2018 Group Project 4

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

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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

Cardiac Neural Crest Cells

File:Neural crest cells.jpg

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.

CNCCs are not critical in the initial formation of vessels but they are needed for the remodelling of subsequent arteries, and will give rise to the smooth muscle tunics of the great arteries.PubmedParser error: Invalid PMID, please check. (PMID: [2])

They have a function in remodeling: PubmedParser error: Invalid PMID, please check. (PMID: [3])

  • the pharyngeal arch arteries
  • outflow tract septation
  • valvulogenesis
  • development of the cardiac conduction system

The cells are also responsible for modulating signaling in the caudal pharynx, including the second heart field.

History of cardiac neural crest cells

CNCC was first discovered in a study carried out on chicks by Kirby et al., (1983), where it was discovered that by ablating a region of neural crest cells, embryos lacked aorticopulmonary septation. The subregion of cranial neural crest ablated by Dr. Kirby is now known as the “cardiac neural crest”, not because the cells of this region are dedicated to migrating to the heart, but rather for their importance in crest-derived ectomesenchyme of cardiovascular development. [1]

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

Cardiovascular System

Embryonic Origins/Embryonic Contributions

Cardiac neural crest cells can become:

  • melanocytes near the heart region
  • neurons associated with the heart
  • 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.

The heart mainly forms from the mesoderm, however cardiac neural crest cells play a crucial part in the development of the heart. CNCC are mixed in to the heart as the heart is forming. They form the septum and the arteries coming from the heart.

Cardiac Neural Crest Derivatives

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

Valvulogenesis

Atrial and Ventricular Separation

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+

Molecular and Cellular Mechanisms in Cardiac Crest Cell Migration

~~ z5229189

  1. Induction of CarNCCs and EMT
  • Cardiac neural crest cells undergo EMT
  • Snail2 inhibits expression of cadherins
  • RhoA/B remodel the cytoskeleton of the cells for ready migration
  1. Initial migration of cardiac neural crest cells
  • CNCC express integrin and MMP-2 to break down ECM to go to the circumpharyngeal ridge
  1. Pause in circumpharyngeal ridge
  • Cardiac neural crest cells stop migrating and briefly populate the circumpharyngeal ridge
  • The pharyngeal arches are still developing and must regress before migration can continue
  1. Migration into the pharyngeal arches and condensation around the arch arteries
  • Cardiac neural crest cells 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.
  1. Migration into the cardiac outflow tract and condensation
  • 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.

→ Cardiac Development, Kirby M., 2010

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. [2]

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

[2]

CHARGE

Fetal Alcohol

Alagille

LEOPARD

Noonan syndromes

Retinoic Acid Embryopathy


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

Current research/main animal models/future questions

Glossary

References

  1. Kirby ML & Stewart DE. (1983). Neural crest origin of cardiac ganglion cells in the chick embryo: identification and extirpation. Dev. Biol. , 97, 433-43. PMID: 6852374
  2. 2.0 2.1 Keyte A & Hutson MR. (2012). The neural crest in cardiac congenital anomalies. Differentiation , 84, 25-40. PMID: 22595346 DOI.