Cardiac neural crest: Difference between revisions

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{{Infobox embryology

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| Name = Cardiac neural crest complex

{{copy edit|date=December 2012}}

| Latin = complexus cristae neuralis cardiacus

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[[Neural crest cells]] are multipotent cells required for the development of cells, tissues and organ systems.<ref name="pmid17619792">{{Cite journal |vauthors=Snider P, Olaopa M, Firulli AB, Conway SJ |date=2007 |title=Cardiovascular development and the colonizing cardiac neural crest lineage |journal=The Scientific World Journal |volume=7 |pages=1090–1113 |doi=10.1100/tsw.2007.189 |pmc=2613651 |pmid=17619792 |doi-access=free}}</ref>

[[Neural crest]] cells are a group of temporary, [[Cell potency#Multipotency|multipotent]] (can give rise to some other types of cells but not all) cells that are pinched off during the formation of the [[neural tube]] (precursor to the [[spinal cord]] and brain) and therefore are found at the dorsal (top) region of the neural tube during development.<ref name ="kirby1987">{{cite journal|last=Kirby|first=M|title=Cardiac Morphogenesis--Recent Research Advances|journal=Pediatric Research|year=1987|volume=21|issue=3|pages=219–224|url=http://www.nature.com/pr/journal/v21/n3/pdf/pr198744a.pdf}}</ref> They are derived from the [[ectoderm]] germ layer, but are sometimes called the fourth germ layer because they are so important and give rise to so many other types of cells.<ref name="kirby1987" /><ref name= "gilbert">{{cite book|last=Gilbert|first=S.F.|title=Developmental Biology|year=2010|publisher=Sinauer Associates|___location=MA|pages=373–389|url=http://www.ncbi.nlm.nih.gov/books/NBK10065/}}</ref> They migrate throughout the body and create a large number of differentiated cells such as [[neuron]]s, glial cells, pigment-containing cells in skin, skeletal tissue cells in the head, and many more.<ref name="kirby1987" /><ref name="gilbert" />

A subpopulation of neural crest cells are the '''cardiac neural crest''' complex. This complex refers to the cells found amongst the midotic placode and somite 3 destined to undergo epithelial-mesenchymal transformation and migration to the heart via [[pharyngeal arches]] 3, 4 and 6.<ref name="pmid20890117">{{Cite journal |vauthors=Kirby ML, Hutson MR |date=2010 |title=Factors controlling cardiac neural crest cell migration |journal=Cell Adhesion & Migration |volume=4 |issue=4 |pages=609–621 |doi=10.4161/cam.4.4.13489 |pmc=3011257 |pmid=20890117}}</ref>

The cardiac neural crest complex plays a vital role in forming connective tissues that aid in outflow septation and modelling of the aortic arch arteries during early development.<ref name="pmid20890117" /> Ablation of the complex often leads to impaired myocardial functioning similar to symptoms present in [[DiGeorge syndrome]].<ref name="pmid17224285">{{Cite journal |vauthors=Hutson MR, Kirby ML |date=2007 |title=Model systems for the study of heart development and disease: cardiac neural crest and conotruncal malformations |journal=Seminars in Cell & Developmental Biology |volume=18 |issue=1 |pages=101–110 |doi=10.1016/j.semcdb.2006.12.004 |pmc=1858673 |pmid=17224285}}</ref> Consequently, the removal of cardiac crest cells that populate in pharyngeal arches has flow on effects on the [[thymus]], [[parathyroid]] and [[thyroid gland]].<ref name="pmid1185098">{{Cite journal |vauthors=Le Lièvre CS, Le Douarin NM |date=1975 |title=Mesenchymal derivatives of the neural crest: analysis of chimaeric quail and chick embryos |journal=Development |volume=34 |issue=1 |pages=124–154 |pmid=1185098}}</ref>

Cardiac neural crest cells (CNCCs) are a type of neural crest cells that migrate to the circumpharyngeal ridge (an arc-shape ridge above the [[pharyngeal arch]]es) and then into the 3rd, 4th and 6th pharyngeal arches and the cardiac outflow tract (OFT).<ref name="kirby1987" /><ref name="gilbert" /><ref name= "kur">{{cite journal|last=Kuratani|first=S.C.|coauthors=Kirby, M.L.|title=Migration and distribution of circumpharyngeal crest cells in the chick embryo. Formation of the circumpharyngeal ridge and E/C8+ crest cells in the vertebrate head region|journal=Anat. Rec.|date=Oct 1992|volume=234|issue=2|pages=263–268|pmid=1384396|doi=10.1002/ar.1092340213}}</ref> They extend from the [[otic placode]]s (the structure in developing embryos that will later form the ears) to the third [[somite]]s (clusters of [[mesoderm]] that will become skeletal muscle, vertebrae and dermis).<ref name="kirby1987" /><ref name="gilbert" />

[[Neural crest]] cells are a group of temporary, [[Cell potency#Multipotency|multipotent]] (can give rise to some other types of cells but not all) cells that are pinched off during the formation of the [[neural tube]] (precursor to the [[spinal cord]] and brain) and therefore are found at the dorsal (top) region of the neural tube during development.<ref name="Kirby (1987)">{{Cite journal |last=Kirby |first=Margaret L |year=1987 |title=Cardiac Morphogenesis—Recent Research Advances |url=https://www.nature.com/articles/pr198744.pdf |journal=Pediatric Research |publisher=Springer Science and Business Media LLC |volume=21 |issue=3 |pages=219–224 |doi=10.1203/00006450-198703000-00001 |pmid=3562119 |issn=0031-3998 |doi-access=free}}</ref> They are derived from the [[ectoderm]] germ layer, but are sometimes called the fourth germ layer because they are so important and give rise to so many other types of cells.<ref name="Kirby (1987)" /><ref name="Gilbert (2010)">{{Cite book |last=Gilbert |first=S. F. |title=Developmental biology |publisher=Sinauer Associates |year=2010 |isbn=978-0-87893-243-6 |edition=6th |___location=Massachusetts |pages=373–389 |chapter=The Neural Crest |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK10065/}}</ref> They migrate throughout the body and create a large number of differentiated cells such as [[neuron]]s, glial cells, pigment-containing cells in skin, skeletal tissue cells in the head, and many more.<ref name="Kirby (1987)" /><ref name="Gilbert (2010)" />

The cardiac neural crest cells:<ref name="kirby1987" /><ref name="gilbert" />

* create the muscular connective tissue walls of large arteries

* help create the septum in the heart

* form part of the [[thyroid]], [[Parathyroid gland|parathyroid]] and [[thymus]] glands

* develop into [[melanocytes]], neurons, [[cartilage]] and [[connective tissue]] of the pharyngeal arches they migrate into

* although not proven, likely create/help to create the carotid body which monitors oxygen in the blood and regulates respiration

Cardiac neural crest cells (CNCCs) are a type of neural crest cells that migrate to the circumpharyngeal ridge (an arc-shape ridge above the [[pharyngeal arch]]es) and then into the 3rd, 4th and 6th pharyngeal arches and the cardiac outflow tract (OFT).<ref name="Kirby (1987)" /><ref name="Gilbert (2010)" /><ref name="Kuratani (1992)">{{Cite journal |last1=Kuratani |first1=Shigeru C. |last2=Kirby |first2=Margaret L. |date=1992 |title=Migration and distribution of circumpharyngeal crest cells in the chick embryo |url=https://onlinelibrary.wiley.com/doi/10.1002/ar.1092340213 |journal=The Anatomical Record |volume=234 |issue=2 |pages=263–280 |doi=10.1002/ar.1092340213 |issn=0003-276X |pmid=1384396|url-access=subscription }}</ref>

== Pathway of a Migratory Cardiac Neural Crest Cell ==

[[File:CNCC migration.png|thumb|Migration of Cardiac Neural Crest Cells. They begin as part of the neural crest and become more specialized after reaching their final destination, where they become either the vascular smooth muscle cells of the outflow tract or the cardiac neurons.]]

