In this review, we summarize how vertebrates change the structures and functions of their circulatory systems according to environmental changes. The heart is a pumping organ that circulates blood containing gases and nutrients to the entire body, which is observed even in animals in a basal position phylogenetically. Acquisition of pulmonary circulation is an important event in cardiac evolution, and the oxygen concentration in the blood is tightly associated with this event. Fish have a single circulation system and use gills as a respiratory organ.
The heart of fish is composed of a sinus venosus, atrium, ventricle and outflow tract OFT. They use gills as the respiratory organ at the larval stage and then use skin and lungs after metamorphosis. The skin provides a large part of the respiratory function; thus, amphibians do not require a septated heart to separate arterial and venous blood completely. Reptiles have a systemic heart adapted to terrestrial life and have a higher metabolic rate.
In reptiles, the sinus venosus is reduced compared to that of amphibians, and the atrium is completely divided into two chambers. In addition, reptiles have a unique OFT that is divided into three arteries; the right arterial trunk derived from the left ventricle and the left arterial trunk and pulmonary artery trunk derived from the right ventricle. In both squamates and chelonians, during aerial respiration, venous blood is mainly sent to the pulmonary artery trunk. By contrast, when they are in the water, venous blood is sent to the left arterial trunk due to the pulmonary resistance working against it.
In addition, crocodilians have a ventricular septum and foramen of Panizza that connects the right and left aortic arches. During aerial respiration, the arterial blood from the left ventricle is circulated into both aortic arches through the foramen of Panizza due to the high pressure of the blood flow from the left ventricle.
However, in an aquatic environment, when a crocodile dives, the blood from the right ventricle mainly flows into the left aortic arch not into the pulmonary artery. Thus, reptiles make their circulation efficient to adapt to their living environment. In birds, the sinus venosus is more reduced than in reptiles, and in mammals, it becomes a part of the right atrial wall. The OFT splits during development and forms a single pulmonary trunk and a single aortic trunk in the adult.
Contrary to the adult heart, embryonic hearts of birds and mammals have systems similar to those of basal vertebrates that inhabit aquatic environments in that it is possible to bypass pulmonary circulation. One bypass is the foramen ovale, through which blood in the right atrium flows into the left atrium directly, and the other is the ductus arteriosus, which is a tunnel connecting the pulmonary artery and aortic arch.
Given these patterns, how do vertebrates establish the developmental programs by which heart morphogenesis has adapted to their living environments? Here, we summarize the current understanding of mechanisms by which vertebrates adapt to the living environment with alterations of the heart structures and functions of their circulation systems.
The OFT is an organ that connects the ventricle and ventral aorta. In fish evolution, teleosts have acquired a unique OFT, called the bulbus arteriosus BA , which has a swollen shape and is rich in elastin. The most characteristic feature of the BA is that the OFTs of nonteleost fish and other vertebrates consist of cardiac muscle, whereas the BA consists of smooth muscle. Teleosts are thought to be fish species well adapted to the aquatic environment through obtaining the BA over the course of evolution. By this function, microvessels in the gills are protected from the high pressure of the bloodstream, and the blood can flow into the gills efficiently.
Therefore, the BA has been considered one of the most important organs in teleosts; however, the molecular mechanism underlying BA acquisition and formation in fish evolution and development was unclear. The KD of elna caused subtle hypoplasia of the BA but not ectopic cardiac muscle formation. Furthermore, the migration pattern of cardiac progenitor cells was not affected in elnb KD embryos.
These results indicate that elnb regulates the cell fate determination of cardiac progenitor cells; elnb converts BA progenitor cells from cardiac into smooth muscle cells. Furthermore, KD of mechanotransducer yap also caused ectopic cardiac muscle formation in the BA. The septation of the OFT is an important event for the development of double circulations. At early stages of heart development, the OFT is a single tube and then is divided by the septum, which separates the OFT into the aorta and pulmonary artery. The OFT septation is also observed in cardiac evolution of vertebrates and is closely related to the establishment of pulmonary circulation.
Fish have a nonseptated OFT; the teleosts have a BA as described above, and the nonteleost fish have a tubular OFT with valves to prevent countercurrent of blood flow. As we mentioned above, reptiles have three great arteries; pulmonary artery and a left visceral and a right systemic aorta. Crocodiles have a unique shunt, the foramen of Panizza, which forms a channel through the aortic half of the distal septal cushion, and then the lumina of the visceral and systemic aorta are joined.
Noncrocodilian reptiles e. In turtles, a structure resembling an interventricular septum was observed at the prehatching stage. This result indicates that the restricted expression of Tbx5 to the left ventricle would be tightly related with the formation of the ventricular septum. The conditional deletion of Tbx5 using Nkx2. These results indicate that the mechanisms of ventricular septum formation between birds and mammals are slightly different.
This result indicates that the functional partitioning is already present in a single ventricle of zebrafish and such regional physiology is under the control of the same transcriptional programs as mammals. The myocardial compact layer epicardial side is composed of immature cardiomyocytes undergoing higher levels of proliferation under lower oxygen tension as compared with cardiomyocytes in the trabeculae endocardial side 28 , 30 , Ultimately, the coronary vasculature is established to meet the increasing demands of the myocardial wall expansion 44 , It has been demonstrated that hypoxia in combination with vascular endothelial growth factor VEGF and platelet-derived growth factor PDGF mediates the formation of the primary capillary plexus angioblasts as well as subsequent vasculogenesis formation of new vessels and angiogenesis budding and sprouting from pre-existing vessels , leading to the establishment of a functional coronary artery tree 84 — 87 Figure 2.
