The Process and Mechanisms of Embryological Folding: Formation of Body Cavities and Organs

During weeks 3-4 of embryo development, the process of folding occurs as a result of the embryo's differentiated growth and rapid restructuring. Initially, at the end of the third week, the embryo takes on the shape of a flat, ovoid, trilaminar disc. However, in the fourth week, it experiences significant growth, particularly in length, and undergoes a rolling process that gives rise to the characteristic shape of vertebrate bodies.

While some remodeling of the tissue layers does occur, the primary force driving the rolling of the embryo is the differentiated growth of various embryonic structures. Notably, during this fourth week, the embryonic disc and the amnion grow rapidly, while the yolk sac hardly grows at all. As the yolk sac is attached to the edges of the embryonic disc, the expanding disc can be likened to a three-dimensional ball with an approximately cylindrical shape.

The notochord, neural tube, and somites establishes the dorsal axis of the embryo, leading to most of the rolling occurring at the thin, flexible outer edge of the embryonic disc. The anterior, posterior, and lateral edges of the disc roll completely around the axial structures, eventually forming the ventral surface of the body. Due to the embryo's faster growth in length compared to width, these folds are more pronounced at the cranial and caudal ends of the embryo than at the edges.

The process of cephalic folding is triggered by the growth and flexion of the cephalic neural plate. Initially, the neural folds, which are wide and thick, become more prominent dorsally due to the proliferation and migration of the mesenchyme located beneath the future head region. This mesenchyme is the embryonic mesoderm responsible for the formation of connective tissue.

Since the cephalic portion of the embryonic axis extends beyond the yolk sac, the neural plate will flex at specific levels. The first flexure to occur is the cephalic or mesencephalic flexure, which takes place in the region where the future mesencephalon will develop. On day 22, the angle between the prosencephalon and rhombencephalon is approximately 150 degrees. By day 23, this angle decreases to 100 degrees.

In the cephalic portion of the embryonic disc, a thin, bilayered zone called the buccopharyngeal membrane starts to form cranial to the neural plate. This membrane represents the future mouth of the embryo. Additionally, cranial to the buccopharyngeal membrane, another significant structure known as the cardiogenic area begins to appear. Shaped like a horseshoe, this area is where the heart will eventually form.

The cranial folding process involves the growth and flexion of the neural plate, which leads to the folding of the thin cranial margin. This folding forms the future ventral surface of the face, neck, and chest. During this process, the future pharyngeal membrane is moved into the region of the future mouth and the cardi thorax. Cephalic folding is facilitated by the transverse septum, which appears on day 22 as a thickened mass of mesoderm. This structure is located between the cardiogenic area and the cranial edge of the embryonic disc. Cephalic folding transports this mesodermal mass ventrally and caudally until it is positioned between the cardiogenic region and the neck of the yolk sac.

The caudal folding process begins on day 23 and involves the folding of the caudal region of the embryo. This folding occurs as the neural tube rapidly elongates and the somites extend beyond the caudal edge of the yolk sac. The dorsal axial structures provide relative rigidity, causing the thin caudal edge of the germinal disc, which contains the cloacal membrane, to roll underneath and become part of the ventral caudal surface of the embryo.

During the caudal folding process, the connecting stalk, which connects the caudal portion of the germinal disc to the developing placenta, is transported cranially. It eventually fuses with the neck of the elongating and narrowing yolk sac. The allantois, a thin endodermal diverticulum of the hindgut, is also included in the root of the connecting stalk.

The trilaminar disc undergoes lateral lifting during craniocaudal folding. This is caused by the ventral tilting of the right and left parts of the disc, which is a result of accelerated growth of the paraxial mesoderm. As a consequence, the neck of the yolk sac becomes constricted and narrower. The lateral edges of the germinal disc in the caudal and cranial terminal portions of the embryo come into contact with each other and fuse towards the umbilicus. During this fusion, the ectodermal, mesodermal, and endodermal layers on each side merge with their corresponding layers on the opposite side. This results in the ectoderm covering the entire surface of the three-dimensional embryo, except for the future umbilical regions where the yolk sac and connecting stalk protrude. The formation of the body's skin is primarily driven by the ectoderm, along with contributions from the dermatomes, lateral mesodermal plate, and neural crest.