They extend from the [[otic placode]]s (the structure in developing embryos that will later form the ears) to the third [[somite]]s (clusters of [[mesoderm]] that will become skeletal muscle, vertebrae and dermis).<ref name="Kirby (1987)" /><ref name="Gilbert (2010)" />

The cardiac neural crest cells have a number of functions including creation of the muscle and [[connective tissue]] walls of large arteries; parts of the cardiac [[septum]]; parts of the [[thyroid]], [[Parathyroid gland|parathyroid]] and [[thymus]] glands. They differentiate into [[melanocytes]] and neurons and the [[cartilage]] and [[connective tissue]] of the pharyngeal arches. They may also contribute to the creation of the carotid body, the organ which monitors oxygen in the blood and regulates breathing.<ref name="Kirby (1987)" /><ref name="Gilbert (2010)" />

== Pathway of the migratory cardiac neural crest cell ==

[[File:CNCC migration.png|thumb|right|200px|Migration of cardiac neural crest cells. CNCCs begin as part of the neural crest and become more specialized after reaching their final destination.]]

=== Induction ===

The[[Neural progenitorsinduction]] (thoseis the differentiation of progenitor cells thatinto their final designation or type. The progenitor cells which will become CNCCs), are found in the [[epiblast]] aroundabout [[Primitive knot|Henson’sHenson's node]].<ref name="kurKuratani (1992)" /><ref name ="Kirby "kirby2010(2010)">{{citeCite journal |lastlast1=Kirby |firstfirst1=M.KMargaret L. |coauthorslast2=Hutson, M.|first2=Mary R. |year=2010 |title=Factors controlling cardiac neural crest cell migration |journal=Cell Adhesion and& Migration |datepublisher=DecemberInforma UK Limited 2010|volume=4 |issue=4 |pages=609–621 |urldoi=http:10.4161//wwwcam.ncbi4.nlm4.nih.gov/pmc/articles/PMC3011257/pdf/cam0404_0609.pdf13489 |issn=1933-6918 |pmc=3011257 |pmid=20890117 |doi-access=free}}</ref> The progenitorProgenitor cells are brought into the [[neural fold]]s. and moleculesMolecules such as [[Wnt signaling pathway|Wnt]], [[fibroblast growth factor]] (FGF) and [[bone morphogenetic protein]] (BMP) provide [[signalingRecognition signal|signalssignal]]s which induce themthe progenitor cells to become CNCCs.<ref name="kurKuratani (1992)" /><ref name="kirby2010Kirby (2010)" /> Little is known about the signalingsignal cascades (activities)cascade that allowpromotes neural crest induction to occur. However, it is known that an intermediate level of BMP is required: if BMP is too high or too low, the cells do not migrate.<ref name="kirby2010Kirby (2010)" />

=== Initial Migrationmigration ===

After induction, the CNCCs lose their cell- to cell contacts,. whichThis allows them to interactmove withthrough the [[extracellular matrix]] components.<refand name="kur"interact /><refwith name="kirby2010"its />components. The extracellularCNCCs, membrane provides an environment in whichwith the cellsassistance canof move and allows them to leave the neural tube and migrate to where they need to be.<ref name="kur" /><ref name="kirby2010" /> They also havetheir [[filopodia]] and [[Lamellipodium|lamellipodia]] ([[actin]] containing extensions of [[cytoplasm]] that helpallow thema cell to move.<refprobe name="kirby2010"its />path of Theymigration), thenleave the neural tube and migrate followalong a [[dorsolateral]] pathway to the circumpharyngeal ridge.<ref name="kirby1987Kirby (1987)" /><ref name="gilbertGilbert (2010)" /><ref name="kurKuratani (1992)" /> Along Thethis cellspathway, CNCCs link together to form a stream of migrating cells and stretch from the neural tube to other CNCCs migrating to the circumpharyngeal ridge.<ref name="kirby2010" /> Cells at the front of the migration stream have a special [[polygonal]] shape and they proliferate at a much faster rate than trailing cells.<ref name="kirby2010Kirby (2010)" />

==Development==

=== Pause in Circumpharyngeal Ridge ===

The cardiac neural crest originates from the region of cells between somite 3 and the midotic placode that migrate towards and into the cardiac outflow tract.<ref name="pmid2197017">{{Cite journal |vauthors=Le Lièvre CS, Le Douarin NM |date=1990 |title=Role of neural crest in congenital heart disease |journal=Circulation |volume=82 |issue=2 |pages=332–340 |doi=10.1161/01.CIR.82.2.332 |pmid=2197017 |doi-access=free }}</ref>

Once the CNCCs make it to the circumpharyngeal arch they have to pause their migration temporarily and wait for the pharyngeal arches to form.<ref name="kirby1987" /><ref name="gilbert" /><ref name="kur" /><ref name="kirby2010" />

The cells migrate from the neural tube to populate pharyngeal arches 3, 4 and 6 with the largest population of the outflow tract originating from those in pharyngeal arches 4.<ref name="pmid20890117" />

From here, a subpopulation of cells will develop into the endothelium of the [[aortic arch]] arteries while others will migrate into the outflow tract to form the aorticopulmonary and truncal septa.<ref name="pmid20890117" /><ref name="pmid18005956">{{Cite journal |vauthors=Bajolle F, Zaffran S, Meilhac SM, Dandonneau M, Chang T, Kelly RG |date=2008 |title=Myocardium at the base of the aorta and pulmonary trunk is prefigured in the outflow tract of the heart and in subdomains of the second heart field |journal=Developmental Biology |volume=313 |issue=1 |pages=25–34 |doi=10.1016/j.ydbio.2007.09.023 |pmid=18005956}}</ref> Other ectomesenchymal cells will form the thymus and parathyroid glands.<ref name="pmid6606851">{{Cite journal |vauthors=Bockman DE, Kirby ML |date=1984 |title=Dependence of thymus development on derivatives of the neural crest |journal=Science |volume=223 |issue=4635 |pages=498–500 |bibcode=1984Sci...223..498B |doi=10.1126/science.6606851 |pmid=6606851}}</ref>

