HWDP 131 Heart & Lung Embryology Fall 2024 PDF

Cardiovascular & Respiratory Embryology HWDP 131 Fall 2024 Meghan M. Newcomer, PhD [email protected] Outline  Cardiovascular development  Early cardiogenesis  Primary & secondary heart fields  Molecular regulation  Format...

Cardiovascular & Respiratory Embryology HWDP 131 Fall 2024 Meghan M. Newcomer, PhD [email protected] Outline  Cardiovascular development  Early cardiogenesis  Primary & secondary heart fields  Molecular regulation  Formation of heart tube & cardiac loop  Development of sinus venosus  Formation of cardiac septa  Formation of blood cells & vasculature  Aortic arches Outline  Respiratory development  Formation of lung buds  Formation of trachea and bronchi  Pericardioperitoneal canals  Formation of diaphragm Cardiovascular Development Development: Germ Layers  Zygote undergoes a series of mitotic divisions, leading to a 16-cell morula  As morula enters uterus on 3rd or 4th day after fertilization, a cavity begins to appear, leading to the formation of the blastocyst Development: Germ Layers  An inner & outer cell mass forms within blastocyst:  Inner cell mass (embryoblast)  forms embryo proper  Outer cell mass  forms trophoblast (contributes to the placenta) Development: Germ Layers  Inner cell mass (embryoblast) differentiates into the hypoblast & epiblast, forming a bilaminar disc  Epiblast is the source of all 3 germ layers  cells in these layers give rise to all tissues and organs in the embryo Development: Germ Layers  During 3rd week gastrulation establishes all 3 germ layers  Primitive streak forms on surface of epiblast  Epiblast cells migrate toward primitive streak; upon arrival, epiblast cells detach & slip beneath streak (invagination)  Some displace the hypoblast creating endoderm; others lie between epiblast & newly created endoderm to form mesoderm  Remaining cells in the epiblast form ectoderm Development: Germ Layers  Germ layers: 1)Ectoderm – Epidermis & its derivatives, Cornea, Enamel, Nervous system 2)Mesoderm – Connective tissue, Muscle, Heart, Blood vessels, Blood cells, Kidneys 3)Endoderm – Epithelial linings of organs (GI, Respiratory, Urinary), Liver, Pancreas, Thyroid & Parathyroid glands Early Cardiogenesis  Cardiovascular system appears in the middle of the 3rd week of development  Embryo no longer able to satisfy its nutritional requirements by diffusion alone  Cardiovascular system is the first system to begin functioning  Heart begins to beat ~ day 21 & begins pumping blood by 24th- 25th day Early Cardiogenesis  Progenitor heart cells originate in the epiblast, immediately adjacent to the cranial end of the primitive streak  From there they migrate through the streak & into the splanchnic layer of the lateral plate mesoderm Early Cardiogenesis  Progenitor heart cells populate a region known as the cardiogenic area  becomes crescent-shaped (cardiac crescent)  At cardiac crescent, cardiac progenitor cells organize into two groups: 1)Primary heart field (PHF) 2)Secondary heart field (SHF) Cardiogenic fields Primary & Secondary Heart Field 1)Primary heart field (FHF) forms:  Part of the atria  Left ventricle 2)Secondary heart field (SHF) forms:  Right ventricle  Outflow tract (conus cordis & truncus arteriosus)  Part of the atria Tan C, M, J, Lewandowski A, J: The Transitional Heart: From Early Embryonic and Fetal Development to Neonatal Life. Fetal Diagn Ther 2020;47:373-386. doi: 10.1159/000501906 Molecular Regulation  Bone Morphogenic Proteins (BMPs)  Bone morphogenic proteins (BMPs) 2 & 4 are secreted by the endoderm & lateral plate mesoderm  BMP expression upregulates expression of fibroblast growth factor 8 (FGF8), which is important for the expression of cardiac-specific proteins Molecular Regulation  WNT Proteins  WNT proteins are secreted by neural tube & inhibit heart development  Inhibitors of WNT proteins (CRESCENT & CERBERUS) are produced by endoderm cells immediately adjacent to heart-forming mesoderm in anterior half of embryo Molecular Regulation  The combination of BMP activity & WNT inhibition by CRESCENT & CERBERUS causes expression of NKX2.5  master gene for heart development  NKX2.5 induces formation of the heart in the visceral layer of the lateral plate mesoderm Inhibition of Wnt activity induces heart formation from posterior mesodermMartha J. Marvin,Giuliana Di Rocco,Aaron