During development, migrating streams of mesodermal cells form the primary mesenchyme (ectomesenchyme) in the cephalic and caudal folds. These cells bypass the cloacal and buccal membranes and then reaggregate and migrate towards the periphery. As they migrate, they form the somatic and splanchnopleura of the lateral plate. The mesenchymal cells from the cephalic and caudal folds migrate towards the periphery of the limiting groove, which will become the future umbilical ring. These cells will eventually form the anatomical elements of the anterior thoracoabdominal wall above and below the umbilicus. It is believed that the sternum and rectus abdominis muscles derive from these streams of primary mesenchyme.

The fragmented somitic mesoderm in the somites serves as the basic material for the formation of secondary mesenchyme. This secondary mesenchyme migrates into the lateral walls of the trunk, known as the lateral folds, and forms the connective and muscular components of these walls, including the ribs, intercostal muscles, and abdominal obliques.

During the migration of both primary and secondary mesenchyme, the gelatinous substrate plays an important role. The vessels formed early in the second and third weeks serve as guiding elements for the migrating mesenchymal cells. The primary mesenchyme from the cephalic and caudal folds migrates along the internal thoracic, superior epigastric, and inferior epigastric arteries to form the trunk walls. From this mesenchyme, the supraumbilical sternum and the part of the rectus abdominis muscles above the umbilicus differentiate. The subumbilical part of the rectus abdominis muscles differentiates from the mesenchyme in the caudal fold. The secondary mesenchyme that migrates from the somites into the somatopleura of the lateral folds migrates along the lateral intersegmental arteries, which will become the intercostal and lumbar arteries. The somites provide the secondary mesenchyme necessary for the formation of the vertebral column.

Trunk wall development involves fusion and curling, which play important roles in the morphogenesis of mesenchymal-derived components. If dorsal or ventral median fusion does not occur, various degrees of median fissures may appear in the trunk walls. The curling process takes place in the caudal region of the embryo as the neural tube rapidly elongates and the somites extend beyond the caudal margin of the yolk sac. Due to the rigidity of the dorsal axial structures, the thin caudal margin of the germ disc, containing the cloacal membrane, curls underneath and becomes part of the ventral caudal surface of the embryo.

As the caudal margin of the disc curls under the body, the connecting stalk, which links the caudal portion of the germ disc to the developing placenta, moves cranially until it fuses with the neck of the yolk sac. At the same time, the yolk sac starts to elongate and narrow. The connecting stalk also includes the allantois, which is a thin, endodermal diverticulum of the hindgut.

During lateral folding, the lateral edges of the germinal disc fuse along the ventral midline. At the same time as craniocaudal flexion, the right and left parts of the embryonic disc tilt ventrally, causing a constriction and narrowing of the yolk sac stalk. In the caudal and cranial terminal portions of the embryo, the lateral edges of the germinal disc come into contact and merge towards the umbilicus. When the edges meet, the ectodermal, mesodermal, and endodermal layers on each side fuse with their corresponding layers on the opposite side. This results in the ectoderm of the original germinal disc covering the entire surface of the three-dimensional embryo, except for the future umbilical regions.

In the cephalic and caudal folds, migratory mesodermal cell streams form the primary mesenchyme. These cells bypass the cloacal and buccal membranes, then reaggregate and migrate towards the periphery, forming the somatic and splanchnopleura of the lateral plate. The mesenchymal cells from the cephalic and caudal folds migrate towards the periphery of the limiting groove (future umbilical ring) and form the anatomical elements of the supra- and subumbilical anterior thoraco-abdominal wall. It is believed that the sternum and rectus abdominis muscles derive from these streams of primary mesenchyme.

The fragmented somitic mesoderm in the somites provides the basis for the formation of secondary mesenchyme. This secondary mesenchyme migrates into the lateral walls of the trunk (the lateral folds) to form the connective and muscular components of these walls.

The gelatinous substrate, especially the vessels formed early in the second and third weeks, play a significant role in the migration of primary and secondary mesenchyme. These vessels serve as guiding elements for migrating mesenchymal cells. The primary mesenchyme from the cephalic and caudal folds migrates to form the trunk walls along specific arteries. From this mesenchyme, the supraumbilical sternum and the supraumbilical part of the rectus abdominis muscles (cephalic fold) as well as the subumbilical part of the rectus abdominis muscles (caudal fold) differentiate. The secondary mesenchyme migrating from the somites into the somatopleura of the lateral folds migrates along the lateral intersegmental arteries. The somites provide secondary mesenchyme for the formation of the vertebral column.