===Epithelial-mesenchymal transition===

=== Migration into the Pharyngeal Arches ===

Prior to migration, during a process known as [[epithelial-mesenchymal transition]] (EMT), there is a loss of cell contact, remodelling of the [[cytoskeleton]] and increased motility and interaction with extracellular components in the matrix.<ref name="pmid8714286">{{Cite journal |vauthors=Hay ED |date=1995 |title=An overview of epithelio-mesenchymal trans-formation |journal=Acta Anatomica |volume=154 |issue=1 |pages=8–20 |doi=10.1159/000147748 |pmid=8714286 }}</ref> An important step in this process is the suppression of adhesion protein [[E-cadherin]] present on [[epithelial cells]] to initiate the migration process. This suppression mechanism occurs via the [[growth factor]] BMP signalling to turn on a transcriptional repressor Smad-interacting protein 1 (Sip1) and marks the beginning of the epithelial-mesenchymal transition.<ref name="pmid11430829">{{Cite journal |vauthors=Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, Mareel M, Huylebroeck D, van Roy F |date=2007 |title=The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion |journal=Molecular Cell |volume=7 |issue=6 |pages=1267–1278 |doi=10.1016/S1097-2765(01)00260-X |pmid=11430829 |doi-access=free}}</ref>

Once the pharyngeal arches have developed, the cranial neural crest cells continue their migration into the pharyngeal arches, specifically the 3rd, 4th and 6th.<ref name="kirby1987" /><ref name="gilbert" /><ref name="kur" /> The leading cells have long filopodia that aid the migration.<ref name="kirby2010" /> Cells in the middle have protrusions at the front and back to allow them to interact and communicate with leading and trailing cells as well as interact and receive signals from the extracellular environment.<ref name="kirby2010" /> A variety of growth factors and transcription factors signal to the cells and target them towards a specific arch.<ref name="kirby2010" /> For example, FGF8 helps to signal cells towards pharyngeal arch 4 and helps keep them viable.<ref name="kirby2010" /> As mentioned before, the neural crest cells that migrate to the arches help form the thyroid and parathyroid glands.<ref name="kirby1987" /><ref name="gilbert" /><ref name="kur" />

===Early migration===

=== Migration into the Cardiac Outflow and Proximal Outflow ===

During migration, crest cells destined for pharyngeal arches maintain contact with each other via [[lamellipodia]] and [[filopodia]]. Short range local contact is maintained with lamellipodia whilst long range non-local contact is maintained with filopodia.<ref name="pmid15548586”">{{Cite journal |vauthors=Teddy JM, Kulesa PM |date=2004 |title=In vivo evidence for short-and long-range cell communication in cranial neural crest cells |journal=Development |volume=131 |issue=24 |pages=6141–6151 |doi=10.1242/dev.01534 |pmid=15548586}}</ref> During this process, [[connexin 43]] (Cx43) regulates cell interaction by regulating the formation of channels known as [[gap junctions]].<ref name="pmid17619792" /> Impaired Cx43 function in transgenic mice leads to altered coronary artery patterns and abnormal outflow tracts.<ref name="pmid9640330">{{Cite journal |vauthors=Huang GY, Wessels A, Smith BR, Linask KK, Ewart JL, Lo CW |date=1998 |title=Alteration in connexin 43 gap junction gene dosage impairs conotruncal heart development |journal=Developmental Biology |volume=198 |issue=1 |pages=32–44 |doi=10.1006/dbio.1998.8891 |pmid=9640330 |doi-access=free}}</ref> Further gap junction signalling is dependent on a [[cadherin]] mediated cell adhesion formed during cross talking with p120 catenin signalling.<ref name="pmid11449002">{{Cite journal |vauthors=Xu X, Li WE, Huang GY, Meyer R, Chen T, Luo Y, Thomas MP, Radice GL, Lo CW |date=2001 |title=Modulation of mouse neural crest cell motility by N-cadherin and connexin 43 gap junctions |journal=Journal of Cell Biology |volume=154 |issue=1 |pages=217–230 |doi=10.1083/jcb.200105047 |pmc=2196865 |pmid=11449002}}</ref>

The cardiac outflow tract is a temporary structure in a developing embryo that connects the ventricles with the [[aortic sac]].<ref name="gilbert" /><ref name="kur" /> Some cells further migrate to the cardiac outflow instead of the pharyngeal arches.<ref name="kirby1987" /><ref name="kur" /><ref name="kirby2010" /> The cardiac neural crest in the outflow tract creates cardiac [[Ganglion

ganglia]] and [[mesenchyme]] at the junction of the subaortic and sub pulmonary myocardium (muscular heart tissue) of the outflow tract.<ref name="kirby2010" /> A small amount of CNCCs also migrates further into the proximal outflow tract where they help to close the ventricular outflow septum.<ref name="kirby1987" /><ref name="kur" />

Appropriate outflow tract formation relies on a [[morphogen]] concentration gradient set up by [[fibroblast growth factor]] (FGF) secreting cells. Cardiac crest cells furthest away from FGF secreting cells will receive lower concentrations of FGF8 signalling than cells closer to FGF secreting cells. This allows for appropriate formation of the outflow tract.<ref name="pmid12223417">{{Cite journal |vauthors=Abu-Issa R, Smyth G, Smoak I, Yamamura K, Meyers EN |date=2002 |title=Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse |journal=Development |volume=129 |issue=19 |pages=4613–4625 |doi=10.1242/dev.129.19.4613 |pmid=12223417}}</ref> Cells located in rhombomeres 3and 5 undergo programmed cell death under signalling cues from [[semaphorins]]. The lack of cells in this region results in the formation of crest-free zones.<ref name="pmmid18625214">{{Cite journal |vauthors=Toyofuku T, Yoshida J, Sugimoto T, Yamamoto M, Makino N, Takamatsu H, Takegahara N, Suto F, Hori M, Fujisawa H, Kumanogoh A, Kukutani H |date=2007 |title=Repulsive and attractive semaphorins cooperate to direct the navigation of cardiac neural crest cells |journal=The Scientific World Journal |volume=7 |issue=1 |pages=1090–1113 |doi=10.1016/j.ydbio.2008.06.028 |pmid=18625214}}</ref>

== Molecular Pathways ==

The CNCCs are required for the formation of the [[aorticopulmonary septum]] (APS) that separates the cardiac outflow into the pulmonary trunk and the aorta in normal heart development. This remodeling of the OFT requires the reciprocal signaling between CNCCs and cardiogenic mesoderm. Cardiovascular dysfunction can result either from a disruption in this signaling or defects in cardiac neural crest cells. The CNCCs interact with the cardiogenic mesoderm cells of the primary and secondary heart fields, which are derived from the cardiac crescent and will give rise to the [[endocardium]], myocardium, and [[epicardium]].<ref name=Pompa2012>{{cite journal|last=de la Pompa|first=J.L.|coauthors=Epstein, JA|title=Coordination Tissue Interactions: Notch Signalling in Cardiac Development and Disease|journal=Developmental Cell|date=|year=2012|month=February|volume=22|issue=2|pages=244–264|doi=10.1016/j.devcel.2012.01.014|accessdate=November 19, 2012}}</ref> The CNCCs themselves are the precursors to vascular smooth muscle cells and cardiac neurons.<ref name=Brown2006>{{cite journal|last=Brown|first=Christopher|coauthors=Baldwin, H|title=Neural Crest Contribution to the Cardiovascular System|journal=Advances in Experimental Medicine|year=2006|volume=589|pages=134–154|doi=10.1007/978-0-387-46954-6_8|accessdate=November 19, 2012}}</ref> Common defects related to CNCCs can result in congenital heart malformations such as [[persistent truncus arteriosus]] (PTA), [[double outlet right ventricle]] (DORV), [[tetralogy of Fallot]] and [[DiGeorge syndrome]].