Gardiner,Sara M. Bush,andAndrew B. Lassar. Genes Dev. Creative commons license.February 1, 200115:316-327;doi:10.1101/gad.855501 Development of Heart Tube  Initially, the cardiogenic region is anterior to the oropharyngeal membrane & neural plate  CNS grows cranially so rapidly that it extends over the cardiogenic region & future pericardial cavity  As a result of growth of the brain & cranial folding of the embryo:  Oropharyngeal membrane is pulled forward  Heart & the pericardial cavity move first to the cervical region & finally to thorax Development of Heart Tube  As lateral body folds move medially, they bring the right & left sides of the first heart field together, & two limbs of the first heart field fuse at the midline  As the two limbs of the first heart field fuse, a recognizable pair of vascular elements called the endocardial tubes develops within each limb of the first heart field  The cells of the endocardial tubes coalesce into a single tube as the limbs of the first heart field join to make the primary heart tube Development of Heart Tube  Heart tube elongates as cells are added from the SHF to its cranial end  This lengthening process is essential for normal functioning of the right ventricle & outflow tract region & for the looping process  If this lengthening is inhibited, a variety of outflow tract defects occur (e.g., tetralogy of Fallot) Anatomy of the Ventricular Outflow Tracts: An Electrophysiology Perspective, Ikram U. Haq, Samuel A. Shabtaie, Nicholas Y. Tan, Nirusha Lachman, Samuel J. Asirvatham Formation of Cardiac Loop  As tubular heart grows & elongates, it develops a series of constrictions & dilations, creating the first sign of the primitive heart chambers: 1)Sinus venosus 2) Primitive atrium 3) Primitive ventricle 4)Bulbus cordis Blood Flow  a)Conus cordis b)Truncus ateriosus Caudal Parts of Heart Tube 1)Sinus venosus – at caudal (inflow) end; gives rise to:  Smooth-walled portion of right atrium (sinus venarum)  Coronary sinus Parts of Heart Tube 2)Primitive atrium – forms trabeculated parts of left & right atrium Parts of Heart Tube 3)Primitive ventricle – forms left ventricle Parts of Heart Tube 4)Bulbus cordis  Proximal 1/3 – forms trabeculated part of right ventricle  Conus cordis (middle part) – forms the outflow tracts of both ventricles  Truncus arteriosus (distal part) – contributes to pulmonary trunk & aorta  Aortic sac – most distal part of truncus arteriosus; give rise to aortic arches Conus cordis Formation of Cardiac Loop  Continued growth & elongation within the confined pericardial cavity force the heart tube to bend on itself on day 23, eventually forming a U-shaped cardiac loop (complete by day 28)  Cephalic portion of the tube bends ventrally, caudally, & to the right  Atrial (caudal) portion shifts dorsocranially & to the left Video showing cardiac looping: https://www.youtube.com/watch?v=oNMdqBUsGoY Clinical Correlation: Dextrocardia  Dextrocardia – condition where heart lies on right side of thorax instead of left  Occurs when heart loops to the left instead of the right  Defect may be induced during gastrulation or later when the cardiac looping occurs  Other organs may also be reversed; if all organs are reverses = situs invertus Development of Sinus Venosus  Sinus venosus is the most caudal dilation at the venous end of the heart tube  Sinus venosus has 2 horns (right & left)  Initially, the sinus venosus opens into the center of the posterior wall of the primitive atrium; two horns are almost equal in size Right sinus horn Development of Sinus Venosus  At first, communication between sinus venosus & atrium is wide; however, the entrance of the sinus shifts to the right  Some of the branches will be obliterated; left horn will become the coronary sinus Coronary Veins: Comprehensive CT-Anatomic Classification and Review of Variants and Clinical Implications Farhood Saremi,Horia Muresian, andDamián Sánchez-Quintana. RadioGraphics201232:1,E1-E32. Development of Sinus Venosus  The right sinus horn enlarges greatly; becomes incorporated into the right atrium to form the smooth-walled part (sinus venarum)  Crista terminalis forms the dividing line between the trabeculated part (pectinate muscles) of right atrium & smooth-walled part (sinus venarum) Formation of Cardiac Septa  Septation of developing atrium, atrioventricular (AV) canal, & ventricle occurs between between days 27 & 37; these events all occur simultaneously  Crucial for dividing heart into four chambers & establishing separate blood flow pathways  There 1) Masses of tissue are two (endocardial methods through which septa form: cushions) actively grow from one or both sides of heart tube 2) Differences in rate of growth (e.g., one portion of tissue fails to grow while areas on each side of it expand rapidly); results in septum that does not completely divide the lumen Endocardial Cushions  Endocardial cushions (anterior (superior), posterior (inferior), right lateral, left lateral) initially begin as swellings of connective tissue layer within the atrioventricular (AV) canal  connection between primitive atrium & ventricle  AV canal is divided by the coalescence of the superior & inferior endocardial cushions  Cushions also participate in the formation of the interatrial septum (closing of ostium primum), atrioventricular valves (mitral & tricuspid), & the membranous portion of the interventricular septum Septum Formation in Atria  Primary atrial septum (Septum Primum)  Begins as a ridge of tissue on the roof of the common atrium that grows downward into the atrial cavity  As it grows downward, it leaves a large opening (ostium primum) between septum & endocardial cushions surrounding the atrioventricular (AV) canal  Ostium primum allows passage of blood between the forming atria Septum Formation in Atria  Eventually, the septum primum fuses with the superior aspect of the endocardial cushions, obliterating the ostium primum  However, before closure of ostium primum is complete, small perforations appear in center of the septum primum that ultimately coalesce to form the ostium secondum, preserving a pathway for blood flow between the atria  Following closure of the ostium primum, a second, more muscular membrane, the septum secundum, begins to develop immediately to the right of the septum primum Septum Formation in Atria  Septum secundum grows downward & overlaps the ostium secundum  Septum secundum eventually partially fuses with the endocardial cushions leaving an oval-shaped opening known as the foramen ovale  Superior edge of the septum primum gradually regresses, leaving lower edge to act as a “flaplike” valve (valve of the foramen ovale)  allows only right to left flow through the foramen ovale Septum Formation in Atria  During development, blood passes from the right atrium to the left atrium because the pressure in the fetal right atrium is greater than the left atrium  After birth, this pressure gradient changes direction when lung circulation begins & pressure in the left atrium increases  This causes the valve of foramen ovale to press against septum secundum, obliterating the foramen ovale  remnant is the fossa ovalis Patent Foramen Ovale  The first breath presses septum primum (valve of foramen ovale) against the septum secundum; constant apposition gradually leads to fusion of the two septa in about 1 year  In ~20% of cases, fusion of the septum primum & septum secundum is incomplete, & a narrow oblique cleft remains between the two atria  This condition is called probe patency of the foramen ovale  not clinically significant; example of an atrial septal defect (ASD) Morphological study of fossa ovalis and its clinical relevance, Joshi et al. 2015 Formation of Pulmonary Vein  Mesenchyme at the caudal end of the dorsal mesocardium (suspends the heart tube in the pericardial cavity) proliferates  As septum primum grows down from roof of the common atrium, this proliferating mesenchyme forms the dorsal mesenchymal protrusion (DMP)  grows with the septum primum toward the atrioventricular canal  The pulmonary vein will grow within the DMP Formation of Pulmonary Vein  The main stem of the pulmonary vein that opens into the left atrium sends two branches to each lung  As left atria expands, the main stem becomes incorporated into the posterior wall until the point where the vessel branches, resulting in four separate openings for pulmonary veins into the atrial chamber Interventricular Septum  At the end of the 4th week, the primitive ventricle begins to grow, leaving a median muscular ridge, the primitive interventricular septum Interventricular Septum  The free edge of the muscular interventricular septum does not fuse with the endocardial