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Open AccessReview

Cardiac Development: A Glimpse on Its Translational Contributions

Department of Experimental Biology B3-362, University of Jaen, 23071 Jaén, Spain
*
Author to whom correspondence should be addressed.
Received: 21 December 2020 / Revised: 18 January 2021 / Accepted: 25 January 2021 / Published: 4 February 2021

Abstract

Cardiac development is a complex developmental process that is initiated soon after gastrulation, as two sets of precardiac mesodermal precursors are symmetrically located and subsequently fused at the embryonic midline forming the cardiac straight tube. Thereafter, the cardiac straight tube invariably bends to the right, configuring the first sign of morphological left–right asymmetry and soon thereafter the atrial and ventricular chambers are formed, expanded and progressively septated. As a consequence of all these morphogenetic processes, the fetal heart acquired a four-chambered structure having distinct inlet and outlet connections and a specialized conduction system capable of directing the electrical impulse within the fully formed heart. Over the last decades, our understanding of the morphogenetic, cellular, and molecular pathways involved in cardiac development has exponentially grown. Multiples aspects of the initial discoveries during heart formation has served as guiding tools to understand the etiology of cardiac congenital anomalies and adult cardiac pathology, as well as to enlighten novels approaches to heal the damaged heart. In this review we provide an overview of the complex cellular and molecular pathways driving heart morphogenesis and how those discoveries have provided new roads into the genetic, clinical and therapeutic management of the diseased hearts.
Keywords: cardiac development; transcriptional regulation; congenital heart diseases cardiac development; transcriptional regulation; congenital heart diseases

1. Introduction

Over the last decades, our understanding of the cellular and molecular mechanisms driving cardiac development has greatly increased. Such discoveries have provided clues to dissect the genetic and molecular bases of congenital heart diseases, as well as provided tools to configure novel cellular and molecular approaches to heal the damaged heart. In this review, we provide a comprehensive summary of the cellular and molecular pathways involved in heart formation, and translational contribution of such findings. Therefore, this review will allow clinical cardiologists to discover the contributions of basic cardiovascular development to the clinics and to cardiovascular developmental biologists to envision their therapeutic and clinical potentials.

1.1. From Gastrulation to the Early Cardiac Linear Tube

Cardiac development is complex developmental process that is initiated soon after gastrulation. Soon thereafter the epiblast starts delaminating and migrating towards the future mesodermal layer, and cardiac precursors can be traced in the primitive streak (Figure 1A). At this stage, mesoderm precursors are characterized by the expression of Brachyury [1], Mesp1 and Mesp2 [2,3,4], having all of them an important contribution to early cardiogenic development [5,6,7,8,9]. Following the first configuration of the mesodermal layer, cardiac precursors migrate anteriorly and they start expressing early cardiogenic transcription factors. At this stage, several members of the Forkhead, Nkx, Gata, and Mef2 families, respectively, are expressed in the precardiac mesoderm [10,11,12,13] in a wide range of different species such as Xenopus [14], zebrafish [15,16,17], chicken [18,19,20,21,22], and mice [23,24,25,26,27,28,29,30], being particularly important Nkx2.5 [31,32,33,34], Gata4 [35,36,37,38], and Mef2c [39,40,41,42,43] for early cardiogenesis in different experimental models. Expression of these cardiogenic markers is regulated by signaling factors from the adjacent tissues such as Bmp2 [44,45,46,47,48,49], Fgf8 [50,51,52,53] and Wnt signaling [54,55,56,57,58,59,60]. Importantly, Bmp2 and Fgf8 signaling is controlled by an intricated molecular cascade in which non-coding RNAs, such as miR-130 and miR-133, are also involved [61]. As development proceed, the initial cardiogenic precursors become configured into a horseshoe shape (Figure 1B) and subsequently the bilateral cardiogenic precursors are fused in the embryonic midline generating a cardiac straight tube [62]. At this stage, the embryonic heart is configured by two distinct epithelial layers, an externally located myocardial layer and an internally located endocardial layer. The two distinct cardiogenic subpopulations can be already recognized at this stage [63,64], the first heart field (FHF) that contributes to the early cardiac straight tube, and the second heart field (SHF) that is medially located and will subsequently contribute to both the arterial and venous poles of the heart [65,66,67] (Figure 1C). FHF specification is dependent of cardiogenic factors such as Nkx2.5 [68], while SHF specification is mostly determined by islet-1 [69] while Bmp signaling contributes to SHF proliferation [70]. On the other hand, Mef2c is required for both FHF and SHF development [71].
Genetically modified mice have uncovered key functional roles of distinct transcription factors during early cardiac developmental stages. In this context, Gata4 systemic mutants leads to absence of cardiac tube formation [94,95]. Mef2c and Foxh1 systemic mutants are arrested at the cardiac linear heart tube stage [28,35], while Nkx2.5 mutants failed to develop right after cardiac looping, providing some cues for ventricular left–right development [96]. Importantly, Mef2c, Gata4, and Nkx2.5 constitute coregulators of early cardiac development [97,98,99,100]. Moreover, these core cardiac transcription factors can also be associated with additional cofactors during early cardiogenesis such as Tbx5 [101,102,103,104], Gata5 [105], and Gata 6 [106], constituting a complex gene regulatory network [107,108,109] that also implies other transcription factors as reported in different experimental models [110,111,112,113,114].
These transcriptional networks have been studied in detail over the last decades, uncovering a multiple of downstream genes [115,116,117,118,119,120,121,122], including non-coding RNAs, such as miR-99/let-7 [123,124], that are involved in multiple steps of cardiac development as reported in different species. Overall, these data demonstrate that early cardiac development is an intricated morphogenetic mechanisms in which multiple factors are critically involved (Table 1).

