Cardiac neural crest
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Neural crest cells are a group of temporary, 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.[1] 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.[1][2] They migrate throughout the body and create a large number of differentiated cells such as neurons, glial cells, pigment-containing cells in skin, skeletal tissue cells in the head, and many more.[1][2]
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 arches) and then into the 3rd, 4th and 6th pharyngeal arches and the cardiac outflow tract (OFT).[1][2][3] They extend from the otic placodes (the structure in developing embryos that will later form the ears) to the third somites (clusters of mesoderm that will become skeletal muscle, vertebrae and dermis).[1][2]
The cardiac neural crest cells:[1][2]
- create the muscular connective tissue walls of large arteries
- help create the septum in the heart
- form part of the thyroid, 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
Pathway of a Migratory Cardiac Neural Crest Cell
Induction
The progenitors, or the cells that will become, CNCCs are found in the epiblast around Henson’s node.[3][4] The progenitors are brought into the neural folds and signaling from molecules Wnt, FGF and BMP help induce the progenitors to become CNCCs.[3][4] Not a lot is known about the signaling cascades that occur for neural crest induction, but it is known that an intermediate level of BMP is needed, too high or low causes the cells not to migrate.[4]
Initial Migration
After induction, the CNCCs lose their cell-cell contacts, which allows them to interact with extracellular matrix components.[3][4] The extracellular membrane provides an environment in which the cells can move and allows them to leave the neural tube and migrate to where they need to be.[3][4] They also have filopodia and lamellipodia that help them to move.[4] They then follow a dorsolateral pathway to the circumpharyngeal ridge.[1][2][3] The cells link together to form a stream of migrating cells and stretch from the neural tube to other CNCCs migrating to the circumpharyngeal ridge.[4] Cells at the front of the migration stream have special polygonal shape and they proliferate at a much faster rate than trailing cells.[4]
Pause in Circumpharyngeal Ridge
Once the CNCCs make it to the circumpharyngeal arch they have to pause their migration temporarily and wait for the pharyngeal arches to form.[1][2][3][4]
Migration into the Pharyngeal Arches
Once the pharyngeal arches have developed, the cranial neural crest cells continue their migration into the pharyngeal arches, specifically the 3rd, 4th and 6th.[1][2][3] The leading cells have long filopodia that aid the migration.[4] 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.[4] A variety of growth factors and transcription factors signal to the cells and target them towards a specific arch.[4] For example, FGF8 helps to signal cells towards pharyngeal arch 4 and helps keep them viable.[4] As mentioned before, the neural crest cells that migrate to the arches help form the thyroid and parathyroid glands.[1][2][3]
Migration into the Cardiac Outflow and Proximal Outflow
The cardiac outflow tract is a temporary structure in a developing embryo that connects the ventricles with the aortic sac.[2][3] Some cells further migrate to the cardiac outflow instead of the pharyngeal arches.[1][3][4] 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.[4] A small amount of CNCCs also migrates further into the proximal outflow tract where they help to close the ventricular outflow septum.[1][3]
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.[5] The CNCCs themselves are the precursors to vascular smooth muscle cells and cardiac neurons.[6] 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.
Many signaling molecules are required for the differentiation, proliferation, migration and apoptosis of the CNCCs. The major molecular pathways involve members of the Wnt, Notch, BMP, FGF8 and GATA families. In addition to these signaling pathways, these processes are also mediated by environmental factors including blood flow, shear stress, and blood pressure.[7]
Wnt
Wnt proteins are extracellular growth factors that activate different intracellular signaling branches.[8] There are 2 types of pathways: canonical and non-canonical.[8] The classic canonical Wnt pathway involves B-catenin protein as a signaling mediator.[8] Wnt maintains B-catenin by preventing against Proteasome degradation.[8] Thus, B-catenin is stabilized in the presence of Wnt and regulates gene transcription through interaction with TCF/LEF transcription factors.[8] The canonical Wnt/B-catenin pathway is important for Proliferation|cell proliferation control.[4] The non-canonical Wnt pathway is independent of B-catenin and has an inhibitory effect on canonical Wnt signaling.[8]
Wnt signaling pathways play a role in CNCC development as well as OFT development.[8] In mice, decrease of B-catenin results in a decrease in the proliferation of CNCCs.[8] 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.[8] Canonical Wnt signaling is especially important for cell cycle regulation of CNCC development and the initiation of CNCC migration.[8] Non-canonical Wnt signaling plays a greater role in promoting cardiac differentiation and OFT development.[8]
Notch
Notch signaling is required for differentiation of CNCCs to vascular smooth muscle cells.[7] Furthermore, Notch is required for the proliferation of cardiomyocytes.[7] 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.[7] In humans, mutations in Notch most often result in bicuspid aortic valve disease and calcification of the aortic valve.[9]
Bone Morphogenetic Proteins (BMPs)
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.[10]
FGF8
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.[11][12]
GATA
GATA transcription factors also play critical roles in cell lineage differentiation restriction during cardiac development. When GATA-6 is inactivated in the CNCCs it can lead to various cardiovascular defects such as persistent truncus arteriorus and interrupted aortic arch. This phenotype was also observed when GATA-6 was inactivated within the vascular smooth muscle cells (VSMCs).[13] Therefore the primary function of GATA-6 in cardiovascular development is to regulate the morphogenetic patterning of the outflow tract and aortic arch. It is also found that GATA6-Wnt2 also play a role in the development of the posterior pole of the heart (inflow tract).[14]
Regenerative Medicine
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.[15] Of those 70,000, over 16,000 Canadians die due to their heart attack.[15] 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.[15] Heart attack survivors may also develop heart failure, coronary artery disease or congenital heart disease, as well as have life threatening abnormal heart rhythms.[15][16] 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.[15]
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.[17] 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.[17] 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.[17]
Another study looked at the fate of these CNCCs after a heart attack (myocardial infarction) in young growing mice.[18] The CNCCs in the young mice were tagged with enhanced green fluorescent protein (EGFP) and then traced.[18] Many were concentrated in the outflow tract, and some were found in the ventricular myocardium.[18] These cells were also shown to be differentiating into cardiomyocytes as the heart grew.[18] Although less were found, these EGFP-labelled CNCCs were still present in the adult heart.[18] 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.[18][19]
References
- ^ a b c d e f g h i j k l Kirby, M (1987). "Cardiac Morphogenesis--Recent Research Advances" (PDF). Pediatric Research. 21 (3): 219–224.