cushions  The opening that remains (interventricular foramen) allows communication between the right & left ventricle Anterior & Posterior endocardial cushions fuse together Interventricular Septum  Interventricular foramen remains open until the end of the 7th week, when the fusion of tissue from the right & left bulbar ridges & endocardial cushions forms the membranous portion of the interventricular septum  Membranous part becomes continuous with aorticopulmonary septum Atrioventricular Valves  The superior & inferior endocardial cushions fuse together, dividing the AV canal into right & left AV canals  Mesenchymal tissue around the AV canals proliferates  Bloodstream hollows out these proliferations & mesenchymal tissue becomes fibrous, forming AV valves (mitral & tricuspid) Septation of Outflow Tracts  During the 5th week, there is a proliferation of neural crest- derived mesenchyme in the conus cordis & truncus arteriosus which creates a pair of protrusions known as the bulbar (conotruncal) ridges Septation of Outflow Tracts  Bulbar ridges fuse in the midline & undergo a 180-degree spiraling process, forming the aorticopulmonary (conotruncal) septum  Septum divides the bulbus cordis & truncus arteriosus into two arterial channels:  Pulmonary trunk (continuous with right ventricle)  Aorta (continuous with the left ventricle) Semilunar Valves  Aortic & pulmonary semilunar valves start to develop just before the completion of the aorticopulmonary septum  three outgrowths of mesenchymal tissue form around both the aortic & pulmonary orifices  These growths are ultimately shaped & excavated by the joint action of programmed cell death & blood flow to create the three thin-walled cusps of the aortic & pulmonary valves Pulmonary valve Aortic valve Heart Defect Statistics  Heart & vascular abnormalities comprise the largest category of birth defects:  Present in 1% of live-born infants  Present in 10% of stillborn infants  33% of babies with a chromosomal abnormality have a heart defect  30% of heart defects occur in infants that also have other major malformations Neural Crest Cells  Cardiac neural crest cells migrate through pharyngeal arches to outflow region of heart, which they invade  In this location, they contribute to endocardial cushion formation in both the conus cordis & truncus arteriosus  Migration & proliferation of neural crest cells is regulated by the secondary heart field through the NOTCH signaling pathway  Therefore, outflow tract defects may occur by insults to secondary heart field or to the cardiac neural crest cells  Because neural crest cells also contribute to craniofacial development, it is not uncommon to see facial & cardiac abnormalities in the same individual Ventricular Septal Defects  Ventricular septal defect (VSDs) are most common congenital heart malformation  Most common VSD is in the muscular region of septum & resolves as the child grows  A small septal defect may have little functional significance & may close spontaneously as child grows  In infants with large septal defects, higher left ventricular pressure creates a left-to-right shunt  Left ventricular dilation & congestive heart failure are common complications of such shunts Tetralogy of Fallot  Tetralogy of Fallot – most frequently occurring abnormality of the outflow tract (conotruncal region); characterized by 4 defects: 1) Pulmonary stenosis = narrow right ventricular outflow region, limiting flow to lungs 2) Interventricular septal defect (allows blood to mix between ventricles) 3) Overriding aorta (straddles both ventricles, receiving blood from both) arising directly above the septal defect 4) Hypertrophy of right ventricular wall (due to increased pressure on right side from narrowed pulmonary artery) *Skin likely blue (cyanosis) due to tissues receiving insufficient Formation of Blood Cells  Blood cells arise from mesoderm  In 3rd week, blood islands appear in mesoderm surrounding the wall of the yolk sac  islands arise from mesoderm cells that are induced to form hemangioblasts, a common precursor for vessel & blood cell formation  While first blood cells arise from blood islands in yolk sac, this population is transitory  Definitive hematopoietic stem cells are derived from mesoderm surrounding the aorta  these cells colonize the liver which becomes the major hematopoietic organ from 2nd – 7th months of development  Stem cells in liver colonize the bone marrow in the 7th month, which becomes the definitive blood-forming tissue Vascular Development  Blood vessel development occurs by two mechanisms: 1)Vasculogenesis – vessels arise by coalescence of angioblasts  The major vessels (e.g., dorsal aorta, cardinal veins) formed via vasculogenesis 2)Angiogenesis – sprouting of vessels from existing vessels  Remainder of blood vessels form via angiogenesis Vascular Development  In addition to the cardiogenic region, other blood islands appear bilaterally, parallel, & close to the midline of the primitive streak  These islands form a pair of longitudinal vessels  the dorsal aortae Aortic Arches  When pharyngeal arches form during the 4th and 5th week, each arch receives its own cranial nerve and its own artery  aortic arch Aortic Arches  Aortic arches arise from the aortic sac, the most distal part of the truncus arteriosus  Aortic arches are embedded in mesenchyme of the pharyngeal arches & terminate in the right & left dorsal aortae  In the region of pharyngeal arches, dorsal aortae remain paired; caudal to pharyngeal arches, they fuse to form a single vessel  eventually becomes descending aorta Aortic Arch 1  Aortic arch 1 forms and then mostly disappears  Small portion persists to form the maxillary artery Aortic Arch 2  Aortic arch 2 forms & disappears; remaining portions are hyoid a. & stapedial a. (both regress) Aortic Arch 3  Aortic arch 3 is a large arch; it forms:  Common carotid artery  External carotid artery  Proximal part of internal carotid artery (*remaining portion formed by cranial portion of dorsal aorta) Aortic Arch 4  Aortic arch 4 persists on both sides, but has different fates  Left side: forms part of arch of aorta (*between left CCA & left subclavian artery)  Proximal part of aortic arch & brachiocephalic trunk formed from part of aortic sac  Right side: forms proximal part of right subclavian artery  Distal part of right subclavian artery is formed by portion of right dorsal aorta Aortic Arch 5  Aortic arch 5 either never forms or forms incompletely and then regresses Aortic Arch 6  Aortic arch 6 (pulmonary arch)  Right side: develops into proximal part of right pulmonary artery  Left side: forms the left pulmonary artery & ductus arteriosus Ductus Arteriosus  Ductus arteriosus is functionally closed through contraction of its muscular wall shortly after birth to form the ligamentum arteriosum  Anatomical closure takes 1-3 months Patent Ductus Arteriosus  A patent ductus arteriosus (PDA) is one of the most frequently occurring abnormalities of the great vessels (8/10,000 births), especially in premature infants  Luminal diameters vary: A small shunt has little effect on the heart Large shunt may divert blood from aorta to the low-pressure pulmonary artery; in severe cases, left ventricular hypertrophy & heart failure ensue because of increase demand for cardiac output Aortic Arches: Recurrent Laryngeal n.  Descent of heart into thorax & disappearance of various portions of aortic arches leads to different courses of right vs. left recurrent laryngeal nerves Aortic Arches: Recurrent Laryngeal n.  When the heart descends, recurrent laryngeal nerves hook around the 6th aortic arches & ascend to larynx  accounts for their recurrent course  On the right: when distal part of 6th aortic arch & 5th arch disappear  nerve moves up & hooks around right subclavian artery  On the left: nerve does not move up because distal part of the 6th arch persists as the ductus arteriosus, which later forms the ligamentum arteriosum Fetal Circulation  Oxygenated blood from placenta passes to fetus via umbilical vein  On approaching the liver, most of this blood flows through the ductus venosus directly into the inferior vena cava, bypassing the liver Fetal Circulation  After short course in the inferior vena cava (where placental blood mixes with deoxygenated blood returning from the lower limbs) it enters right atrium  Blood bypasses the right ventricle (as lungs are not yet functioning) to enter left atrium via foramen ovale Fetal Circulation  Blood from superior vena cava enters the right atrium, passes to the right ventricle, & moves into the pulmonary trunk  Most of this blood enters the aorta via the ductus ateriosus Fetal Circulation  The partially oxygenated blood in the