2018 Group Project 4: Difference between revisions

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{{#pmid: PMC3389200|PMC3389200}}
{{#pmid: PMC3389200|PMC3389200}}
=== Fetal Alcohol ===
=== Alagille ===
=== LEOPARD ===
=== Noonan syndromes ===
Retinoic Acid Embryopathy





Revision as of 21:09, 10 September 2018

Projects 2018: 1 Adrenal Medulla | 3 Melanocytes | 4 Cardiac | 5 Dorsal Root Ganglion

Project Pages are currently being updated (notice removed when completed)

Neural Crest and Cardiac Development

Introduction of the heart

The heart is a muscular organ which plays a critical role in the circulatory system by mechanically pumping blood to various organs around the body for the exchange of nutrients and gases. It is located at the center of the chest, right behind the sternum and is tilted slightly to the left. The heart has four different chambers which are compartmentalized by semilunar and atrioventricular valves into the left and right atria and ventricles


Anatomy and Physiology of the Cardiovascular Network

Structure of the Adult Human Heart


http://baldaivirtuves.info/copyright/

The is heart is considered the hardest working organ in the body. Without the heart functioning the human body would cease to function and carry out everyday tasks. The heart consists of four chambers separated by the septum containing, two atria (right atrium, left atrium), two ventricles (left & right). The right side of the heart contains deoxygenated blood and the left side of the heart contains oxygenated blood. The right atrium collects blood returning from the body (Deoxygenated), the left atrium collects blood (oxygenated) returning from the lungs. The right ventricle pumps blood to the lungs and the left ventricle propels blood into the aorta where blood is dispersed to the rest of the body for consumption. There are four valves located in the heart that prevent the backflow of blood. An average heart rate is anywhere between 60-100 beats per minute. For babies, it can be higher around 120-140 beats per minute, for well-conditioned athletes their heart rates can be below 40 beats per minute.

Directional flow of blood through the Heart and its chambers (Red= Oxygenated, Blue=Deoxygenated)

Inferior and superior vena cava--->Right Atrium--->through Tricuspid valve--->Right Ventricle--->Pulmonary Semi-Lunar Valve--->Pulmonary Trunk--->left & Right Pulmonary arteries---> Left & Right Pulmonary Veins---> Left Atrium---> Bicuspid Valve---> Left Ventricle---> Aortic Semilunar Valve---> Trunk of the Aorta---> Aortic Arteries---> Descending Aorta. Then after the blood has traveled through the body and the oxygen has been consumed by the bodies tissues, the blood returns to the heart via veins and the inferior vena cava and superior vena cava. The process repeats.

Histology

Histology of the Heart


Cardiovascular System

Heart development

This begins with formation of two endocardial tubes which merge to form the tubular heart. This loops and separates into the four chambers and paired arterial trunks that form the adult heart. The tubular heart differentiates into the truncus arterioles, bulbus cordis, primitive ventricle, primitive atrium and the sinus venosus. The truncus arteriosus splits into the ascending aorta and pulmonary artery. The bulbus cordis forms part of the ventricles. The sinus venosus connects to the fetal circulation. Septa form within the atria and ventricles to seperate the left and right sides of the heart.

Cardiac Neural Crest Cells

Neural crest cells are a population of multipotent cells which arises during embryonic development at the dorsal neural tube. These cells are capable of migrating and differentiating throughout the body to give rise to many different cell types. The cardiac neural crest cells (CNCCs) are a subpopulation of the cranial neural crest cells and migrate ventrally from the dorsal neural tube and accumulate in the circumpharyngeal ridge. PubmedParser error: Invalid PMID, please check. (PMID: [1]) The cardiac neural crest wells will then proceed into the pharyngeal arches as each arch develops.

Cardiac neural Cells can develop into:

  • Melanocytes near the heart region
  • neurons associated with cardiac innervation
  • cartilage
  • connective tissue (they form the connective tissue wall of the large arteries from the heart, as well as the septum between the branches in the heart)
  • provide signals required for the maintenance and differentiation of the other cell layers in the pharyngeal apparatus

Early Development

1. From neural crest to circumpharyngeal ridge

The cardiac neural crest is located caudally. The cells undergo an epithelial-to-mesenchymal transition, to emigrate from the neural tube, to the circumpharyngeal ridgePubmedParser error: Invalid PMID, please check. (PMID: [2]). Snail2 inhibits expression of cadherins. RhoA/B remodel the cytoskeleton of the cells for ready migration. CNCC express integrin and MMP-2 to break down ECM to go to the circumpharyngeal ridge.


2. Formation of pharyngeal arches and cardiac outflow tract

CNCC express different factors that target the cells to the pharyngeal arches. Slit cells can target cells to migrate to arch 3. FGF-8 targets for arch 4. EphA targets for arch 6. Rac1 and Sdf1 are both expressed in the cells, causing them to condensate around the arch arteries. Semaphorin is expressed and causes the cells to migrate further to the cardiac outflow tract. Notch and BMP are then expressed condensing the cells, forming the semilunar valve and aoticopulmonary septum.