The process of migration requires a permissive extracellular matrix.<ref name="pmid20890117" /> The [[enzyme]] [[arginyltransferase]] creates this environment by adding an arginyl group onto newly synthesised proteins during [[post-translational modification]].<ref name="pmid20300656">{{Cite journal |vauthors=Kurosaka S, Leu NA, Zhang F, Bunte R, Saha S, Wang J, Guo C, He W, Kashina A |date=2010 |title=Arginylation-dependent neural crest cell migration is essential for mouse development. |journal=PLOS Genetics |volume=6 |issue=3 |pages=e1000878 |doi=10.1371/journal.pgen.1000878 |pmc=2837401 |pmid=20300656 |doi-access=free }}</ref> This process aids cells motility and ensures the proteins contained within the actin cytoskeleton is prepped for migration.<ref name="pmid20890117" />

Many signaling molecules are required for the differentiation, proliferation, migration and [[apoptosis]] of the CNCCs. The major molecular pathways involve members of the [[Wnt signaling pathway|Wnt]], [[Notch signaling pathway|Notch]], [[Bone Morphogenetic Protein|BMP]], [[FGF8]] and [[GATA transcription factor|GATA]] families. In addition to these signaling pathways, these processes are also mediated by environmental factors including blood flow, shear stress, and blood pressure.<ref name=Niessen2008 />

===Circumpharyngeal ridge===

Cell migration towards the circumpharyngeal ridge is forced to paused to allow for the formation of the caudal pharyngeal arches.<ref name="pmid20890117" /> Little is known about this pausing mechanism, but studies conducted in chicks have uncovered the role of [[mesoderm]] expressed factors EphrinB3 and EphrinB4 in forming fibronectin attachments.<ref name="pmid12117812">{{Cite journal |vauthors=Santiago A, Erickson CA |date=2002 |title=Ephrin-B ligands play a dual role in the control of neural crest cell migration |journal=Development |volume=129 |issue=15 |pages=3621–3623 |doi=10.1242/dev.129.15.3621 |pmid=12117812}}</ref>

===Caudal pharynx and arch artery condensation===

Pharyngeal arches are tissues composed of mesoderm-derived cells enclosed by an external [[ectoderm]] and an internal [[endoderm]].<ref name="pmid20890117" /> Once the caudal pharyngeal arches are formed, cardiac neural crest complexes will migrate towards these and colonise in arches 3, 4 and 6. Cells leading this migration maintain contact with the extracellular matrix and contain filopodia which act as extensions towards the ectodermal pharyngeal arches.<ref name="pmid20890117" /><ref name="pmid15548586”" /> A range of secreted factors ensure appropriate directionality of the cells. FGF8 acts as a chemotactic attraction in directing cellular movement towards pharyngeal arch 4.<ref name="pmid17619792" /><ref name="pmid15548586”" />

A second signalling pathway that directs crest cell movement are the family of endothelin ligands. Migrating cardiac neural crest cells will populate at the correct pharyngeal arches under signalling guidance from EphrinA and Ephrin B variations. This corresponds with receptor expression at the pharyngeal arches. Pharyngeal arch 3 expresses EphrinA and EphrinB1 receptors and pharyngeal arch 2 expresses EphrinB2 and allows for the binding of EphrinA and EphrinB variations to guide migration of the cardiac neural crest cells.<ref name="pmid20890117" />

===Aortic arch remodeling===

The aortic arch arteries transport blood from the [[aorta]] to the head and trunk of the [[embryo]].<ref name="pmid9558464">{{Cite journal |vauthors=Creazzo TL, Godt RE, Leatherbury L, Conway SJ, Kirby ML |date=1998 |title=Role of cardiac neural crest cells in cardiovascular development |journal=Annual Review of Physiology |volume=60 |issue=1 |pages=267–286 |doi=10.1146/annurev.physiol.60.1.267 |pmid=9558464}}</ref> Normally, early development of the outflow tract begins with a single vessel that forms bilateral symmetrical branches at the aortic sac within pharyngeal arches. This process requires the elongation of the outflow tract as a prerequisite to ensure the correct series of looping and cardiac alignment.<ref name="pmid17619792" /> The cardiac neural crest complex then colonises in the truncal cushion and is localised to the subendothelial layer prior to spiralisation of the endocardial cushion to form the conotruncal ridges. This later undergoes remodelling to form the left-sided aortic pattern present in adult hearts.<ref name="pmid17619792" /> The group of cells found in the third aortic arch gives rise to common [[carotid arteries]]. Cells found in the fourth aortic arch differentiates to form the distal aortic arch and right [[subclavian artery]], whilst cells in the sixth aortic arch develops into the [[pulmonary arteries]]. Cardiac neural crest cells express ''Hox'' genes that supports the development of arteries 3, 4 and 6 and the simultaneous regression of arteries 1 and 2. The ablation of ''Hox'' genes on cardiac neural crest cells causes defective outflow septation.<ref name="pmid9558464" />

==Ablation of cardiac neural crest complex==

[[File:Common abnormalities that arises during cardiac neural crest differentiation.png|thumb|A comparison between normal development and common abnormalities that arises during cardiac neural crest differentiation]]

===Cardiac outflow anomalies===

One of the main cardiac outflow anomalies present during cardiac neural crest complex ablation is [[persistent truncus arteriosus]].<ref name="pmid2197017" /> This arises when the arterial trunk fails to divide and cause the separation of [[pulmonary artery]] and aorta.<ref name="pmid17619792" /> This results in a lack of aorticopulmonary septum as the vessels which would normally disappear during normal development remains and interrupts the carotid vessels.<ref name="pmid2197017" /> The malformation of the heart and its associated great vessels depends on the extent and ___location of the cardiac neural crest complex ablation.<ref name="pmid2197017" /> Complete removal of cardiac neural crests results in persistent truncus arteriosus characterised in most cases by the presence of just one outflow valve and a ventricular septal defect.<ref name="pmid10946058">{{Cite journal |vauthors=van den Hoff MJ, Moorma AF |date=2000 |title=Cardiac neural crest: the holy grail of cardiac abnormalities? |journal=Cardiovascular Research |volume=47 |issue=2 |pages=212–216 |doi=10.1016/s0008-6363(00)00127-9 |pmid=10946058 |doi-access=free}}</ref> Mesencephalic neural crest cells interfere with normal development of cardiac outflow septation as its presence leads to persistent truncus arteriosus.<ref name="pmid2744240">{{Cite journal |vauthors=Kirby ML |date=1989 |title=Plasticity and predetermination of mesencephalic and trunk neural crest transplanted into the region of the cardiac neural crest |journal=Developmental Biology |volume=134 |issue=2 |pages=402–412 |doi=10.1016/0012-1606(89)90112-7 |pmid=2744240}}</ref> However, the addition of trunk neural crest cells results in normal heart development.<ref name="pmid2197017" />