aorta returns to the placenta via the paired umbilical arteries that arise from the internal iliac arteries Postnatal Circulation 1) As pulmonary respiration begins at birth, pulmonary blood pressure falls, causing blood from pulmonary trunk to enter pulmonary arteries 2) The foramen ovale and ductus arteriosus close, eliminating the fetal left-to- right shunts 3) Pulmonary and systemic circuits are now separate 4) As the infant is separated from the placenta, the umbilical arteries (median umbilical ligaments) occlude, along with the umbilical vein (round ligament of liver) and ductus venosus (ligamentum venosum) 5) Blood to be metabolized now passes through liver Respiratory System Development Respiratory Development  Sources of Respiratory Tissues:  Endoderm  Epithelium of internal lining the larynx, trachea, bronchi, & lungs  Mesoderm  Cartilaginous, muscular, & connective tissue components of the trachea & lungs Formation of Lung Buds  At the beginng of week 4, the respiratory diverticulum (lung bud) appears as an outgrowth from the ventral wall of the foregut (endoderm) Formation of Lung Buds  Formation & location of lung bud are dependent upon an increase in retinoic acid produced by adjacent mesoderm  This increase in retinoic acid upregulates the transcription factor TBX4 expressed in the endoderm of the gut tube at the site of the respiratory diverticulum  TXB4 induces formation of the bud and the continued growth and differentiation of the lungs Formation of Lung Bud  Initially, the lung bud (respiratory diverticulum) is in open communication with the foregut  Lung bud expands caudally & two longitudinal ridges (tracheoesophageal ridges) separate it from the foregut  These ridges fuse to form the tracheoesophageal septum, diving foregut into a dorsal portion (esophagus) & a ventral portion (trachea) Tracheoesophageal Defects  Abnormalities in partitioning of the esophagus & trachea by tracheoesophageal septum result in esophageal atresia with or without tracheoesophageal fistulas  90% of these defects result in the upper portion of the esophagus ending in a blind pouch & the lower segment forming a fistula with the trachea  Swallowing not possible; milk or saliva will spill out of mouth or will be inhaled into lungs Trachea & Bronchi  During its separation from the foregut, the lung bud forms the trachea & two lateral outpocketings (primary bronchial buds)  At the beginning of the 5th week, each of these buds enlarges to form right & left primary bronchi  The right primary bronchus then forms 3 secondary bronchi & the left primary bronchus forms 2 Pericardioperitoneal Canals  With subsequent growth in caudal & lateral directions, the lungs expand into the body cavity  The spaces for the lungs, the pericardioperitoneal canals, are narrow  lie on each side of the foregut; gradually filled by the expanding growth of the lungs Pericardioperitoneal Canals  Pleural cavities openly communicate with peritoneal (abdominal) cavity via pericardioperitoneal canals  During development, communication is partially closed by crescent- shaped folds, the pleuroperitoneal folds  Folds become thinner, forming pleuroperitoneal membranes which continue to grow until they fuse with each other & completely cover the septum transversum (thick plate of mesodermal tissue that is situated between the primitive thoracic & abdominal cavities) Pleuroperitoneal Membranes  Central region of pleuroperitoneal membranes forms the central tendon of the diaphragm  Periphery forms connective tissue that serves as a scaffold & guide for migrating myoblasts  These muscle cells originate in cervical segments C3-C5 to form the musculature of the diaphragm; innervation of diaphragm is via the phrenic nerves derived from spinal nerves originating from C3-C5  Muscle cells & nerve fibers from cervical segments populate & innervate the diaphragm because the development of the diaphragm originated in the cervical region Diaphragmatic Hernias  Congenital diaphragmatic hernias are some of the more common malformations (1/2,000)  Most occur when muscle cells fail to populate of the pleuroperitoneal membranes, resulting in a weakened area & subsequent herniation of abdominal organs into thoracic cavity https://radiopaedia.org/cases/congenital-diaphragmatic-hernia-48 Questions? 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