- ^ a b c d e f g h i j Gilbert, S.F. (2010). Developmental Biology. MA: Sinauer Associates. pp. 373–389.
- ^ a b c d e f g h i j k l Kuratani, S.C. (1992). "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". Anat. Rec. 234 (2): 263–268. doi:10.1002/ar.1092340213. PMID 1384396.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ a b c d e f g h i j k l m n o p Kirby, M.K. (2010). "Factors controlling cardiac neural crest cell migration" (PDF). Cell Adhesion and Migration. 4 (4): 609–621. PMC 3011257. PMID 20890117.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) Cite error: The named reference "kirby2010" was defined multiple times with different content (see the help page). - ^ de la Pompa, J.L. (2012). "Coordination Tissue Interactions: Notch Signalling in Cardiac Development and Disease". Developmental Cell. 22 (2): 244–264. doi:10.1016/j.devcel.2012.01.014.
{{cite journal}}:|access-date=requires|url=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ Brown, Christopher (2006). "Neural Crest Contribution to the Cardiovascular System". Advances in Experimental Medicine. 589: 134–154. doi:10.1007/978-0-387-46954-6_8.
{{cite journal}}:|access-date=requires|url=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ a b c d Niessen, Kyle (2008). "Notch Signaling in Cardiac Development". Circulation Research. 102: 1169–1181. doi:10.1161/CIRCRESAHA.108.174318. PMID 18497317.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ a b c d e f g h i j k Gessert, S (2010). "The multiple phases and faces of wnt signaling during cardiac differentiation and development". Circulation Research. 107 (2): 186–199. doi:10.1161/CIRCRESAHA.110.221531. Retrieved 19 November 2012.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Garg, V (2005). "Mutations in NOTCH1 cause aortic valve disease". Nature. 437 (7056): 270–274. Retrieved 20 November 2012.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ Kaartinen, V (2004). "Cardiac outflow tract defects in mice lacking ALK2 in neural crest cells". Development. 131 (14): 3481–90. doi:10.1242/dev.01214. PMID 15226263.
{{cite journal}}:|access-date=requires|url=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ Abu-Issa, Radwan (2012). "Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse". Development. 129 (19): 4613–4625. Retrieved November 19, 2012.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ Frank, DU (2002). "An Fgf8 mouse mutant phenocopies human 22q11 deletion syndrome". Development. 129 (19): 4591–603. PMC 1876665. PMID 12223415.
{{cite journal}}:|access-date=requires|url=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ Lepore, John J (3). "GATA-6 regulates semaphorin 3C and is required in cardiac neural crest for cardiovascular morphogenesis" (PDF). Journnal of Clinical Investigation. 116 (4): 929–939. doi:10.1172/JCI27363. PMC 1409743. PMID 16557299. Retrieved November 19, 2012.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ Tian, Ying (16). "Characterization and In Vivo Pharmacological Rescue of a Wnt2-Gata6 Pathway Required for Cardiac Inflow Tract Development" (PDF). Developmental Cell. 18 (2): 275–287. doi:10.1016/j.devcel.2010.01.008. PMC 2846539. PMID 20159597. Retrieved November 19, 2012.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ a b c d e "Canadian Heart and Stroke Foundation Statistics". Heart and Stroke Foundation. Retrieved 20 November 2012.
- ^ "Congential Heart Disease". PubMed Health. Retrieved 20 November 2012.
- ^ a b c Tomita, Y (2005). "Cardiac neural crest cells contribute to the dormant multipotent stem cell in the mammalian heart". J Cell Biol. 170 (7): 1135–1146. doi:10.1083/jcb.200504061. PMC 2171522. PMID 16186259.
{{cite journal}}:|access-date=requires|url=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ a b c d e f Tamura, Y (2011). "Neural crest-derived stem cells migrate and differentiate into cardiomyocytes after myocardial infarction" (PDF). J Am. Heart Assoc. 31 (3): 582–589. Retrieved 20 November 2012.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ Axford-Gatley, R.A. (1988). "The "border zone" in myocardial infarction: An ultrastructural study in the dog using an electron-dense blood flow marker". Am. J. Pathol. 131 (3): 452–464. PMC 1880711. PMID 3381878.
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