Other outcomes of cardiac outflow anomalies includes [[Tetralogy of Fallot]], Eisenmenger's complex, transposition of the great vessels and double outlet right ventricle.<ref name="pmid2197017" />

===Aortic arch arteries anomalies===

[[Overriding aorta]] is caused by the abnormal looping during early development of the heart and is accompanied with ventricular septal defects.<ref name="pmid17224285" /> Instead of abnormal formation of the aorticopulmonary septum, partial removal of cardiac neural crest results in an overriding aorta, whereby the misplacement of the aorta is found over the ventricular [[septum]] as opposed to the left ventricle.<ref name="pmid10946058" /> This results in a reduction of oxygenated blood as the aorta receives some deoxygenated blood from the flow of the [[right ventricle]]. There is a reduction in the quantity of endothelial tubes of [[ectomesenchyme]] in pharyngeal arches that surround the aortic arch arteries.<ref name="pmid2197017" />

Other outcomes of aortic arch artery anomalies includes a double aortic arch, variable absence of the carotid arteries and left aortic arch.<ref name="pmid2197017" />

===Functional changes to the heart===

Functional changes to the heart becomes apparent well before structural changes are observed in the phenotype of ablated chicks. This is due to the embryo compromising morphological changes to the heart to maintain cardiac functioning via [[vasodilation]]. Despite an increase in embryonic [[stroke volume]] and [[cardiac output]], this compensation of decreased contraction results in misalignment of the development vessels due to incomplete looping of the cardiac tube.<ref name="pmid2197017" />

In an adult heart, myocardium contraction occurs via [[excitation-contraction coupling]] whereby cellular [[depolarisation]] occurs and allows an influx of calcium via [[voltage-gated calcium channels]]. A subsequent reuptake of calcium into the [[sarcoplasmic reticulum]] causes a decrease in intracellular calcium to cause myocardium relaxation.<ref name="pmid9558464" /> The removal of the cardiac neural crest complex causes a reduction in contractility of the myocardium. In embryos containing persistent truncus arteriosus, there is a significant 2-fold reduction in calcium currents, thereby interrupting the cardiac excitation-contraction coupling process to cause a reduction in contractility.<ref name="pmid2197017" /><ref name="pmid9558464" />

===Pulmonary venous system===

During [[cardiogenesis]], migration of the cardiac neural crest complex occurs prior to the development of the pulmonary system. There is no visible difference in the pulmonary veins of chick embryos that developed persistent truncus arteriosus and embryos with an intact cardiac neural crest complex. Ablation of the cardiac neural crest complex do not play a role in the systemic or pulmonary venous system as no visible venous defects is observed.<ref name="pmid2923280">{{Cite journal |vauthors=Phillips III MT, Waldo K, Kirby ML |date=1989 |title=Neural crest ablation does not alter pulmonary vein development in the chick embryo. |journal=The Anatomical Record |volume=223 |issue=3 |pages=292–298 |doi=10.1002/ar.1092230308 |pmid=2923280 |s2cid=11552278 }}</ref>

===Derivative development===

Due to its population in pharyngeal arches, removal of the cardiac neural crest complex has flow on effects on the thymus, parathyroid and thyroid gland.<ref name="pmid6606851" />

==Location==

Into the [[pharyngeal arches]] and [[Truncus arteriosus (embryology)]], forming the [[aorticopulmonary septum]]<ref name="pmid10725237">{{Cite journal |vauthors=Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM |date=April 2000 |title=Fate of the mammalian cardiac neural crest |url=http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=10725237 |journal=Development |volume=127 |issue=8 |pages=1607–16 |doi=10.1242/dev.127.8.1607 |pmid=10725237 |url-access=subscription}}</ref> and the [[smooth muscle]] of [[great arteries]].

Anterior of the aorta to become the four [[pre-aortic ganglia]]: ([[celiac ganglion]], [[superior mesenteric ganglion]], [[inferior mesenteric ganglion]] and [[aortical renal ganglia]]).

=== Pause at the circumpharyngeal ridge ===

At the circumpharyngeal arch the CNCCs must pause in their migration while the pharyngeal arches form.<ref name="Kirby (1987)" /><ref name="Gilbert (2010)" /><ref name="Kuratani (1992)" /><ref name="Kirby (2010)" />

=== Migration to the pharyngeal arches ===

The CNCCs continue their migration into the newly formed pharyngeal arches, particularly the third, fourth and sixth arches. In the pharyngeal arches the CNCCs assist in the formation of the thyroid and parathyroid glands.<ref name="Kirby (1987)" /><ref name="Gilbert (2010)" /><ref name="Kuratani (1992)" />

The leading cells have long filopodia that assist migration while cells in the middle of the migration have protrusions at their front and back allowing them to interact and communicate with leading cells, trailing cells and receive signals from the extracellular matrix.<ref name="Kirby (2010)" />

A variety of [[growth factor]]s and [[transcription factor]]s in the extracellular matrix signal cells and direct them toward a specific arch.<ref name="Kirby (2010)" /> For example, signalling by [[Fibroblast growth factor|FGF8]] directs CNCCS to the fourth arch and keeps the cells viable.<ref name="Kirby (2010)" />

=== Migration to the cardiac outflow tract ===

{{anchor|Cardiac outflow tract}}The '''cardiac outflow tract''' is a temporary structure in the developing embryo that connects the ventricles with the [[aortic sac]]. Some CNCCs migrate beyond the pharyngeal arches to the cardiac outflow tract.<ref name="Kirby (1987)" /><ref name="Kuratani (1992)" /><ref name="Kirby (2010)" /> CNCCS in the cardiac outflow tract contribute to the formation of the cardiac [[Ganglion|ganglia]] and [[mesenchyme]] at the junction of the [[aorta|subaortic]] and sub pulmonary [[myocardium]] (muscular heart tissue) of the outflow tract.<ref name="Kirby (2010)" /> A smaller portion of the CNCCs migrate to the proximal outflow tract where they help to close the ventricular outflow septum.<ref name="Kirby (1987)" /><ref name="Kuratani (1992)" />

== Molecular pathways ==

Many signaling molecules are required for the differentiation, proliferation, migration and [[apoptosis]] of the CNCCs. The molecular pathways involved include the [[Wnt signaling pathway|Wnt]], [[Notch signaling pathway|Notch]], [[Bone Morphogenetic Protein|BMP]], [[FGF8]] and [[GATA transcription factor|GATA]] families of molecules. In addition to these signaling pathways, these processes are also mediated by environmental factors including blood flow, shear stress, and blood pressure.<ref name="Niessen (2008)" />

The CNCCs interact with the cardiogenic mesoderm cells of the primary and secondary heart fields, which are derived from the cardiac crescent and will give rise to the [[endocardium]], myocardium, and [[epicardium]]. The CNCCs themselves are the precursors to vascular smooth muscle cells and cardiac neurons.<ref name="Brown (2006)">{{Cite book |last1=Brown |first1=Christopher B. |chapter-url=http://link.springer.com/10.1007/978-0-387-46954-6_8 |title=Neural Crest Induction and Differentiation |last2=Baldwin |first2=H. Scott |date=2006 |publisher=Springer US |isbn=978-0-387-35136-0 |volume=589 |publication-place=Boston, MA |pages=134–154 |chapter=Neural Crest Contribution to the Cardiovascular System |series=Advances in Experimental Medicine and Biology |doi=10.1007/978-0-387-46954-6_8 |pmid=17076279 }}</ref>