1.2. Clinical and Translational Perspectives of Early Cardiogenic Development

Our current understanding of the molecular determinants acting on early cardiogenic differentiation has greatly contributed to provide molecular instruments to convert embryonic stem cells (ESC) into differentiated cardiomyocytes, in both mouse and human ESC, opening thus the possibility to provide novel therapeutic tools to heal the failing heart [79,80,81,82,83,84,85,86,87,88] (Figure 1E). Furthermore, several of these key developmental factors have been more recently proposed as developmental clues to differentiate induced pluripotent stem cells into the cardiomyogenic lineage [89,90,91] even when starting from somatic differentiated fibroblasts [72,92,93], further supporting their plausible application to regenerate the damaged heart.
In addition, the understanding of the early cardiogenetic program have also unraveled the critical role of distinct transcription factors in cardiac adult pathologies [73,74,75], as well as a fundamental reactivation of these transcription factors in distinct adult cardiac pathological conditions, such as cardiac hypertrophy and dilated cardiomyopathy [75,76,77] (Figure 1D). Such findings support the notion that cardiac insults primarily respond activating the embryonic genetic program aiming to cope with the dysfunctional capacities caused by such pathologies [221].

1.3. Cardiac Linear Heart and Left–Right Symmetry Break

Soon after the configuration of the cardiac straight tube, the first morphological left–right asymmetry arises as the heart is detached from the dorsal mesocardium and a rightward bending is invariably observed (Figure 2A). Molecular left–right asymmetry is initiated at earlier developmental stages emanating from the node [222] and transferred to the lateral plate mesoderm by distinct mechanisms including retinoic acid [223,224], Fgf [225,226,227], Bmp [228,229,230,231,232,233], Shh signaling [234] and non-coding RNAs [235,236] in a species-specific manner [227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247]. This cascade ultimately converges on Nodal activation in the left lateral plate mesoderm (LPM) [248,249,250,251]. Nodal subsequently leads to expression of the homeobox transcription factor Pitx2 in the left LPM [143,144,145,146] and thereafter in the emerging mesodermal embryonic structures such as the heart and the gut [147,148,149,150,151,152,153,154,155] (Table 1). Importantly, impaired expression of Nodal in the left-right lateral plate mesoderm have enormous consequences in early cardiac development, as the looping of the heart can become randomized [156].
Subsequently, expression of Pitx2 is maintained in the left-sided of the embryonic heart providing thus positional clues to direct left–right cardiac asymmetric morphogenesis [157,158,159,160,161,162,163,164,165]. Importantly, while overexpressing Pitx2 experiments in the right lateral plate mesoderm are able to drive cardiac leftward looping in Xenopus and chicken embryos [143,144], Pitx2 loss of function in mice does not impairs cardiac looping [145,146], demonstrating that Pitx2 is dispensable for asymmetric cardiac looping. More recently, it has been demonstrated that asymmetric right sided cues directly by Prrx1 are crucial to direct rightward cardiac looping, independent of Pitx2 expression [168] configuring an enhanced epithelial-to-mesenchymal transition (EMT) in the right as compared to the left lateral plate mesoderm, a process that is modulated by distinct microRNAs [252].