A complex coordination exists between the fetal cardiovascular system and the placenta to ensure stable oxygen levels 73 , 88 — Low maternal blood oxygen levels, cardiovascular failure, or impairment of placenta formation and function can induce pathological fetal hypoxia 89 — In pathological hypoxia, the fetus responds by favoring circulation to vital organs such as the brain and heart.
In addition, a concomitant activation-specific stress response for example, Hif-dependent and vascular endothelial growth factor pathways 80 , 81 , 83 occurs. Chronic fetal pathological hypoxia induces heart septation defects 93 , myocardial wall thinning, chamber dilation, and epicardium detachment 79 as well as decrease of cardiomyocyte proliferation and increase of apoptosis Of note, in utero stress is also driven by other environmental stressors, including malnutrition that culminates with cardiac malformations and increased predisposition to adult chronic diseases 95 — A color code and symbols were assigned and followed to define the microenvironment condition depicted in the legend.
E, embryonic day. The ability to maintain oxygen homeostasis is essential for many biological processes, including cell survival and overall development and tissue maintenance. Specialized cells for example, smooth muscle cells and carotid and neuroepithelial bodies mobilize proteins and regulate gene expression in order to adapt to hyperoxia or hypoxia — This physiological hypoxia is important for placental and fetal morphogenesis and growth During development, fetal arterial blood oxygen tension ranges between 22 and 32 mmHg but in the adult systemic tissues is about 80 to mmHg Fetal arterial blood persistently contains less oxygen, suggesting that fetal development occurs in a state of relative hypoxia that is, physiological hypoxia in comparison with the adult The murine heart is the first organ to function during development E8.
The developing heart relies primarily on carbohydrates that is, glucose and lactate as a source of ATP 74 , Glucose is transported to the cytosol of cardiomyocytes and used for glycolysis, glycogen synthesis, or pentosephosphate shunt metabolic pathway parallel to glycolysis. Glycogen synthesis and storage in fetal cardiomyocytes have been shown to be important sources of phosphorylated glucose, which protects cardiomyocytes from hypoxia. During fetal development, cardiomyocytes have low mitochondrial content 75 , In summary, embryonic and fetal cardiac development occurs in a physiological hypoxic state, which is essential for the ability of cardiac progenitors to proliferate, self-renew, and differentiate for example, immature cardiomyocyte hyperplasia or neo-angiogenesis.
The mammalian heart undergoes a marked increase in workload upon birth, and, in the mouse, the first few weeks of postnatal life are characterized by extensive ventricular remodeling coincident with switch from anaerobic metabolism glycolysis to aerobic metabolism oxidative phosphorylation of fatty acids 99 , Experiments performed in rabbits show that while circulating levels of fatty acid are high following birth, the switch from glycolysis to aerobic metabolism occurs only at the end of the first week and the neonate heart retains an enriched ability to produce ATP by glycolytic metabolism 75 Figure 2.
Postnatal myocardium growth involves an increase in hemodynamic demands and is characterized by a thickening and vascularization of the ventricular myocardial wall 27 , — Mouse postnatal growth follows three main steps: hyperplasia postnatal day 0 [P0] to P4 , the transitional phase when hyperplasia and hypertrophy processes occur simultaneously P5 to P15 , and hypertrophy after P15 , , Studies in rodent models have shown that a last round of DNA synthesis and karyokinesis takes place without cytokinesis during the hypertrophy phase, culminating in the bi-nucleation of postnatal cardiomyocytes , , — In addition to cardiomyocyte maturation, there is a marked growth and maturation of the coronary vasculature The perinatal period is characterized by angiogenesis and an expansion of the capillary network , This increase of the coronary tree is due to the proliferation of pre-existing capillary endothelial cells and increase of the capillary length as well as increases in the thickness, length, and branching of arterial and venous coronary vasculature , , In , Porrello and colleagues demonstrated that the mouse neonatal heart regenerates in response to ventricular apex resection as well as experimentally induced myocardial infarction MI The regenerative process of the neonate heart is characterized by clot formation at the site of injury coupled with an inflammatory response followed by epicardial cell and cardiomyocyte proliferation, ultimately leading to a restoration of cardiac function , It is of interest that this regenerative capacity is lost during the first few days after birth , , which, as noted above, corresponds to the time point during which the terminal differentiation of cardiomyocytes is concluded , Although these studies support the proposal that the mammalian neonatal heart possesses pronounced regenerative capacity, including the ability to replace cardiomyocytes, these results have been challenged by using the same experimental model in which limited cardiomyocyte proliferation and deficient neo-angiogenesis coupled with extensive scarring were observed , These different outcomes have been suggested to be due to technical variation — , difficulties in tracking mouse cardiomyocyte proliferation during the first week of life , and timing of post-injury follow-up, where longer post-injury period allows more time for scar tissue deposition Although there remains considerable debate regarding the efficiency of neonatal heart regeneration, it is generally agreed that the neonatal myocardium has some proliferative and angiogenic capacity which is lost in the adult heart What might explain this more robust repair capacity during the first week of postnatal life in the mouse?
