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Blood cells, blood vessels and heart Learning objectives Describe the origin of the embryonic blood cells and blood vessels. Describe the development of the heart including the formation of the primitive heart tube, cardiac looping and formation of the heart chambers. Consider briefly some conge...

Blood cells, blood vessels and heart Learning objectives Describe the origin of the embryonic blood cells and blood vessels. Describe the development of the heart including the formation of the primitive heart tube, cardiac looping and formation of the heart chambers. Consider briefly some congenital abnormalities in the development of the heart. Embryonic development is largely dictated by the availability of nutrients and the ability of these nutrients to reach all the cells and tissues of the growing embryo. Before implantation and development of the placenta, oxygen and nutrients entered the embryo and were distributed to all the embryonic cells by diffusion. As the embryo enlarges and increases in complexity, diffusion alone results inadequate for carrying nutrients to and removing waste from all the tissues and organs. At this point, the development of a functional embryonic circulatory system becomes essential for the embryo to survive. The first blood and vascular elements appear by the end of the third week in mammals, or by the end of the first day of incubation in birds. Blood cells and blood vessels start to develop simultaneously in the visceral mesenchyme lining the yolk sac and the allantois. These extraembryonic circulations (vitelline and allantoic blood networks) rapidly merge with the intraembryonic circulation which moves the blood inside of the embryo. Formation of blood cells The process by which the blood cells are formed is called haematopoiesis (also spelt hematopoiesis or hemopoiesis). Although the formation of blood and blood vessels is an early event, these processes must persist throughout the life of the individual to replenish the cellular constituent of the blood as needed. The first site of blood formation is the walls of the yolk sac. Later in embryonic life, the liver becomes the most important red blood cell-forming organs, but they are soon succeeded by the bone marrow, which in adult life is the only source of both red blood cells and the granulocytes. Therefore, three haematopoietic stages, mesoblastic period, hepatolienal period, and medullary period, are described. Prenatally, the three periods overlap one after the other, but the latter will persist postnatally throughout life. Mesoblastic period. It is the first extra-embryonic haematopoietic period that takes place approximately during the first third of embryonic development (in human, from the third week to two months). The first blood cells appear in the visceral mesoderm of the yolk sac wall from small nests of blood cell progenitors called blood islands. The blood islands are composed of clusters of splanchnic mesenchyme cells called haemangioblast which are the multipotent precursor cells that can differentiate into both haematopoietic (blood cells) and endothelial cells (blood vessels). Cells in the centre of the blood island turn into haematopoietic stem cells (HSCs), also called haemocytoblast, which are the precursors of all the blood cell types. Primitive red blood cells (primitive erythrocytes) are the first cell type to be originated in the yolk sac. Erythroid cells differentiate in the centre of the blood islands as erythroblasts, nucleus-containing large cells that complete their maturation, including enucleation, in the bloodstream. Peripheral cells develop into angioblast which forms the endothelial lining of the primitive blood vessels. The first blood vessels, with blood cells inside, are formed in the yolk sac when contiguous blood islands coalesce into larger units. This results in the formation of a network of primitive vitelline capillaries lined by a single layer of endothelial cells. Like in the yolk sac, angiogenesis also extends into the visceral mesoderm of the allantochorion to form the allantoic capillaries of the tertiary villi and the umbilical vessels. With continuous budding, the extraembryonic vessels gradually penetrate the embryo proper while haemodynamic factors induce the differentiation of the additional layers of tissue that characterise the walls of arteries and veins. The hepatolienal period. During the middle third of pregnancy, haematopoiesis moves inside the embryo. At this stage, haematopoiesis takes place in the mesenchyme of the liver, which, during this phase, is also called the haematopoietic sinus. Pluripotent stem cells migrate within the embryo and colonise the liver (hepatic phase). The erythrocytes that arise in the liver are nucleus-free - in contrast to those formed outside the embryo. A small portion - primarily for erythropoiesis – also appears in the spleen (lienal phase). First differentiation of leukocytes (white blood cells) and thrombocytes (platelets) can also be seen during this period. The medullary period. This period occurs in the last third of pregnancy. The haematopoietic activity is located in the bone marrow and further, in the lymph nodes, thymus and spleen. Haematopoietic stem cells emigrate and colonise the vessel system into the bone marrow and increasingly take over the formation of the blood. They