1.4. Clinical and Translational Perspectives of Left–Right Symmetry Break

The heart is the first organ to display morphological left–right asymmetry during embryogenesis [168]. Abnormal left–right signaling, thus, have a great impact in heart development leading to laterality defects. In humans, three distinct conditions can be observed, situs solitus, in which left–right signaling occurs normally, situs inversus in which left–right signaling is inverted and situs ambiguus in which left–right signaling is randomized. While in situs solitus and situs inversus, cardiac development occurs normally, with no observable morphogenetic defects, in situs ambiguus a large array of morphogenetic defects have been reported, globally termed as heterotaxia syndrome [301,302,303,304,305,306,307,308,309,310] (Figure 2C). Namely, isomeric atrial appendages are frequently observed, including abnormal configuration of the venous connections [304,305,306,307,308]. Ventricular chambers are normally not affected while the arterial pole might range from normal connections to double outlet right ventricle (DORV) and in most severely affected cases to permanent truncus arteriosus [304,305,306,307,308].
Our understanding of the molecular events leading to impaired left–right signaling has greatly increased over the last years. Primary events leading to symmetry break occurs at the node, as cilia triggered leftwards directional flow is established [253,254,255,256,257,258], a process that is rather conserved during evolution [259,260,261]. Impaired cilia function (i.e., primary cilia dyskinesia) underlies cardiac heterotaxia and also several associated syndromes such as Kartagener syndrome [262,263]. Mutations in a wide variety of cilia associated genes have been recently linked to heterotaxia in humans and impaired left–right signaling, including herein ZIC3 [264], dyneins [265,266,267,268,269,270], LRRC50 [271], CCDC39 [272], and TTC25 [273], among others [274]. In addition to the contribution to heterotaxia of the early left–right symmetry break events, several components of this pathway, such as Nodal, Lefty-1, Lefty-2, and Pitx2 plays a fundamental role in cardiac isomerism in mice. For example, Lefty-1 knockouts resulted in left isomerism [230], while Pitx2 loss-of-function leads to right atrial isomerism with abnormal venous connections [154,155]. Importantly, impaired Pitx2 ventricular expression in iv/iv mutants correlated with presence of distinct congenital cardiac defects, such as DORV, supporting the notion that molecular ventricular isomerism is also occurring [159].

1.5. Externally Covering the Naked Myocardium; the Rise of the Epicardium and Its Derivatives

Concomitantly with the late stages of cardiac looping the heart is progressive externally covered by a new epithelial layer, the embryonic epicardium. The embryonic epicardium originates from the proepicardium, an epithelial protrusion with a cauli-flower like structure emanating at the junction between the cardiac and the hepatic primordia [275,276] (Figure 2B). The formation of the proepicardium is triggered by distinct factors [277,278,279,280], among which it is important to highly the antagonist roles of Bmp [282,283,284,285] and Fgf [288,289,290] family members. After covering the embryonic naked myocardium, the embryonic epicardium is instructed to an epithelial-to-mesenchymal transformation (EMT) leading to the epicardial-derived cells (EPDC) that will subsequently migrate into the embryonic myocardium and will progressively differentiate into distinct cell derivatives such as cardiac fibroblasts as coronary vasculature components such endothelial, smooth muscle cells, and adventitial fibroblasts [291,292,293,294,295,296,297,298,299] (Figure 2D). The understanding of the molecular events governing proepicardium to embryonic epicardium transition is still in its infancy, yet several cardiac-enriched transcription factors such as Gata4 and Isl1 seems to be playing a critical role [125,126]. Similarly, configuration of the proepicardium (PE) is dependent of several transcription factors such as Wt1 [169,170,311], Tcf21 [171,172,242,243], and Tbx18 [312], some of which are also crucial to direct epicardial EMT (Table 1). Importantly, microRNAs such as miR-21 also play a role in this developmental process [313,314,315]. However, when and how EPDCs acquire their differentiation cues remains yet undetermined although there are some evidence that cell specification might already take place in the PE [316,317,318,319], a process that might be dependent of non-coding RNAs [320,321].