As outlined in the previous section, the murine heart undergoes a metabolic switch to oxidative metabolism coupled with the maturation and bi-nucleation of cardiomyocytes, and the maturation of the coronary vasculature, which is driven by the availability of oxygen. This raises the hypothesis that low levels of oxygen during early postnatal life present a permissive context in which regeneration can occur. The adult mammalian heart is one of the least-regenerative organs in the body; thus, injury, most notably MI, leads to a progressive decrease in heart function and ultimately results in heart failure.
De novo dNTP production is essential for normal postnatal murine heart development
In the past two decades, several studies have shown that the uninjured adult heart replaces a low percentage of the total cardiomyocytes — Renewal of pre-existing cardiomyocytes is approximately 0. This low turnover rate implies that the vast majority of cardiomyocytes present at the conclusion of postnatal development remain throughout the entirety of adult life , It has been demonstrated that adult cardiomyocytes undergo a fourfold increase in turnover following injury , — ; however, the origin of new cardiomyocytes remains unclear.
Several studies have provided evidence for the existence of adult resident CPCs that are able to give rise to cardiomyocytes and non-myocytes that represent a potential source for heart regeneration Table 1. CPCs have been defined and isolated by the expression of different markers clustered in niches in specific regions such as the atria, apex, and epicardium 58 , , Table 1 ; however, it is still unclear whether these different subsets belong to the same cell population or represent different CPC populations or do both.
After injury, CPCs are activated and give rise to different cell types that is, myofibroblasts and smooth muscle cells and, to a lesser extent, endothelial cells and cardiomyocytes Of note, the contribution of these cells to new cardiomyocytes during steady-state and injury is highly debated One high-profile example is the c-kit expressing CPCs, which have been reported to possess proliferative capacity and the ability to differentiate into cardiomyocytes — , , whereas other studies have refuted these observations and observe little to no cardiomyogenic potential — Other studies have provided evidence demonstrating that the formation of new cardiomyocytes comes from pre-existing cardiomyocytes that proliferate in human steady-state young heart as well as in pathological conditions , , — Similarly, in the mouse, studies have suggested that new cardiomyocytes are derived from pre-existing cardiomyocytes that re-enter the cell cycle , , , — or arise from dedifferentiated myocytes , Regardless of whether one or both of these models are accurate, it is clear that the adult heart is unable to functionally restore the adult myocardium following cardiac injury , , , , In addition to the inefficient renewal of cardiomyocytes after injury, little revascularization is observed in the adult heart following injury, which likely contributes to poor cardiac regeneration , Some studies revealed that endocardial cells, resident endothelial cells, or even fibroblasts can adopt an endothelial cell-like fate and contribute to angiogenesis in response to cardiac injury; however, the involvement of CPCs in this process remains largely controversial — In the next section, we consider whether the potential of the heart to neovascularize following injury is a key process for future therapeutic targeting for heart disease.
The adult myocardium is surrounded and protected by the epicardium, which consists of a single mesothelial cell layer. As described in the previous section, the fetal epicardium is a source of cellular components and paracrine signals that promote coronary vasculature formation and myocardial growth — Once the heart is mature, EPDCs progressively lose their capacity to undergo EMT and the epicardium enters a primarily quiescent state , , Figure 3.
In the adult, the role of the epicardium is to provide a physical barrier against infection More recently, it has been shown that the epicardium is a key responder to heart injury , , Figure 3. Specifically, the epicardium re-expresses genes typically observed during fetal epicardial development in response to injury, including Wt1 , Tbx18 , and Raldh2 , coupled with proliferation and EMT to form a thick layer of EPDC mesenchymal cells , EPDCs contribute to adventitial and interstitial fibroblasts and smooth muscle cells , , Figure 3 , suggesting that the adult epicardium serves as a reservoir for mesenchymal progenitor cells Both the microenvironment and the cellular component are represented.
A color code was assigned and followed to define each of the cardiac cell types and their associated cells depicted in the legend. EMT, epithelial-to-mesenchymal transition.
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The different transgenic models used in the two studies may explain the discrepancy of the results obtained. Wagner and colleagues demonstrated that Wt1 , the epicardial master transcription factor, is expressed in the coronary vessels of injured heart, suggesting a role for Wt1 in the vascular growth after cardiac injury. In addition to providing a protective role for the heart, the epicardium serves as a reservoir for CPCs that are activated in response to injury. As such, the adult epicardium merits future research for targeting and ameliorating mammalian heart repair.
The heart continually adapts to changing workloads brought about by aging, physical activities, and disease. The heart produces energy using multiple metabolic substrates such as fatty acids, glucose, ketone bodies, lactate, and amino acids — It is estimated that the heart uses between 3. Fatty acids are more energy-dense and thus provide more ATP molecules per consumed carbon as compared with the other substrates; however, fatty acid pathway requires more oxygen , , To meet this high ATP demand, the heart requires oxygen. When the body is at rest, myocardial oxygen consumption is greater than the oxygen consumption of any other organ of the body , , Coronary circulation ensures the delivery of metabolic substrates and oxygen to the myocardium.