are lifelong able to renew and differentiate themselves; they remain in the bone marrow and, according to need, can differentiate into every type of myeloid and lymphoid cells. In the postnatal period, the bone marrow produces all the red blood cells and 60–70 per cent of the white cells. The lymphatic tissues, particularly the thymus, the spleen, and the lymph nodes, produce the lymphocytes (comprising 20–30 per cent of the white cells). The reticuloendothelial tissues of the spleen, liver, lymph nodes and other organs produce the monocytes (4–8 per cent of the white cells). The platelets, which are small cellular fragments rather than complete cells, are formed from bits of the cytoplasm of the giant cells (megakaryocytes) in the bone marrow. https://sway.office.com/L7IOgfKWghJtx5UH#content=nwVnPWILYXdUpK - Stages in haematopoiesis. Hematopoiesis is the process that leads to the regulated formation of the highly specialized circulating blood cells from pluripotent hematopoietic stem cells (HSCs). The earliest stage of hematopoiesis takes place in the blood islands of the yolk sac; then, the haematopoietic cells migrate to the liver and spleen; finally, once the bones are present, marrow takes over the hempoyesis. - Differentiation of the blood cell types. The Haematopoietic Stem Cells (HSCs) are a heterogeneous population that gives rise to all the other blood cells. They are able to differentiate into any of the mature blood cells, which is greatly determined by micro-environmental factors such as haematopoietic growth factors and other cytokines. Formation of blood vessels Blood vessels can be formed by two distinct processes: vasculogenesis and angiogenesis Vasculogenesis. It is the de novo formation of vessels from endothelial progenitor cells, so- called angioblasts. This process is responsible for the formation of the firsts blood vessels which develop from blood islands in the wall of the yolk sac and allantois. Therefore, the vascularisation of the foetal membranes (yolk sac and allantois) is the result of the local formation of new capillaries from mesenchymal precursor cells in the yolk sac and allantois, rather than protrusion of embryonic vessels into the placenta. Angiogenesis is a lifelong process involving the growth of new blood vessels from pre- existing vessels. Angiogenesis is responsible for remodelling and expanding already formed vascular networks. Angiogenesis is a normal and vital process in growth and development, as well as in repairing damaged tissues (wound healing). However, it is also a necessary step in the pathological transition of tumours from a benign state to a malignant one (angiogenesis inhibitors are used in cancer treatments). https://sway.office.com/L7IOgfKWghJtx5UH#content=WBiahLlBzKBvMI - Development of the blood vessels. The first blood vessels are formed directly in the periphery of the blood island (vasculogenesis). Then, a second mechanism called angiogenesis gives rises to the formation of new blood vessels from existing vessels via sprouting and remodelling (angiogenesis) The first blood vessels to be formed are single-layer capillaries. Flow dynamics is considered the main driving force for arterial-venous specialisation. Blood under high pressure leaves the heart and is distributed to the body by a branching system of thick-walled vessels called arteries and arterioles when they are smaller. Arteries are comprised of three distinct layers, intima (epithelial cells or endothelium), media (muscular cells) and adventitia (connective tissue), but the proportion and structure of each vary with the size and function of the particular artery. As the number of arterial branches expands steadily, blood pressure and flow speed decrease progressively towards capillary beds. Capillaries are coated by a single epithelium (endothelium) favouring the interchange of oxygen, nutrients, waste products, and other substances with the extracellular fluid. Blood from the capillary bed passes into thin-walled venules and veins, which collects the blood from the periphery and directs it back to the heart. Veins are similar to arteries but, because they transport blood at a lower pressure, they are not as strong as arteries. Like arteries, veins have three layers: an outer layer of connective tissue, muscle cells in the middle, and a smooth inner layer of epithelial cells. However, they have much thinner walls, more irregular outlines and contain valves to prevent the backflow of blood. There is a tendency to regard any vessel which carries oxygenated blood as an artery, and any vessel which carries blood poor in oxygen and high in carbon dioxide content as a vein. This is a misconception that hinders the understanding of blood circulation. The differentiation between arteries and veins which holds good for all forms, both embryonic and adult blood circulation, is based on the structure of the walls of the vessels, and on the direction of the blood flow with reference to the heart. An artery is a vessel carrying blood away from the heart under relatively high fluctuating pressure due to the pumping of the heart. Correlated with the pressure conditions in it, its walls are heavily reinforced by elastic and muscle tissue. A vein is a vessel carrying blood toward the heart under relatively low and constant pressure from the blood welling into it from capillaries. Correlated with the