For example, CNCCs are required for the formation of the [[aorticopulmonary septum]] (APS) that directs cardiac outflow into two tracts: the pulmonary trunk and the aorta of the developing heart. This is an example of [[remodelling]] which is dependent on signalling back and forth between CNCCs and the [[cardiogenic]] [[mesoderm]]. If this signalling is disrupted or there are defects in the CNCCS, cardiovascular anomalies may develop. These anomalies include [[persistent truncus arteriosus]] (PTA), [[double outlet right ventricle]] (DORV), [[tetralogy of Fallot]] and [[DiGeorge syndrome]].<ref name="Pompa (2012)">{{Cite journal |last1=de la Pompa |first1=José Luis |last2=Epstein |first2=Jonathan A. |date=2012 |title=Coordinating Tissue Interactions: Notch Signaling in Cardiac Development and Disease |url=https://www.cell.com/article/S1534580712000482/pdf |journal=Developmental Cell |volume=22 |issue=2 |pages=244–254 |doi=10.1016/j.devcel.2012.01.014 |pmc=3285259 |pmid=22340493 |doi-access=free}}</ref>

=== Wnt ===

Wnt proteins are extracellular [[growth factorsfactor]]s that activate different intracellular signalingsignalling branchespathways.<ref name="gessert">{{cite journal|last=Gessert|first=S|coauthors=Kuhl M|title=The multiple phases and faces of wnt signaling during cardiac differentiation and development.|journal=Circulation Research|year=2010|volume=107|pages=186–199|doi=10.1161/CIRCRESAHA.110.221531|url=http://circres.ahajournals.org/content/107/2/186.full|accessdate=19 November 2012|issue=2}}</ref> There are two types of pathways: canonical and non-canonical.<ref name="gessert" /> The classic canonical Wnt pathway involves [[Beta-catenin|Bβ-catenin]] protein as a signaling mediator.<ref name="gessert" /> Wnt maintains Bβ-catenin by preventing against [[Proteasome]] degradation.<ref name="gessert" /> Thus, Bβ-catenin is stabilized in the presence of Wnt and regulates gene transcription through interaction with TCF/LEF transcription factors.<ref name="gessertGessert (2010)">{{Cite journal |last1=Gessert |first1=Susanne |last2=Kühl |first2=Michael |date=2010-07-23 |title=The Multiple Phases and Faces of Wnt Signaling During Cardiac Differentiation and Development |url=https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.110.221531 |journal=Circulation Research |volume=107 |issue=2 |pages=186–199 |doi=10.1161/CIRCRESAHA.110.221531 |pmid=20651295 |issn=0009-7330|url-access=subscription }}</ref> The canonical Wnt/Bβ-catenin pathway is important for Proliferation|control of cell proliferation control.<ref name="kirby2010Kirby (2010)2">{{citeCite journal |lastlast1=Kirby |firstfirst1=MLMargaret L. |coauthorslast2=Hutson MR|first2=Mary R. |date=2010 |title=Factors controlling cardiac neural crest cell migration |journal=Cell adhesionAdhesion and& migration|date=DecemberMigration 2010|volume=4 |issue=4 |pages=609–621 |doi=http://dx.doi.org/10.4161/cam.4.4.13489 |accessdateissn=201933-6918 November|pmc=3011257 2012|pmid=20890117 |doi-access=free}}</ref> The non-canonical Wnt pathway is independent of Bβ-catenin and has an inhibitory effect on canonical Wnt signaling.<ref name="gessertGessert (2010)" />

Wnt signaling pathways play a role in CNCC development as well as OFT development.<ref name="gessertGessert (2010)" /> In mice, decrease of Bβ-catenin results in a decrease in the proliferation of CNCCs.<ref name="gessertGessert (2010)" /> Downregulation of the Wnt coreceptor [[Lrp6]] leads to a reduction of CNCCs in the dorsal neural tube and in the pharyngeal arches, and results in ventricular, septal, and OFT defects.<ref name="gessertGessert (2010)" /> Canonical Wnt signaling is especially important for cell cycle regulation of CNCC development and the initiation of CNCC migration.<ref name="gessertGessert (2010)" /> Non-canonical Wnt signaling plays a greater role in promoting cardiac differentiation and OFT development.<ref name="gessertGessert (2010)" />

=== Notch ===

[[Notch proteins|Notch]] is a transmembrane protein whose signaling is required for differentiation of CNCCs to vascular [[smooth muscle]] cells.<ref name=Niessen2008>{{citeand journal|last=Niessen|first=Kyle|coauthors=Alyfor Karsan|title=Notchproliferation Signalingof incardiac Cardiac[[myocytes]] Development|journal=Circulation(muscle Research|year=2008|volume=102|pages=1169–1181|doi=10.1161/CIRCRESAHA.108.174318|pmid=18497317}}</ref>cells Furthermore, Notch is required forof the proliferation of cardiomyocytesheart).<ref name=Niessen2008 /> In mice, disruption of Notch signaling results in the neural crest in aortic arch branching defects and pulmonary stenosis, as well as a defect in the development of the smooth muscle cells of the sixth aortic arch artery, which is the precursor to the pulmonary artery.<ref name=Niessen2008"Niessen (2008)">{{Cite journal |last1=Niessen |first1=Kyle |last2=Karsan |first2=Aly |date=2008-05-23 |title=Notch Signaling in Cardiac Development |journal=Circulation Research |volume=102 |issue=10 |pages=1169–1181 |doi=10.1161/CIRCRESAHA.108.174318 |issn=0009-7330 |pmid=18497317 |doi-access=free}}</ref> In humans, mutations in Notch most often result in bicuspid aortic valve disease and calcification of the aortic valve.<ref name="Garg (2005)">{{citeCite journal |lastlast1=Garg |firstfirst1=VVidu |coauthorslast2=Muth AN,|first2=Alecia N. |last3=Ransom JF,|first3=Joshua F. |last4=Schluterman MK,|first4=Marie K. |last5=Barnes R,|first5=Robert |last6=King IN,|first6=Isabelle N. |last7=Grossfeld PD,|first7=Paul D. |last8=Srivastava D|first8=Deepak |date=2005-07-17 |title=Mutations in NOTCH1 cause aortic valve disease |journal=Nature |datepublisher=SeptemberSpringer Science and Business Media LLC 2005|volume=437 |issue=7056 |pages=270–274 |urldoi=http://www10.nature.com/nature/journal/v437/n7056/full1038/nature03940.html |accessdatepmid=2016025100 November 2012|doibibcode=102005Natur.1038/nature03940437..270G |issn=0028-0836}}</ref>