However, hypoxic conditions resulting from either physiological states for example, during exercise or pathological states for example, coronary artery disease with mild ischemia require the glycolytic pathway in order to produce ATP , , Although the high levels of environmental oxygen and adult stem cell niches for example, bone marrow — are characterized by low concentration of oxygen tension, this favors glycolytic metabolism. Although it has been shown to be essential, the exact mechanism of glycolytic metabolism and hypoxia in the maintenance of stemness properties is not well understood , A protective mechanism of the adult stem cells against reactive oxygen species ROS has been implicit, but more studies are needed , , As described previously, the epicardium represents a reservoir of adult CPCs and, like other adult stem cell niches, displays a low oxygen tension and relies on glycolysis-dependent metabolic pathways cytoplasmic glycolysis , — Figure 3.
Cardiovascular diseases are a major cause of human mortality At present, long-term and effective treatments are missing. It is noteworthy that in high-altitude regions, cardiovascular diseases are less prevalent — , which has been attributed to continuous low-level hypoxia , , Hypoxia activates an evolutionarily conserved adaptive process that allows mammals to cope with restricted oxygen tension. Indeed, as already described in this review, the hypoxic environment promotes a metabolic switch from aerobic mitochondrial metabolism to anaerobic cytoplasmic glycolysis, which is an essential feature of heart development driving cell proliferation, self-renewal, and differentiation 78 , 80 — 83 as well as of specific cardiac processes such as ventricular wall expansion through cardiomyocyte hyperplasia 28 , 30 , 83 or stimulation of angiogenesis and formation of coronary vasculature 84 — This feature of adult progenitor cells allows ATP production in the absence of oxygen, providing an advantage in a hypoxic environment Additionally, it has become clearer that while oxidative metabolism is more efficient for producing ATP, cellular senescence and cell cycle arrest are a consequence of the resultant oxidative stress Although this review is focused on mammalian heart biology, it is important to note that lower vertebrates such as the zebrafish maintain a capacity to fully regenerate large domains of damaged myocardium through the proliferation of pre-existing cardiomyocytes , , which is similarly triggered by a hypoxic protective response These results prompted Sadek and colleagues , to explore the response of the mammalian heart to injury under hypoxic environmental conditions.
Sadek and colleagues proposed that the gradual reduction of environmental oxygen promotes glycolytic metabolism and reduces oxidative phosphorylation. This metabolic switch decreases ROS and cellular senescence and promotes the activation of proliferation of a small fraction of pre-existing cardiomyocytes , ; however, it is also likely that additional progenitor populations contribute to this response. Additionally, Sadek and colleagues noted that there is a marked cardiac vascular network expansion that is, the increase of coronary collaterals and capillary size in the infarcted area after exposure to low levels of oxygen as compared with controls As discussed above, the angiogenesis is dependent upon the oxygen tension and thus on the metabolic status of the microenvironment.
Emerging evidence suggests that the epicardium is an important source of stromal progenitor cells during development and that it maintains this capacity in the adult, potentially because of the particular hypoxic and glycolytic environment preserved in this adult heart compartment. While chronic exposure to high altitude carries collateral health risks in humans, it is tempting to propose that low oxygen tension can maintain the epicardium in an activated state, thus preserving perinatal plasticity, which in turn leads to improved cardiac repair.
Further investigation of the adult CPCs and their microenvironment will provide important leads for improving cardiac repair following injury. Taken altogether, while robust heart regeneration in the adult has yet to be achieved through therapeutic intervention, an understanding of the environmental clues and metabolic state of the developing heart will provide essential clues for novel therapeutic approaches.
In the short term, it may be important to reconsider methodologies used during patient recovery following heart injury or insufficiency or both. How this can be achieved in a clinical setting and what additional clues can be translated to the clinic will be an interesting focus for the next decade.
AS and MV contributed to original draft preparation and to reviewing and editing. DS contributed to conceptualization and to reviewing and editing. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. F Faculty Reviews are written by members of the prestigious F Faculty. They are commissioned and are peer reviewed before publication to ensure that the final, published version is comprehensive and accessible.
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Close Copy Citation Details. This important insight highlights the key interplay between DNA-binding factors and chromatin-remodeling complexes. The potential role of histone acetylation in cardiac development is highlighted largely by work performed on the HATs p and CBP and their interactions with cardiac transcriptional regulators. Mice lacking p have multiple defects in embryogenesis, including cardiac defects such as reduced ventricular trabeculation and impaired expression of cardiac genes Yao et al. Thus, pmediated histone acetylation is likely to be a widespread mechanism for coactivating cardiac genes.
Thus, defective Tbx5-mediated histone acetylation may contribute to the congenital heart defects associated with the syndrome. Repressing transcription by epigenetic regulators is also important for normal heart development. Histone deacetylases HDACs , which repress gene expression, have been largely characterized from mouse knockouts as important for adaptive gene regulation in the adult heart, but their roles in the developing heart are emerging. Of potential significance to the developing heart, HDAC function is highly regulated by cellular signaling processes.