  • The 3rd arch gives rise to the right common carotid and basal part of the left internal carotid.
  • The 4th arch gives rise to the segment of the aortic arch that connects the aortic sac to the descending aorta
  • The 6th arch gives rise to the ductus arteriosus (an embryonic structure that connects the pulmonary artery with the descending aorta). This shunt allows blood from the right ventricle to bypass the lungs because the fetal blood is oxygenated through the placenta. {{#pmid:https://www.sciencedirect.com/science/article/pii/S0070215314000076?via%3Dihub

3. Pharyngeal arch remodeling

The pharyngeal arch arteries are remodeled to form the aortic arch, subclavian and carotid arteries.

Later Development

Development of the heart in the fetus and partitioning of the heart into four chambers

Outflow Septation

The distal outflow tract (trunks) septets into the aorta and pulmonary trunk via the fusion of two streams or prongs of cardiac neural crest that migrate into the distal outflow tract.

--> https://pdfs.semanticscholar.org/42cc/ee7fbb545ea6752e1c126cc2769e8e33e7b7.pdf

three components are responsible for forming the septa in the outflow tract:

  1. conus septum
  2. truncus septum
  3. aorto-pulmonary septum

--> https://www.sciencedirect.com/science/article/pii/B9780124017306000120

Valvulogenesis

The cNCC also contribute to the aortic and pulmonary valves, thereby connecting the heart to the vascular system. OFT endothelial cells that have undergone endoMT are thought to give rise to the bulk of the semilunar valves, which form within the aorta and pulmonary artery, to prevent the back flow of blood into the ventricles. In addition, cardiac NCCs also colonize the semilunar valves, where they mainly contribute to the two leaflets adjacent to the aorticopulmonary septum. Cells of the NCC have also been found to contribute to the atrioventricular valves, consisting of the bicuspid(mitral) valve and tricuspid valve, which are located between the upper atria and the lower ventricles.

Atrial and Ventricular Separation

Signaling Molecules

  1. Wnt: extracellular growth factors that activate intracellular signaling pathways. Decrease of B-catenin results in a decrease in the proliferation of cardiac neural crest cells.
  2. Notch: a transmembrane protein whose signaling is required for differentiation of CNCCs to vascular smooth muscle cells and for proliferation of cardiac myocytes.
  3. BMP (bone morphogenetic proteins): they are required for neural crest cell migration into the cardiac cushions (=precursors to heart valves and septa) and for differentiation of neural crest cells to smooth muscle cells of the aortic arch arteries.
  4. FGF8(fibroblast growth factor 8): are essential for regulating the addition of secondary heart field cells into the cardiac outflow tract.
  5. GATA: play a critical role in cell lineage differentiation restriction during cardiac development.
  • Meis2 PubmedParser error: Invalid PMID, please check. (PMID: [3])

Developmental time course

neural crest migration starts week 3-4 day 22-28
cardiac neural crest migrates through the aortic arches and enters the outflow tract of the heart week 5-6, day 32-37
Outflow tract and ventricular septation complete week 9, day 57+


Human Congenital Heart Diseases associated with Neural Crest Cells

The loss of neural crest cells or their dysfunction may not always directly cause abnormal cardiovascular development, but are involved secondarily because crest cells represent a major component in the complex tissue interactions in the head, pharynx and outflow tract. [1]

Persistent Truncus Arteriosus

if the cardiac neural crest is removed before it begins to migrate, the conotruncal septa completely fails to develop, and blood leaves both the ventricles through what is termed a persistent truncus arteriosus, a rare congenital heart anomaly in humans.(Martinson)

Failure of outflow tract separation

Failure of outflow tract septation may also be responsible for other forms of congenital heart disease, including transposition of the great vessels, high ventricular septal defects, and tetralogy of Fallot (Martinson)

DiGeorge Syndrome and Velocardiofacial Syndrome

  • Caused by a chromosomal 22q11.2 deletion.
  • Characterized by interrupted aortic arch type B, outflow tract malformations that include xxx

[1]

CHARGE syndrome

  • Coloboma
  • Heart anomaly
  • Atresia of choanae
  • Retardation of physical and mental development
  • Genital hypoplasia
  • Ear anomalies and/or deafness

PubmedParser error: Invalid PMID, please check. (PMID: [4])


--> https://pdfs.semanticscholar.org/42cc/ee7fbb545ea6752e1c126cc2769e8e33e7b7.pdf

Current research/main animal models/future questions

  • Can cardiac neural crest cells be used to repair human heart tissue? They are basically neural crest stem cells. In 2005, Tomita transplanted neural crest cells from mammal hearts to the neural crest of chick embryos --> find more research for this
  • Main animal models are chick and mouse

Glossary

References

  1. 1.0 1.1 Keyte A & Hutson MR. (2012). The neural crest in cardiac congenital anomalies. Differentiation , 84, 25-40. PMID: 22595346 DOI.