If dorsal or ventral median fusion does not occur during the morphogenesis of mesenchyme-derived components, various degrees of median fissures of the trunk walls can occur.

The formation of the embryonic coelom involves the rolling up of the embryo, which converts the intraembryonic coelom into a closed cavity. The lateral mesodermal plate gives rise to the intraembryonic coelom, its serous membranes (somatic and splanchnopleura), and the mesentery. This plate divides into two layers: somatopleura, which attaches to the ectoderm, and splanchnopleura, which attaches to the endoderm. The space between these layers initially opens into the amniotic cavity but later becomes the intraembryonic coelom when the embryo's folds fuse along the ventral midline. The somatopleura lines the interior of the trunk wall, while the splanchnopleura envelops the viscera derived from the intestinal tube.

The dorsal mesentery plays a role in suspending the abdominal intestinal tube in the coelom. As the coelom forms, the intestine becomes attached to the posterior wall through mesenchyme. However, in the region of the future abdominal viscera, the mesenchyme gradually disperses during the fourth week, forming a thin, bilayered dorsal mesentery that suspends the abdominal viscera in the coelomic cavity. These suspended structures are referred to as intraperitoneal viscera, although this term is technically incorrect as the peritoneal cavity contains only serous fluid and, in females, a monthly ovulated oocyte.

In the body, the majority of the intestine and its derivatives are located intraperitoneally, meaning they are suspended by the mesentery. However, there are a few visceral organs that develop differently. These organs develop in the body wall and are separated from the coelom by a thick covering, making them retroperitoneal.

Some organs may initially be intraperitoneal but later become retroperitoneal due to the shortening and degeneration of the dorsal mesentery. This process is known as parietalization. For example, the kidneys and the urinary bladder develop in the retroperitoneal space from the beginning.

Additionally, certain portions of the intestinal tube that are initially suspended by the mesentery can later fuse with the posterior wall of the body, taking on the characteristics of retroperitoneal organs. These organs, such as the ascending and descending colon, the duodenum, and the pancreas, are referred to as secondary retroperitoneal or parietalized organs.

The coelomic cavity is subdivided into four cavities by the formation of the pericardial sac and the diaphragm. The transverse septum, also known as the anterior diaphragm, plays a key role in the formation of the anterior diaphragm, which partially separates the thoracic and abdominal cavities. It develops from the cardio-hepato-diaphragmatic mesenchyme and attaches ventrally and laterally to the trunk wall, and dorsally to the mesenchyme surrounding the anterior intestine. The upper portion of the coelomic cavity, known as the primitive pericardial cavity, contains the developing heart, while the lower portion is the future peritoneal cavity. The primitive pericardial cavity and the peritoneal cavity are connected by two large openings called the pericardio-peritoneal canals, located dorsolateral to the transverse septum.

The transverse septum develops from the cardio-hepato-diaphragmatic mesoderm, which appears cranial or rostral to the bucco-pharyngeal membrane in the second week of development. The endocardial tubes, which form the heart, appear in this mesoderm. The growth of the neural tube, somites, and other mesodermal components determine the cranio-caudal and dorso-latero-ventral growth of the embryo. At this stage, the embryonic folds tilt and the embryonic body closes. The tilting of the cephalic fold brings the heart and surrounding mesenchyme between the embryo's head and the yolk sac. As the heart develops into an active contractile organ, it exerts compressive mechanical effects on the mesenchyme located caudal to it.

During the fourth and fifth weeks of development, the transverse septum gradually moves downward. Its ventral edge eventually attaches to the anterior wall of the body at the level of the 7th thoracic vertebra, while the dorsal connection to the esophageal mesenchyme is found at the level of the T12 vertebra. Simultaneously, myoblasts in the transverse septum differentiate to become part of the future diaphragm muscle. These myoblasts are innervated by the cervical spinal nerves C3, C4, and C5, which will form the phrenic nerves. As the transverse septum migrates downward, the phrenic nerves also lengthen.

The development of the liver begins in the mesenchyme located below the heart, above the vitelline duct, and in front of the anterior intestine. In the third week of development, the hepatic endodermal bud forms through the invagination and budding of the ventral wall of the anterior intestine. This marks the initiation of liver development, an organ that plays a crucial role in shaping the transverse septum and the diaphragm.