1.6. Clinical and Translational Perspectives of Proepicardium and Epicardium Formation

Impaired development of the proepicardium and/or failure of the embryonic epicardium to proceed into epithelial to mesenchymal differentiation has profound effects on the development of the embryonic myocardium, leading to a thin ventricular phenotype and absence of proper coronary vessels development [299,322,323,324]. Such defects are reminiscent of the thin ventricular myocardium phenotype observed in humans, such as left ventricular non-compaction [325,326,327] although the plausible contribution of the epicardium to this phenotype is still controversial. In addition, impaired epicardial formation also leads to abnormal coronary vasculature development, linking therefore embryonic impairment with adult vascular defects [328]. Therefore, understanding of the cellular and molecular events that takes place during proepicardium to embryonic epicardium transition and their subsequent contribution to the developing cardiac chambers will provide novel candidate genes for genetic screening and counseling in distinct cardiac pathologies such as thin ventricular myocardium phenotypes and coronary vasculature impairment (Figure 2D).

1.7. Cardiac Ballooning and the Configuration Cardiac Conductive System

Soon after cardiac looping takes place, the prospective atrial and ventricular chambers are progressively formed [329,330]. The process by which these prospective chambers is formed is mediated by local increase in proliferation on those areas leading to the working myocardium chambers, whereas lower proliferation is observed on the flanking segments [331] and the embryonic conduction system [332]. In addition to differential cell proliferation, activation of an specific working myocardium gene expression program is initiated, while in the flanking segments such activation is repressed [332,333]. T-box family members such as Tbx2 [173,174,175,176,177,178], Tbx3 [179,180,181,182], Tbx5 [137,138], and Tbx20 [186,187] play a fundamental role instructing these signals [188,189,190] while atrial and ventricular identities are orchestrated by Irx [191,192,193], Hey [194,195,196], and Coup-TF [198] family members. Several non-coding RNAs are differentially expressed during cardiogenesis [334,335,336,337,338], some of which regulate distinct cardiac enriched transcription factors such as Mef2c [334] while other such as miR-25 promotes cardiomyocyte proliferation [336] while others such as miR-143 and miR-138 are essential for cardiac chamber morphogenesis [339,340].
Importantly, both atrial and ventricular chambers are also progressively acquiring left (systemic) and right (venous) identities a process that is directed in first instance by Pitx2 [143,166,341], and subsequently by eHand and dHand transcription factors [200,201,202] (Figure 3A). Importantly, transcription factors such as Nkx2.5, Mef2c, and Gata4, that previously provided essential clues during early stages of development, also provide pivotal roles in chamber specific expression during cardiac chamber formation [127,136].
As development proceeds, the atrial and ventricular chamber are progressively maturing. Atrial chambers display minor modifications, with the exception of the development of the pectinated muscles while the ventricular chambers progressively develop a compact myocardial layer while the trabecular network is dynamically restructured. Several key factors have been involved in ventricular trabecular initiation, including herein Notch [342,343,344,345] and Neuregulin [346,347,348,349,350] signaling pathways. In addition, several other transcription factors such as Foxm1 [203], Hop [204], Klf13 [205], and Srf [206,207] also play crucial roles at different stages of ventricular trabeculation and compact myocardium maturation (Table 1), resulting in all cases into a thin ventricular phenotype and impaired cardiac function.
Concomitant with these events, the “primitive” myocardium is also re-structured, leading to the formation of the major components of the ventricular conduction system, i.e., the atrioventricular node, the bundle of His, the left and right bundle branches and the peripheral Purkinje fiber network [351,352,353,354,355,356,357,358,359,360,361,362,363] (Figure 3B). Several evidence in chicken demonstrate that certain components of the cardiac conduction system were derived from “working” myocardium by endothelin signaling [364,365,366,367,368,369,370,371]. Curiously, such mechanism seems not be involved in mice, where cardiac conduction system and working myocardium display a progressive mechanism of differentiation as revealed by systematic retrospective clonal analyses [372,373,374,375,376,377]. Furthermore, multiple transcription factors distinctly contribute to the formation of distinct components of the cardiac conduction system such as Nkx2.5 [128,129,130,131,132], Shox2 [208,209,210,211,212,213], Tbx3 [378], Tbx5 [128], Pitx2 [379], and Wnt signaling [380] (Table 1) and recent evidences also support a role for microRNAs in cardiac conduction system development [381,382].