Thus, in the developing heart, HDACs may have complex functions that depend on interactions with DNA-binding transcription factors and growth factor signaling pathways. Indeed, two transcription factors essential for heart development—Smyd1 also known as mBop and homeodomain-only protein Hopx —function in part by associating with HDACs Gottlieb et al. Thus, through their associations with transcription factors, HDACs are important for heart development. One of the best-studied repressive marks is the trimethylation of lysine 27 of histone H3 H3K27me3. This mark is laid down by the polycomb repressive complex 2 PRC2 , which comprises three core subunits: Suz12, Eed, and the catalytic histone methyltransferase, Ezh2 Surface et al.
Ezh2 deletion in cardiac precursors leads to defective cardiac morphogenesis, including thinned myocardial walls and ventricular septation defects He et al. This is perhaps as a result of impaired proliferation, as a result of the derepression of negative regulators of the cell cycle. Interestingly, cardiac progenitor genes that would normally no longer be expressed in the heart are still on, indicating that PRC2 function is essential to shut off progenitor genes permanently once they are no longer needed in differentiating cardiomyocytes. A slightly different ablation of Ezh2 , in a more restricted domain of cardiac progenitors, leads not to defects in cardiac morphogenesis, but instead to cardiac enlargement after birth Delgado-Olguin et al.
This results mainly from lack of repression of one transcription factor that functions in cardiac precursors, the homeodomain transcription factor encoded by Six1. When its expression persists, Six1 can still activate noncardiac genes, including genes normally restricted to skeletal muscle. Therefore, epigenetic repression of developmental regulators by PRC2 is an essential component of early cardiac development. Ezh2 may also function independently of histone methylation, as a direct methylator of GATA4; GATA4 methylation represses its transcription activation potential He et al.
Studying early heart development yielded many important lessons that are relevant to lineage specification and differentiation. Transcriptional regulation of cardiac differentiation underscored the importance of combinatorial factor interactions in robust regulation of tissue-specific gene expression.
Furthermore, from modeling human CHD in the mouse, these interactions are dosage sensitive, indicating a very fine integration of transcriptional inputs Bruneau et al. Understanding how transcription factors and chromatin remodelers interface contributes to a model by which transcription factors promote or repress target gene expression in a specific cell type.
The study of early gene expression and its regulators has also led to important insights into mechanisms of lineage determination and lineage allocation that are relevant to most mammalian cell types. Integrating these investigations will yield a comprehensive view of cell lineage determination and regulation of differentiation.
Heart formation includes several important steps that precisely organize the various cellular subtypes into chambers and associated structures. Along the way, precise patterning of gene expression underlies many of the events that drive organogenesis see Fig. Patterning the developing heart. In situ hybridization in mouse embryos illustrates the complexity and precision of patterning. Shown are in situ hybridizations for Bmp2 with expression in atrial precursors at E8.
Adapted from Bruneau , On differentiation, the bilateral regions of mesoderm that will form the heart migrate toward the midline to form a linear heart tube. Defective convergence of the two sides of the heart-forming region results in cardia bifida, in which cardiac differentiation proceeds independently in two separate areas, and a normal heart does not form.
In striking cases, cardiac development proceeds some distance. Sometimes, the paired hearts form primitive chambers Li et al. Although the cellular mechanisms required for bilateral migration and fusion are not well understood, several transcriptional regulators are known to be important for this process. Mesp1 is required early on, presumably to allow migration of cardiac precursors to their appropriate location Saga et al. Gata4 is also essential for cardiac fusion Kuo et al.
The proprotein convertase furin also has essential functions in regulating embryonic ventral closure, and in its absence cardia bifida is a common phenotype Roebroek et al. At the onset of heart looping, the chambers begin to form. The first evident chamber is the single ventricle that bulges out from the looping heart tube.
As this chamber grows, a morphologically recognizable right ventricle begins to form, and the atria begin to grow into the laterally paired appendages visible behind the more evident ventricular chambers. One interesting hypothesis suggests how the ventricular and atrial chambers grow, whereas the rest of the heart tube remains more or less in its original tubular form. This ballooning model is attractive as it neatly explains what appeared to be an overly complex means of allocating cells to a particular structure.
The model of directional growth leading to morphogenesis of structures of specific shape and cellular orientation is directly supported by the same retrospective lineage analyses that defined the early cardiac lineages: By examining smaller clones of labeled cells, the patterns of cell division that cells had followed could be understood during recent organogenesis Meilhac et al. For example, ventricular growth was observed as radial, explaining the large rounded shape of the primitive ventricles.
Conversely, growth in the outflow tract is initially linear, corresponding to its elongation, and then is radial, which corresponds to the broadening and rotation of the outflow tract. Lineage analyses confirmed that the chambers form as thought Meilhac et al. For example, Tbx2 -expressing cells, which are predominantly confined to the AV canal Fig. This is apparent during chamber morphogenesis as the AV canal forms. Patterning cues establish boundaries along the primitive heart tube, within which the AV canal forms.
This region of the heart expresses a distinct complement of genes, especially those involved in conduction of impulses, such as connexins. The AV canal myocardium is important in coordinated impulse propagation: It forms the insulating conduction system tissue that directs the impulses that initiate in the atrium along a specific insulated path Hoogaars et al. Signals that initiate and maintain formation of the AV valves arise from the AV canal.
The specialization of the conduction system and valve formation will be reviewed later in this section. Little is understood about what regulates these growth processes, except that differential rates of proliferation may drive early chamber morphogenesis Soufan et al. The Tbx2 transcription factor, which is restricted to the AV canal, is important for maintaining a lower level of proliferation in this segment of the heart Aanhaanen et al.
