outflow tract commits these to becoming cranial cardiac structures