=== Bone Morphogeneticmorphogenetic Proteins (BMPs)proteins ===

[[Bone morphogenetic protein]]s (BMPs) 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. In neural crest–specific Alk2-deficient embryos, the cardiac cushions of the outflow tract are deficient in cells because of defects in neural crest cell migration.<ref name=Kaartinen2004"Kaartinen (2004)">{{citeCite journal |lastlast1=Kaartinen |firstfirst1=VVesa |coauthorslast2=Dudas M,|first2=Marek |last3=Nagy A,|first3=Andre |last4=Sridurongrit S,|first4=Somyoth |last5=Lu MM,|first5=Min Min |last6=Epstein JA|first6=Jonathan A. |date=2004-07-15 |title=Cardiac outflow tract defects in mice lacking ALK2 in neural crest cells |url=https://journals.biologists.com/dev/article/131/14/3481/52362/Cardiac-outflow-tract-defects-in-mice-lacking-ALK2 |journal=Development|date=July 2004|volume=131 |issue=14 |pages=3481–90|accessdate=193481–3490 November 2012|pmid=15226263|doi=10.1242/dev.01214 |issn=1477-9129 |pmid=15226263|url-access=subscription }}</ref>

=== FGF8Fibroblast growth factor 8 ===

[[Fibroblast growth factor 8]] (FGF8) transcription factors are essential for regulating the addition of secondary heart field cells into the cardiac outflow tract. FGF8 mouse mutants have a range of cardiac defects including underdeveloped arch arteries and transposition of the great arteries.<ref name="Abu-Issa2002Issa (2002)">{{citeCite journal |lastlast1=Abu-Issa |firstfirst1=Radwan |coauthorslast2=Smyth, G,|first2=Graham |last3=Smoak, I,|first3=Ida |last4=Yamamura, K, &|first4=Ken-ichi |last5=Meyers, EN|first5=Erik N. |date=2002-10-01 |title=Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse |journalurl=Developmenthttps://journals.biologists.com/dev/article/129/19/4613/20179/Fgf8-is-required-for-pharyngeal-arch-and |datejournal=OctoberDevelopment 2012|volume=129 |issue=19 |pages=4613–4625 |urldoi=http:/10.1242/dev.biologists.org/content/129/.19/.4613.full.pdf+html |accessdatepmid=November 19,12223417 2012|issueissn=191477-9129|url-access=subscription }}</ref><ref name=Frank2002"Frank (2002)">{{citeCite journal |lastlast1=Frank |firstfirst1=DUDeborah U. |coauthorslast2=Fotheringham, LK,|first2=Lori K. |last3=Brewer, JA,|first3=Judson A. |last4=Muglia, LJ,|first4=Louis J. |last5=Tristani-Firouzi, M,|first5=Martin |last6=Capecchi, MR,|first6=Mario R. |last7=Moon, AM|first7=Anne M. |date=2002-10-01 |title=An <i>Fgf8</i> mouse mutant phenocopies human 22q11 deletion syndrome |journal=Development |datepublisher=OctoberThe Company of Biologists 2002|volume=129 |issue=19 |pages=4591–6034591–4603 |accessdatedoi=10.1242/dev.129.19.4591 November|issn=1477-9129 |pmc=1876665 2012|pmid=12223415 |pmcdoi-access=1876665free}}</ref>

=== GATA ===

[[GATA transcription factorsfactor]]s, alsowhich are complex molecules that bind to the DNA sequence ''GATA'', play a critical rolesrole in cell lineage differentiation restriction during cardiac development. WhenThe GATA-6primary isfunction inactivatedof [[GATA6]] in cardiovascular development is to regulate the CNCCsmorphogenetic itpatterning canof leadthe tooutflow tract and aortic arch. When [[GATA6]] is inactivated in CNCCs, various cardiovascular defects such as persistent truncus arteriorusarteriosus and interrupted aortic arch may occur. This phenotype (anomaly) was also observed when GATA-6GATA6 was inactivated within the vascular smooth muscle cells (VSMCs).<ref name=Lepore2006"Lepore (2006)">{{citeCite journal |last=Lepore |first=JohnJ. J. |coauthorsdate=Mericko, PA, Cheng,2006-03-23 L., Lu, MM, Morrisey, EE, & Parmacek, MS|title=GATA-6 regulates semaphorin 3C and is required in cardiac neural crest for cardiovascular morphogenesis |url=http://www.jci.org/articles/view/27363/files/pdf |journal=JournnalJournal of Clinical Investigation|date=3 April 2006|volume=116 |issue=4 |pages=929–939 |doi=10.1172/JCI27363 |urlissn=http://www.ncbi.nlm.nih.gov/0021-9738 |pmc/articles/PMC1409743/pdf/JCI0627363.pdf|accessdate=November 19,1409743 2012|pmid=16557299 |pmcdoi-access=1409743free}}</ref> Therefore the primary function of GATA-6GATA6 in cardiovascularcombination developmentwith is to regulate the morphogenetic patterning of the outflow tract and aortic arch. It is also found thatWnt (Wnt2-GATA6-Wnt2) also playplays a role in the development of the posterior pole of the heart (the inflow tract).<ref name=Tian2010"Tian (2010)">{{citeCite journal |lastlast1=Tian |firstfirst1=Ying |coauthorslast2=Yuan, LJ,|first2=Lijun |last3=Goss, AM,|first3=Ashley M. |last4=Wang, T,|first4=Tao |last5=Yang, J,|first5=Jifu |last6=Lepore, JJ,|first6=John J. |last7=Zhou, D,|first7=Diane |last8=Schwartz, RJ,|first8=Robert J. |last9=Patel, V.,|first9=Vickas |last10=Cohen, ED,|first10=Ethan &David |last11=Morrisey, EE|first11=Edward E. |display-authors=6 |date=2010 |title=Characterization and In Vivo Pharmacological Rescue of a Wnt2-Gata6 Pathway Required for Cardiac Inflow Tract Development|journal=Developmental Cell|date=16 February 2010|volume=18|issue=2|pages=275–287|url=httphttps://www.ncbicell.nlm.nih.govcom/pmc/articlesarticle/PMC2846539S153458071000047X/pdf/nihms177061.pdf |accessdatejournal=NovemberDevelopmental 19,Cell 2012|pmcvolume=284653918 |pmidissue=201595972 |pages=275–287 |doi=10.1016/j.devcel.2010.01.008 |pmc=2846539 |pmid=20159597 |doi-access=free}}</ref>

== CNCCS and ischaemic heart disease ==

==Regenerative Medicine==

There is interest amongst researchers as to whether CNCCs can be used to repair human heart tissue. [[Myocardial infarction|Heart attacks]] in humans are common and their rate of mortality is high. There are emergency treatments that hospitals can administer, such as [[angioplasty]] or [[surgery]], but after that patients will likely be on medication for the long term and are more susceptible to heart attacks in the future. Other complications of heart attacks include [[cardiac arrhythmia]]s and [[heart failure]].<ref name="Canada (2012)">{{Cite web |title=Statistics |url=http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics.htm |archive-url=https://web.archive.org/web/20130104212608/http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics.htm |archive-date=2013-01-04 |website=Heart and Stroke Foundation of Canada}}</ref>