The transverse septum, located between the heart and the liver, undergoes a laminating process. This process is then continued by the evolution of the lungs. The two phrenic nerves, dependent on the transverse septum, grow within it and contribute to its histogenesis through nervous induction.

In the transverse septum, the two phrenic nerves are implanted on either side of the venous sinus of the primitive cardiac tube. The venous sinus is closely related to the transverse septum, as the post-hepatic segment of the inferior vena cava derives from the terminal end of the right vitelline vein, which is incorporated into the transverse septum.

The right phrenic nerve approaches the diaphragm on the right side of the inferior vena cava and is located laterally to the venous sinus, specifically next to the right vitelline vein. Initially, the implantation site of the left phrenic nerve in the diaphragm is at a similar point to the right, but it is displaced due to changes in the position and volume of the heart. These changes elongate, curve, and modify the phrenic implantation point to an anterior position.

The transverse septum shares a common fate with the entire mesenchyme of the cephalic fold. The primary mesenchymal cells of this fold are guided and conducted in their migration by the internal thoracic arteries and their branches, which approach the anterior diaphragm on its superior surface. The irrigation territory of these arteries provides a more accurate indication of the origin of the transverse septum compared to the phrenic nerves.

The pleuropericardial folds detach from the lateral wall of the body and form the pericardial sac. These folds originate along the lateral walls of the body and are located in a frontal plane. They start as wide folds of mesenchyme and pleura in the fifth week and grow medially towards each other between the developing heart and lungs. By the end of the fifth week, the folds meet and fuse with the mesenchyme of the anterior gut, dividing the primitive pericardial cavity into three compartments: a definitive, completely closed pericardial cavity, and two dorsolateral pleural cavities. The pleural cavities communicate with the peritoneal cavity through pericardio-peritoneal or pleuro-peritoneal canals.

The tips of the pleuropericardial folds grow medially towards each other, while their roots extend ventrally along the inside of the body wall towards the ventral midline. Eventually, the tips of the folds meet and close the pericardial cavity, and their roots originate from the ventral midline. This transformation converts the lateral portion of the primitive pericardial cavity into the ventrolateral part of the right and left pleural cavities.

The pleuropericardial folds consist of three layers: the mesenchyme of the body wall sandwiched between two layers of somatopleura. The thin (definitive) pericardial sac retains this tristratified composition, which includes two serous membranes: an internal serous pericardium and an external mediastinal pleura. These layers are separated by connective tissue derived from mesenchyme, known as the fibrous pericardium. In adults, the phrenic nerves, initially located in the mesenchyme of the body wall and incorporated into the pleuropericardial folds, are situated along the fibrous pericardium.

The development of the diaphragm involves different sources of mesenchyme. Some myoblasts migrate into the pleuroperitoneal membranes, pushing their branches of the phrenic nerves towards the posterior diaphragm. The tendinous center of the diaphragm is derived from the majority of the transverse septum. The portion of the diaphragm muscle originating from the pleuroperitoneal membranes is innervated by the phrenic nerves. On the other hand, the outer edge of the diaphragm muscle comes from a paraaxial ring of the body wall and is innervated by the intercostal spinal nerves T7-T12. Additionally, the mesenchyme adjacent to the anterior intestine condenses to form two muscular bands (the right and left pillars) that originate from the lumbar vertebral column and terminate on the dorsomedial diaphragm. The right pillar originates from the vertebral bodies L1 to L3, while the left pillar originates from the vertebral bodies L1 and L1.

In summary, the anterior and posterior diaphragm have different origins, which is evident in their histological structure. The arterial supply to the diaphragm also reflects its two major sources of origin. The peripheral part of the diaphragm is muscular and thick, while the center is thin and composed of connective tissue due to the influence of mesodermic and neural promoting factors.

References

1. Anatomia Omului, Volumul I: Embriologie; Semestrul I; Prof. univ. dr. med. Andrei Motoc; Editura „Victor Babeș”, Timișoara, 2018

2. Embriologie - Sinteze didactice; Romeo Chiriac, Anca Indrei ;Editura Fundatiei Chemarea, Iasi, 1997

3. Embriologie Umană; Lidia Chircor, Loredana Surdu;Editura Ex Ponto, Constanța, 2014

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