Formation of trabeculae, the fingerlike projections that protrude inside the developing chambers, is important in cardiac chamber morphogenesis. The trabeculae ensure the growth of the heart from a thin-walled organ to one that can pump against high pressures. A trabeculated heart can also exert force, while being easily oxygenated before development of coronary circulation. Trabeculae are highly conserved in evolution and, in more primitive hearts, such as amphibians and reptiles, are retained into adulthood.
Bmp10 is expressed within developing trabeculae and is essential for proliferation of trabecular myocardium Chen et al. Nrg1, produced from the endocardium, signals to ErbB receptors in the myocardium to allow trabeculation Gassmann et al. EphrinB2 and its receptor EphB4 are also important for trabeculation Wang et al.
Notch signaling in the endocardium adjacent to the trabeculae is also essential for trabeulation, and is implicated in many signaling pathways: Notch signaling sustains Bmp10 expression and promotes expression of Nrg1 and EphrinB2 in the endocardium Grego-Bessa et al. Chamber septation involves separation of the left and right sides of the atria and ventricles by growth of specific regions of myocardium Fig. Septation of the ventricles is simpler and occurs at the junction of the two heart fields. Ventricular septation defects are the second most common CHDs.
However, the patterning events that dictate ventricular septation and the subsequent cellular changes that govern septal morphogenesis are not understood. Later steps in cardiac morphogenesis. Shown are ventricular septation, atrial septation, and septation of the outflow tracts. Early embryological studies determined that the interventricular septum IVS is formed by outgrowth of two adjacent populations of cells in a small segment of the left and right ventricles.
These observations suggest patterning of the developing ventricles that dictates the location of the IVS. Although these genes are all important for forming the IVS, their loss results in pleiotropic effects on the heart as a whole or in defects in, but not a complete absence of, IVS formation. Therefore, the molecular determinants that pattern the location of the IVS and promote its formation are not well understood.
At least one gene might be directly related to patterning the myocardium guiding IVS formation. Tbx5 is expressed in a dynamic pattern that extends, in the ventricles, just up to the region where the IVS forms Bruneau et al. Genetic manipulation of Tbx5 in the chick and mouse suggested that the position of the IVS relative to the ventricles is determined by the boundary of cells that do and do not express Tbx5 Fig.
Misexpression of Tbx5 across the boundary between the left and right ventricles eliminates IVS formation Koshiba-Takeuchi et al. In mice with Tbx5 deleted from ventricular myocardium or a segment of the ventricular myocardium that includes the cells that will contribute to the IVS, grossly normal hearts form, but fail to initiate IVS formation Koshiba-Takeuchi et al.
Therefore, the patterning of Tbx5 expression is essential for IVS formation, but how this boundary functions to form an IVS is unknown. Function of a Tbx5 boundary in ventricular septation. A Effect of misexpression of Tbx5 on septum formation. Left : diagrammatic representation of the experimental design and resulting phenotype. Right : in situ hybridization for Nppa on sections from wild-type WT and Tbx5 misexpression hearts, showing absence of septum formation and expansion of expression of Nppa.
B Phenotype resulting from deletion of Tbx5 from ventricular myocardium V-del. Two distinct strategies are shown. Left : Optical projection tomography scans of heart from WT and Tbx5 deletion hearts. Note the lack of septation in the absence of Tbx5. From Koshiba-Takeuchi et al. Tbx5 is also critical for atrial septation, via the integration of diverse cell signaling pathways. Its function in the endocardium is required for establishing signaling cascades that ensure septal formation Nadeau et al.
An earlier role in the origin of the atrial septum primum from the SHF implicates Tbx5 in regulating response of the posterior SHF to Hedgehog signaling, and provides a mechanism for the dosage-sensitive defects in atrial septation that result from Tbx5 haploinsufficiency Xie et al.
Tbx5 directly regulates Hh-pathway genes, and also may act in parallel to regulate Osr1 Xie et al. As the heart septates, connections between the atria and ventricles are maintained, and valves ensure unidirectional blood flow. Valve formation arises from complex coordinated signaling between the myocardium and the overlying endocardium. Signals from the myocardium initiate local endothelial-to-mesenchymal transformation EMT. EMT location depends on the initial patterning of the heart segments and thus the localized expression of EMT-inducing factors, such as Bmp2 Ma et al.
Bmp2 is also required for patterning the AV canal and outflow tract, in a feedback loop involving Tbx2 , and for the expression of genes required for the establishment of the cardiac jelly, in which transformed endocardial cells migrate Harrelson et al. Patterning of the AV canal also involves Notch signaling in the endocardium, which represses Bmp2 outside of its domain of expression Luna-Zurita et al.
Septation of the outflow tract OFT and establishment of the pulmonary and aortic valves follows a similar yet distinct set of signaling pathways as AV valve formation. Within the forming OFT, cells of the cardiac neural crest migrate in, establishing themselves as an important source of cells for the cushions of the distal outflow tract. The proximal cushions of the OFT are derived from the underlying endothelium.