pressure conditions characteristic for it, the walls of a vein have much less elastic and muscle tissue than artery walls, and more non-elastic fibres reinforcing them. https://sway.office.com/L7IOgfKWghJtx5UH#content=LOgs5fBrJ1Z1fc - Differentiation of arteries, veins and capillaries. Arteries and veins are primarily defined by the direction of blood flow. Differences in oxygenation and blood pressure result in specific anatomical and functional features. Heart development The heart is the first functional organ in vertebrate embryos. In mammals, it beats spontaneously by week 4 of development and by the second day of incubation in birds. This emphasises the critical role of the heart in distributing blood through the vessels and in the vital exchange of nutrients, oxygen, and wastes. The quick development of the heart is reflected by a cardiac bulge or prominence that appears on the cranial surface of the early embryos. Early cardiac development involves the formation of a heart tube, looping of the tube and formation of chambers. These processes are highly similar among all vertebrates, which suggest the existence of evolutionary conservation of the building plan of the heart. The tubular heart Development of the heart begins with the formation of two special endothelial vessels from an area of splanchnic mesoderm situated in the wall of the yolk sac anterior to the head process of the embryo that is called the cardiogenic plate. This cardiogenic mesenchyme is the origin of two bilateral endothelial blood vessels, called endocardial tubes, on either side of the embryonic midline. Each tube is continuous cranially with a dorsal aorta that conveys the blood inside the embryo, and caudally with a vitelline vein, that collects the blood from the yolk sac. - Formation of the cardiogenic plates and endocardial tubes. The heart comes from a special pair of blood vessels which differentiate from an area of the splanchnic mesoderm situated cranially to the developing neural tube called the cardiogenic plate. At their cranial ends, the cardiac tubes will be continued with the primitive aortae thus forming the outlet of the heart. At their caudal ends, the tubes will be joined to venous systems, defining the inlet of the heart. Eventually, the two tubes will fuse into a single developing heart that expands in diameter and begins to pump blood out into the aortic system. As the embryo folds and the head process grows, the paired endocardial tubes move ventral to the pharynx, meet at the midline and fuse into a single tubular heart. The endothelium of the primitive vessels turns into the definitive cardiac endocardium. Splanchnic mesoderm surrounding the tube forms the myocardium, the cardiac muscle cells capable of pumping blood. The outer layer of the heart is called epicardium and will be established with the development of the body cavities. The primary heart tube undergoes pronounced elongation and subsequently, the tube itself bends as the heart is enclosed within the pericardial cavity. At first, the tubular heart grows into a C-shaped loop. Then, as the four-chambers develop, the C-shaped loop rotates and elongates to form an S- shaped loop with the left and right segments projected on each body side. Also, this curved shape creates a convergence of vessels entering and leaving the heart in such a way that the inflow and outflow of the heart end up located at the base of a conical heart. Cardiac looping is the first visible sign of right-left asymmetry during embryonic development. Left- right development of the heart (and other organs) is critically dependent upon upstream signalling pathways that impose asymmetry onto what is initially a bilaterally symmetric body plan. These early-acting pathways are collectively known as “left-right axis determination”. Deviations in left-right axis determination during embryogenesis result in a wide spectrum of abnormal laterality phenotypes that are generally classified as either situs inversus or situs ambiguous. Situs inversus is a condition in which the left-right axis is reversed in alignment with the other two body axes, resulting in a mirror image of a normal body and organ locations. https://sway.office.com/L7IOgfKWghJtx5UH#content=WfRxIyKcsitMl9 - Looping of the tubular heart. During the early stages of embryonic development, the heart is a smooth-walled, muscle-wrapped tube that bends and rotates in a vital, but poorly understood, a morphogenetic process called looping. Some portions of the cardiac tube expand more quickly than others, resulting in a segmented tube with dilatation separated by indentation. In caudo-cranial order the expanded portions of the cardiac tube are: Sinus venosus. A paired region into which veins drain. Over time, the left sinus venosus becomes the coronary sinus; the right is incorporated into the wall of the right atrium. Atrium. A region that receives blood, and when the heart muscle contracts, pump blood to the ventricle. At the level of the atrioventricular channel, the endocardial wall develops two thickenings known as endocardial cushions; they are the origin of the atrioventricular valves. Ventricle. It is one large chamber that collects and expels the blood received from the atrium towards the periphery of the body. This primary ventricle is destined to become the left ventricle. Bulbus cordis. The bulbus cordis, or bulb of the heart