1.8. Clinical and Translational Perspectives of Cardiac Ballooning and Conductive Myocardium

Impairment of the compact myocardium has been observed in multiple mutants [383,384,385,386,387,388,389], supporting a causative link with human diseases such as left ventricular non compaction. Similarly, genetic manipulation of several genes [386,387], including transcription factors such as Srf [206,207], Hop [204], Foxm1 [203], and Klf13 [205] led to defects in ventricular compaction, reminiscent of the human left ventricular non-compaction or as in the case of Irx4 [390], to impaired ventricular expression and cardiomyopathy. Therefore, these observations have provided candidate genes to dissect the genetic bases of these human cardiac pathological conditions [391,392,393,394] (Figure 3C), including also some microRNAs [395,396,397,398] and thus providing tools for genetic screening and counseling. In addition, the generating patient specific induced pluripotent stem cells [399] and also opens up new tools for personalized drug testing and reparative medicine.
Instructive signals such as those provided by Tbx2 and Tbx3 configure the precursor backbone of the cardiac conduction system, while the atrial and ventricular chambers are mainly specified by the expression of Hey, Hrt and Irx transcription factors [191,192,193,194,195,196]. Failure of the proper configuration of the early cardiac conduction system has tremendous effects such as those reported by Aanhaanen et al. [400] and Frank et al. [401] leading the formation of accessory pathways in the adult heart and thus to arrhythmogenic events (Figure 3D).

1.9. The Formation of a Four-Chambered Heart: Cardiac Septation

As development proceeds, septation of the distinct cardiac structures is initiated. At the venous pole, the embryonic atrium is divided into distinct left and right atrial chambers, the atrioventricular canal is remodeled to give rise to the right and left atrioventricular valves, i.e., tricuspid and mitral valve, respectively. At the arterial pole, the embryonic ventricle is divided pulmonary (right) and systemic (left) ventricles and the outflow tract into the prospective aortic and pulmonary valves, as detailed below.

1.9.1. Atrial Septation

At the venous pole of the heart, atrial chambers are divided through the formation of the primary atrial septum that initially partially separated the right and left atrial chambers. Subsequently, a second atrial septum is formed, providing a two components system of atrial septation that is only fully operative at birth. Primary atrial septation is guided by the cross-talk between the dorsal mesocardial protrusion and the underlying atrial myocardium while second atrial septation seems to be mainly directed by myocardial growth. Atrial septal defects represent the most common cardiac congenital anomaly with an estimate incidence of 1:1000 in newborns. Our understanding of the molecular mechanisms underlying atrial septation have enormously increased over the last decades. Several transcription factors have been reported to play pivotal role in atrial septation, such as Odd1 [214], Nkx2.5 [133,134,135], Gata4 [433], and Tbx5 [139,140,141,142], among others (Table 1). These observations support a critical role of early cardiogenic factors also in atrial septation.