A fine interplay between signals secreted from the mesoderm of the SHF to the adjacent neural crest and endocardial cells is essential for their survival and differentiation Park et al. Fgf8 signals, under control of the T-box transcription factor Tbx1 Hu et al. The role of Tbx1 in initiating the signaling is particularly interesting, as heterozygous loss of human TBX1 underlies 22q11 microdeletion syndrome or DiGeorge syndrome Jerome and Papaioannou ; Lindsay et al. Instead of a cell-autonomous function of Tbx1 within neural crest cells, it activates autocrine and paracrine signals that influence OFT development and cardiac morphogenesis.
After cushion formation is initiated in the OFT and AV canal, subsequent steps in valve formation involve elongation and maturation of the valve tissue Hinton et al. Similar signaling is deployed. Although less well understood than the early stages of valvulogenesis, maturation of valves involves profound changes in gene expression and cellular identity, with the loss of early markers such as Twist1 and Tbx20 , and the acquisition of a tendonlike phenotype, with expression of Sox9 and Scleraxis Lincoln et al. During heart formation, various cell types specialize.
Myocardial cells, in particular, specialize into atrial, ventricular, pacemaker, AV node, and His-Purkinje cells, the latter three cell types being the major constituents of the cardiac conduction system. Patterning and intrinsic cellular programs are responsible for this diversity of cell-type specialization.
The factors leading to establishment of atrial and ventricular cells, corresponding to the left and right chambers, are unclear. The determinants of atrial versus ventricular identity are also unclear, although candidates have been proposed Pereira et al. Diversification into left and right ventricular myocytes is likely owing to antero-posterior patterning of the heart tube and specific expression of transcription factors, such as Tbx5 and Hand1 Bruneau et al. The left and right atria are patterned based on left-right signaling cascades that initiate early on in establishing the embryonic body plan Shiratori and Hamada ; Galli et al.
In particular, left-sided expression of the Pitx2 transcription factor establishes left and right atrial identity, in part by suppressing in the left atrium the initiation of pacemaker tissue differentiation, which is critical for normal initiation and conduction of the heartbeat Mommersteeg et al. Within the atrial and ventricular tissues, cell-type specialization forms the fibers that conduct impulses coordinately for each heartbeat.
The patterning of the sinoatrial node, where impulses initiate, is dictated by the localized expression of Tbx3 , which partly represses a working myocardium phenotype, while promoting the expression of ion channels that are essential for the spontaneous depolarization that is a key feature of sinoatrial node pacemaker cells Hoogaars et al. Tbx3 is also important for forming the atrioventricular conduction system, which includes the atrioventricular node, where impulses slow to ensure coordination between atrial and ventricular contraction.
Tbx3 expression outlines the atrioventricular conduction system Hoogaars et al. Tbx3 is important for forming the atrioventricular node Frank et al. Without this important electrical insulation, accessory pathways develop that lead to lethal arrhythmias Aanhaanen et al. The distal conduction system, the fast conducting fibers of the His-Purkinje system, is patterned by the concerted dosage-sensitive function of Tbx5 and Nkx , which act upstream of a third transcription factor, Id2 Moskowitz et al. It is partly established by the function of the Irx3 transcription factor, which acts predominantly to maintain a balance between gap junction proteins to ensure electrical isolation of the fibers from the rest of the myocardium to ensure fast impulse propagation Zhang et al.
Finally, the patterning of cardiac repolarization coordinates the resetting of currents so that the next heartbeat can spread; this is accomplished by a transmural gradient of the Irx5 transcription factor, which establishes an inverse gradient of ion channels Costantini et al. The mammalian heart cannot regenerate after injury. Because the hearts of other vertebrates, such as fish, regenerate Poss et al. Indeed, mammalian hearts have a short-lived capacity for regeneration, which disappears a few days after birth Porrello et al. This temporary regenerative capacity seems related to proliferative potential of existing cardiomyocytes Porrello et al.
The knowledge acquired from understanding specification and allocation of cardiac lineages may provide strategies for cardiac regeneration Fig. Regeneration in zebrafish is based on proliferation of cardiomyocytes Jopling et al. After injury, such as after a myocardial infarction, there also does not seem to be significant myocardial proliferation. Several approaches have been suggested to increase cardiac proliferation, and although some success has been reported Kuhn et al.
Strategies for cardiac regeneration. Various strategies that have been suggested are shown, including A implantation of in vitro-generated cardiomyocytes, B differentiation and implantation of cardiac progenitors, C mobilization of endogenous precursors by inductive signals, or D direct reprogramming.
From Alexander and Bruneau Endogenous cardiac stem cells in the adult heart might be an excellent starting point for devising strategies to promote cardiac regeneration. Several studies claimed to isolate cardiac progenitors of various types from the mouse heart, using a variety of surface markers Laflamme and Murry , ; Leri et al.
For the most part, cells with cardiogenic properties are difficult to identify in the endogenous heart, and thus their identity and lineage origin are not clear. When reintroduced into a damaged heart, these cells seldom become new cardiac myocytes. Thus, under these conditions, they do not possess cardiogenic properties. For example, c-kit-expressing cells were thought to be resident cardiac stem cells Beltrami et al. In the neonatal heart, these cells can function as bona fide cardiac precursors Jesty et al. However, their ability to contribute to regenerating adult heart was not confirmed Tallini et al.