is a bulb-shaped region destined to become right ventricle. The rounded shape is mostly due to the development of two opposing subendocardial thickening called bulbar ridges. Truncus arteriosus. It is the common arterial trunk that originates from the ventricle in the single tubular heart. With the partition of the right and left chambers, the truncus arteriosus will divide into the aorta and the pulmonary trunks. https://sway.office.com/L7IOgfKWghJtx5UH#content=g9hE0W8EKMyg5f - Structure of the tubular heart. The tubular heart or primitive heart tube is the earliest stage of heart development. From the inflow to the outflow, it consists of sinus venosus, primitive atrium, the primitive ventricle, the bulbus cordis, and truncus arteriosus. Formation of the four chambers of the heart The heart development is not completed until the tubular heart is transformed into a complex organ with four valves and four chambers. Gradually, septa begin to grow in the primary atrium, ventricle and bulbus cordis to give rise to the right and left atria, right and left ventricles and the origin of two great arterial trunks, the aortic and pulmonary trunks. From an evolutionary perspective, the formation of the four-chambered heart reflects the changes that had to take place in aquatic ancestors, with two-chambered heart, to evolve into air-breathing species. Fish have a single circulatory system where blood flows unidirectionally from the two- chambered heart through the gills and then the rest of the body. This unidirectional flow of blood produces a gradient of oxygenated to deoxygenated blood around the fish’s systemic circuit. Amphibians partially separate two circulatory routes: one to provide blood with oxygen through the lungs and skin, and the other to carry oxygen to the body. Consequently, amphibians develop a three-chambered heart with two atria and a single ventricle where blood from both circuits mixes, which reduces the efficiency of oxygenation. Reptiles also have two circulatory routes; however, blood is only oxygenated through the lungs. The heart is three-chambered, but the ventricles are partially separated so that little mixing of oxygenated and deoxygenated blood occurs, except in crocodilians. Mammals and birds have the most efficient circulatory circuit with four chambers completely separated (double circulatory system): two left chambers pumping the oxygenated blood to the body (systemic circulation) and two right chambers moving the deoxygenated blood toward the lungs (pulmonary circulation). However, embryos of terrestrial animals keep developing in an aquatic environment, where the complete separation of the pulmonary and systematic circulations does not make any sense. Accordingly, much of the prenatal circulation depends on a sort of three- chambered circulation that has to be able to bypass the non-functional pulmonary circulation; simultaneously, the prenatal circulation must be compatible with the development of a four- chambered heart necessary for a double (systematic/pulmonary) postnatal circulation. Upon birth, with the first breaths of air, the new-born must change from the aquatic-like prenatal circulation to a lung based double circulation with complete separation of the systematic and pulmonary circulation. Amazingly enough, throughout all these major structural changes the foetal heart must keep functioning effectively without interruption. Although the partition of the atrium and the ventricle take place simultaneously, we are going to consider them as separate events for descriptive purposes. Division of the atrium An interatrial first partition, called septum primum, grows from the dorsal wall of the atrium toward the endocardial cushions leaving a transient open gap, called foramen primum. It progressively decreases in size as the septum grows downwards and eventually disappears when the septum primum meets the endocardial cushion. The closed foramen primum is replaced by a foramen secundum that is formed by small perforation in the dorsal region of septum primum. A second interatrial septum, septum secundum, semilunar in shape, grows downward from the dorsal wall of the atrium immediately to the right of the septum primum. The septum remains incomplete because its free edge establishes the limit of a wide hole called foramen ovale. The foramen ovale is an opening in the foramen secundum that allows temporary communication between the right and left atria. During prenatal life, the blood pressure in the right atrium exceeds that of the left atrium; as a result, blood flows from the right atrium to the left: blood from the right atrium enters the foramen ovale and exits into the left atrium. At birth, when the pressure in the left atrium exceeds the pressure in the right atrium, the septum primum is forced against the foramen ovale, acting as a valve to preclude the flow of blood between both atria. Initially, after birth, the foramen ovale closes due to a functional change in the relative pressure of the two atrial chambers. This functional closure can be reversed during the immediate neonatal period. Over time, the two overlapped septa fuse to give rise to the final inter-atrial septum. Nevertheless, a remnant of the foramen ovale is always visible as an indentation in the wall of the right atrium, the fossa ovalis. https://sway.office.com/L7IOgfKWghJtx5UH#content=c3QlHUO1D8VPAK - Partition of the atrium. Membranous tissue forming the septum primum grows from the ceiling of the atrium, dividing it into left and right halves. A strong muscular septum secundum grows immediately to the right of the septum primum and gradually overlaps the foramen secundum during the fifth and sixth weeks of development. The incomplete partition of the atrium by the septum secundum forms the foramen ovale. Blood flows from the right atrium through the foramen ovale and foramen secundum to the left atrium, forming a right-to-left shunt. The remaining portion of the septum primum acts as the valve of the foramen ovale. Blood cannot flow in the opposite direction, as the muscular strength of the septum secundum prevents prolapse of the septum primum. Division of the ventricle The primary ventricle and the bulbus cordis are the origin of the left and right ventricle, respectively. Both ventricles are gradually separated by an interventricular septum that growth from the ventral part of the tubular heart. The dorsal part next to the atrioventricular communication is gradually closed by a membranous part. The proper closure of the interventricular septum is completed with the partition of the truncus arteriosus and endocardial cushions, all of which should be completed before birth. https://sway.office.com/L7IOgfKWghJtx5UH#content=WdnLn0SfCdQoWQ - Partition of the ventricle. The first stages of the division of the primordial ventricle into two is by means of the primordial interventricular septum. This is a muscular ridge, a thick crescentic fold with a concave free edge. There is a temporary crescent-shaped interventricular foramen between the free edge of the interventricular septum and the endocardial cushions. This foramen is closed by the membranous part of the interventricular septum which fuses with the endocardial cushions. Division of the endocardial cushions The endocardial cushions grow until they meet and fuse in the midline to form the septum intermedium; thereby, the primary atrioventricular channel is divided into the right and left atrioventricular openings. The endocardial cushions will be transformed into the atrioventricular valves. The left atrioventricular valve is made of two flaps (bicuspid or mitral valves); the right one comprises three flaps (tricuspid valves). The valves are attached to the bottom of the ventricular wall by the tendinous chords and papillary muscles. These irregularities of the internal ventricular wall are all sculptured by a selective excavation of the ventricular wall tissue. A variety of congenital defects may result from improper valve sculpturing. https://sway.office.com/L7IOgfKWghJtx5UH#content=bVPAUML6GVfLLG - Formation of the atrioventricular valves. The partitioning also affects the atrioventricular canal where two masses of cardiac mesenchyma, known as endocardial cushions, fuse in the middle of the canal to form the septum intermedium, which divides the common canal into the left and right atrioventricular openings. Mesenchyme from the endocardial cushions gives rise to the left and right atrioventricular valves. Division of the truncus arteriosus The partition of the ventricle is correlated with the division of the exit of the heart: the bulbus cordis and truncus arteriosus. This provides separated outlets from the left and right ventricles into the aortic trunk, and pulmonary trunk, respectively. Two subendocardial swellings, called bulbar ridges, appear along the lumen of the wall of the bulbus cordis, grow inwardly and merge to create the spiral septum, also called aorticopulmonary septum. As a result, the bulbus cordis and the adjacent truncus arteriosus are divided into the initial segment of the aortic and pulmonary trunks which spiral around one another. Upon completion of the aorticopulmonary septum, the bulbar ridges also contribute to the formation of the aortic and pulmonary semilunar valves which develop by a selective excavation of endocardial swelling in initial part of those vessels. https://sway.office.com/L7IOgfKWghJtx5UH#content=Oox0L9IgoWzegd - Partitioning of the Bulbus Cordis and the Truncus Arteriosus. Active proliferation of mesenchymal cells in the walls of the bulbus cordis and arterial trunk results in the formation of bulbar ridges (left and right). The bulbar ridges undergo a spiral growth, resulting in the formation of the aorticopulmonary septum when they fuse. The spiralling is possibly caused by the streaming of blood from the ventricles. The spiralling of the aorticopulmonary septum causes the pulmonary trunk to twist around the aortic trunk. The first portion of the pulmonary artery and the aorta are connected in the developing foetus by a short blood vessel called ductus arteriosus. During development, the ductus arteriosus stays open to allow oxygenated blood to bypass the pulmonary circulation (since breathing is not yet possible) and enter directly into the systemic circulation. After birth, the ductus arteriosus closes and becomes the ligamentum arteriosum. - The ductus arteriosus, is a blood vessel in the developing fetus connecting the trunk of the pulmonary artery to the proximal part of the aorta. It allows most of the blood from the right ventricle to bypass the fetus's fluid-filled non- functioning lungs. Upon closure at birth, it becomes the ligamentum arteriosum.

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