Although CNCCs are important in embryos, some CNCCs are retained in a dormant state to adulthood where they are called ''[[neural crest]] [[stem cells]]''. In 2005, Tomita transplanted neural crest stem cells from mammal hearts to the neural crest of chick embryos. These CNCCs were shown to migrate into the developing heart of the chick using the same dorsolateral pathway as the CNCCs, and differentiate into neural and glial cells.<ref name="Tomita (2005)">{{Cite journal |last1=Tomita |first1=Yuichi |last2=Matsumura |first2=Keisuke |last3=Wakamatsu |first3=Yoshio |last4=Matsuzaki |first4=Yumi |last5=Shibuya |first5=Isao |last6=Kawaguchi |first6=Haruko |last7=Ieda |first7=Masaki |last8=Kanakubo |first8=Sachiko |last9=Shimazaki |first9=Takuya |last10=Ogawa |first10=Satoshi |last11=Osumi |first11=Noriko |last12=Okano |first12=Hideyuki |last13=Fukuda |first13=Keiichi |display-authors=6 |date=2005-09-26 |title=Cardiac neural crest cells contribute to the dormant multipotent stem cell in the mammalian heart |url=https://rupress.org/jcb/article-pdf/170/7/1135/1320291/jcb17071135.pdf |journal=The Journal of Cell Biology |volume=170 |issue=7 |pages=1135–1146 |doi=10.1083/jcb.200504061 |issn=1540-8140 |pmc=2171522 |pmid=16186259 |doi-access=free}}</ref>

===Problem===

According to the Canadian Heart and Stroke Foundation, there are approximately 70 000 heart attacks in Canada each year, which is roughly one heart attack every 7 minutes.<ref name= "hsf">{{cite web|title=Canadian Heart and Stroke Foundation Statistics|url=http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics.htm|publisher=Heart and Stroke Foundation|accessdate=20 November 2012}}</ref> Of those 70,000, over 16,000 Canadians die due to their heart attack.<ref name="hsf" /> There are emergency treatments that hospitals can administer, such as [[angioplasty]] or [[surgery]], but after that patients will likely be on medication for the rest of their lives and will be more susceptible to future heart attacks depending on the damage done to their heart.<ref name="hsf" /> Heart attack survivors may also develop heart failure, coronary artery disease or congenital heart disease, as well as have life threatening abnormal heart rhythms.<ref name="hsf" /><ref>{{cite web|title=Congential Heart Disease|url=http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002103/|publisher=PubMed Health|accessdate=20 November 2012}}</ref> Medical treatments such as pacemakers and heart transplantations are current methods to treat cardiovascular conditions, however new treatments are being discovered and non-invasive approaches are being developed.<ref name="hsf" />

Tamura's study of 2011 examined the fate of CNCCs after a heart attack (myocardial infarction) in young mice. The CNCCs in the young mice were tagged with enhanced [[green fluorescent protein]] (EGFP) and then traced. Tagged CNCCs were concentrated in the cardiac outflow tract, and some were found in the ventricular myocardium. These cells were also shown to be differentiating into cardiomyocytes as the heart grew. Although less were found, these EGFP-labelled CNCCs were still present in the adult heart. When a heart attack was induced, the CNCCs aggregated in the ischemic border zone area (an area of damaged tissue that can still be saved) and helped contribute to the regeneration of the tissue to some extent via differentiation into cardiomyocytes to replace the necrotic tissue.<ref name="Tamura (2011)">{{Cite journal |last1=Tamura |first1=Yuichi |last2=Matsumura |first2=Keisuke |last3=Sano |first3=Motoaki |last4=Tabata |first4=Hidenori |last5=Kimura |first5=Kensuke |last6=Ieda |first6=Masaki |last7=Arai |first7=Takahide |last8=Ohno |first8=Yohei |last9=Kanazawa |first9=Hideaki |last10=Yuasa |first10=Shinsuke |last11=Kaneda |first11=Ruri |last12=Makino |first12=Shinji |last13=Nakajima |first13=Kazunori |last14=Okano |first14=Hideyuki |last15=Fukuda |first15=Keiichi |display-authors=6 |date=2011 |title=Neural Crest–Derived Stem Cells Migrate and Differentiate Into Cardiomyocytes After Myocardial Infarction |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |volume=31 |issue=3 |pages=582–589 |doi=10.1161/ATVBAHA.110.214726 |pmid=21212399 |issn=1079-5642 |doi-access=free}}</ref><ref name="Axford (1988)">{{Cite journal |last1=Axford-Gatley |first1=R A |last2=Wilson |first2=G J |title=The "border zone" in myocardial infarction. An ultrastructural study in the dog using an electron-dense blood flow marker |journal=The American Journal of Pathology |date=1988 |volume=131 |issue=3 |pages=452–464 |pmc=1880711 |pmid=3381878}}</ref>

===Previous Relevant Research===

Although CNCCs are more prevalent in developing embryos, they have been shown to be retained in adult tissues in a dormant stage called neural crest stem cells.<ref name= "tomita">{{cite journal|last=Tomita|first=Y|coauthors=et al|title=Cardiac neural crest cells contribute to the dormant multipotent stem cell in the mammalian heart|journal=J Cell Biol|date=September 2005|volume=170|issue=7|pages=1135–1146|accessdate=20 November 2012|pmc=2171522|pmid=16186259|doi=10.1083/jcb.200504061}}</ref> Recent studies have been able to isolate these cardiac neural crest stem cells from mammal hearts and transplant them into the neural crest of a chick embryo.<ref name="tomita" /> These CNCCs were shown to migrate into the developing heart using the same lateral pathway as the embryonic cardiac neural crest cells, and differentiated into neural and glial cells.<ref name="tomita" />

Another study looked at the fate of these CNCCs after a heart attack (myocardial infarction) in young growing mice.<ref name= "tamura">{{cite journal|last=Tamura|first=Y|coauthors=et al|title=Neural crest-derived stem cells migrate and differentiate into cardiomyocytes after myocardial infarction|journal=J Am. Heart Assoc.|date=January 2011|volume=31|pages=582–589|url=http://atvb.ahajournals.org/content/31/3/582.full.pdf|accessdate=20 November 2012|issue=3}}</ref> The CNCCs in the young mice were tagged with enhanced [[green fluorescent protein]] (EGFP) and then traced.<ref name="tamura" /> Many were concentrated in the outflow tract, and some were found in the ventricular myocardium.<ref name="tamura" /> These cells were also shown to be differentiating into cardiomyocytes as the heart grew.<ref name="tamura" /> Although less were found, these EGFP-labelled CNCCs were still present in the adult heart.<ref name="tamura" /> When a heart attack was induced, the CNCCs aggregated in the ischemic border zone area (BZA, an area of damaged tissue that can still be saved) and helped contribute to the regeneration of the tissue to some extent via differentiation into cardiomyocytes to replace the necrotic tissue.<ref name="tamura" /><ref name= "bza">{{cite journal|last=Axford-Gatley|first=R.A.|coauthors=Wilson, G.J.|title=The "border zone" in myocardial infarction: An ultrastructural study in the dog using an electron-dense blood flow marker|journal=Am. J. Pathol.|date=June 1988|volume=131|issue=3|pages=452–464|accessdate=20 November 2012|pmc=1880711|pmid=3381878}}</ref>

== References ==

{{reflist}}

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{{Development of nervous system}}

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[[Category:Embryology of cardiovascular system]]

[[Category:Embryology of nervous system]]