Isl1-expressing progenitors have been detected postnatally, but their numbers are very small and all but gone in adulthood Laugwitz et al. Finally, a cardiac mesenchymal stem cell-like population was identified in the perivascular niche of the adult mouse heart Chong et al. Whether these cells can participate in endogenous heart repair is not clear. The epicardium has been suggested broadly as a source of cells that can regenerate myocardium after injury.
The number of new cardiomyocytes that appear to be epicardially derived is very small, but it is intriguing that a population of cells that would normally not contribute new myocardium could be coaxed into doing so under the right conditions. The best evidence for endogenous renewal of cardiac myocytes and, by extrapolation, the existence of cardiac stem cells comes from a genetic experiment in the mouse. Cardiac myocytes were genetically labeled with cardiac-specific inducible Cre recombinase transgenes MyhMerCreMer [ Sohal et al.
If the number of labeled cells does not change, the originally labeled cells would still be present, and few or no new cardiomyocytes would have been generated. If the number of labeled cells decreases, new cells that did not receive the original genetic tag would have been generated. Although the origin of these cells cannot be ascertained, they would necessarily have arisen later than the early pulse of genetic recombination.
During normal aging, there was little change in the number of labeled cells. However, after injuring the heart by imposing a myocardial infarction, the heart had fewer labeled cells. Thus, in response to injury, over time, cardiac myocytes were renewed from sources other than the genetically labeled cells. The knowledge accumulated in studies of the developing heart has become useful in developing strategies to induce the formation of new cardiomyocytes Fig.
Two distinct approaches based on pathways that regulate cardiac differentiation have been deployed to attempt to regenerate injured myocardium. One approach has been to differentiate ES cells, or induced pluripotent stem iPS cells, into cardiomyocytes that could then be implanted into an injured heart. Based on the endogenous signaling cues that are important for inducing cardiac cells in vivo, protocols have been derived that achieve varying degrees of cardiac differentiation from ES and iPS cells Laflamme et al.
When implanted in an injured mouse or rat heart, however, human ES cell-derived cardiomyocytes cannot achieve long-term contribution to the myocardium, or do not couple effectively Laflamme et al. The lack of long-term engraftment has been considered to be an important hindrance to any potential for use of pluripotent cell-derived cardiomyocytes.
It may be that the use of small, rapidly beating rodent hearts is the main source of failure in these sets of experiments. Use of a guinea-pig infarct model has shown that, in fact, human ES cell-derived cardiomyocytes can very effectively incorporate into injured myocardium, couple to their endogenous neighbors, and survive long term Shiba et al.
Importantly, in this experimental setting, the implantation of in vitro-generated human cardiomyocytes does not lead to arrhythmogenic events, and in fact, is antiarryhthmic. An attractive scenario in regenerative medicine is to induce one cell type to become another to replace lost or damaged cells.
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This is known as direct reprogramming Graf and Enver In the heart, loss of cardiomyocytes after infarct is accompanied by an overproliferation of fibroblasts, which contribute to formation of scar tissue that impairs the proper contraction of the heart. A desirable strategy would be to convert the excess of fibroblasts into functional cardiomyocytes, which would both replenish the heart with functional units and reduce the amount of scar tissue. Recent studies have shown great promise Ieda et al. In cell culture, introducing three transcription factors Gata4, Mef2c, and Tbx5 [GMT] , or these three factors plus Hand2 GHMT , induced cardiac fibroblasts to radically change phenotypes to resemble cardiomyocytes Ieda et al.
These factors induced fibroblasts to express a full battery of cardiac genes, form sarcomeres, develop cardiomyocyte-like electrical activity, and in a few cases even elicit beating activity.
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This approach also worked in dermal fibroblasts, indicating that the potential of the introduced factors was not limited to only one cell type. Thus, a limited set of transcription factors could impose an entire cardiac program on a noncardiac cell. This approach has also been extended to human ES cells, to determine if initial success with driving mesoderm to become cardiomyocytes Takeuchi and Bruneau could be applied to pluripotent cell in culture.
Would a directed differentiation approach be effective in the endogenous heart? This has turned out to be promising Qian et al. Injection of viruses overexpressing GMT or GHMT into a mouse heart immediately after a myocardial infarction led to expression of the added factors only in the highly proliferating fibroblasts as ascertained by Cre-loxP-based cell marking. Therefore, these factors converted endogenous fibroblasts into functional cardiomyocytes.
The increased efficiency in vivo contrasts with the initial foray in cell culture, and predicts that the environment in vivo is more favorable for directed differentiation than culture conditions. The de novo production of cardiomyocytes significantly affected the heart. Cardiac function was partially restored and infarct scar size was greatly reduced.
The reduction in scar size cannot be accounted for solely by the production of new myocytes, so there must be some paracrine effects on fibroblast proliferation that contributes as well. This study suggests functional myocardium can be reliably regenerated in vivo by direct reprogramming of endogenous cardiac fibroblasts Qian et al. Combined with additional factors, specific types of cardiomyocytes might be generated, such as biological pacemakers, by the inclusion of Tbx3 Bakker et al.
The outlook for cardiac regeneration is encouraging. Nevertheless, significant challenges remain, and it is not clear if strategies that work in a small heart, such as mouse, will work in the much larger hearts of humans.
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