1.9.2. Atrioventricular Septation

Concomitant with atrial septation, the separation of the atrioventricular canal is also initiated. Morphogenetically, the atrioventricular canal is initially connecting the future left atrium with the future left ventricle, and thus movements should be generated to provide proper connections with the remaining cardiac chambers, i.e., right ventricle and right atrium [329]. In addition, endocardial cushions of the atrioventricular canal are similarly remodeled, passing from two to four endocardial cushions that subsequently will give rise to the tricuspid and mitral atrioventricular valves, respectively. Our understanding of the molecular and morphogenetic processes leading to endocardial cushion formation and remodeling has greatly enhanced [434]. On the other hand, understanding the mechanisms driven myocardial remodeling of the atrioventricular canal remains more elusive. Importantly, defects in endocardial cushion formation or remodeling results in valvular septal defects, a highly prominent percentage of cardiac congenital anomalies, while impairment of myocardial AVC remodeling might underlie complex morphogenetic defects such as double-inlet left ventricle, which are indeed less frequent. At the molecular level, multiple transcription factors have been reported to play essential roles in atrioventricular septation such as Klf2 [215], Sox9 [216], Gata4 [217,433,435], Smad4 [217], and Mef2 [436], that if impaired, lead to distinct cardiac congenital heart diseases (Table 1).

1.9.3. Ventricular Septation

Ventricular septation is initiated with the formation of a muscular interventricular septum that progressively increases in size from the apex to the base of the heart [389]. Complete closure of the interventricular communication is established as the muscular component meets the mesenchymal component at the base of the heart, a structure that is derived from the atrioventricular endocardial cushions [329]. The understanding of the molecular processes that trigger the formation of the muscular interventricular septum are scarce, beyond the fact that both right and left ventricular myocytes contribute to it [437] and that Tbx5 and eHand play a fundamental role directing the precise position of the interventricular septum (IVS) [201,438] (Table 1). Similarly, our understanding of the molecular mechanisms driving the mesenchymal contribution are also scarce, even most IVS septal defects lack proper development of this mesenchymal component [439,440] and scarce evidence are reported affecting the muscular component [441].

1.9.4. Outflow Tract Septation and Aortic Arch Remodeling

Septation of the arterial pole of the heart is initiated with the configuration of the endocardial cushions and the progressive rotation of the outflow tract [442,443]. The endocardial cushions are separated into four main and two accessory cushions that progressively become separated into the prospective aortic and pulmonary semilunar valves. Septation is triggered by the progressive invasion of the cardiac neural crest cells at the most anterior part of the outflow tract, orchestrating the proper subdivision [444,445,446]. Failure or impaired migration of the neural crest into the outflow tract results in severe cardiac congenital malformations such as permanent truncus arteriosus (PTA) or in the lesser form of DORV [447,448,449,450].
Beside septation of the outflow tract, the final configuration of the arterial outlets is dependent on the proper remodeling of the aortic arches. The paired aortic arches are remodeled in such a way that the IV aortic arch is configured as the aorta and the VI aortic arch into the pulmonary arteries in mice and humans. Failure or improper remodeling of the aortic arches leads to life-threatening defects [451,452,453]. Cellular and molecular pathways of aortic arch development have been extensive studied, supporting a pivotal role to cardiac neural crest cells [447,448,449,450], endothelin [454,455,456], and retinoic acid [457,458,459] signaling as well as distinct transcription factors such as Tbx1 [218] and Foxc1/2 [219] and Prx1/2 [220], among others (Table 1) as well as distinct microRNAs [460,461].

1.10. Clinical and Translational Perspectives of Cardiac Septation

Understanding the molecular mechanisms that drive impaired cardiac septation has become an entry site for genetic counseling. Over the last decade our understanding of the genetic culprits underlying cardiac septation has enormously increased. Mutations in NKX2.5 and GATA4, have been associated to atrial septal defects [404,405,406,407,408,409] while mutations HAND2, NKX2.5, and NKX2.6 have been associated to ventricular septal defects [411,412,413]. Similarly, other genes have been associated to controtuncal defects [414,415,416], including DORV [417] as well as to complex congenital cardiopathies such as Tetralogy of Fallot [418,419] (Figure 3C). Such information guided to develop genetic strategies for early detection and progressively correction of these congenital heart diseases.

2. Conclusions

We have provided in this review an overview of the cellular and molecular mechanisms that contribute to cardiac development, although we aware that it only provides a glimpse of those previously reported mechanisms. We subsequently highlighted the translational applications of the study of heart morphogenesis to distinct aspects of human cardiac diseases, starting from the understanding of the genetic bases of congenital and adult cardiac diseases to the application of these finding in genetic screening and counseling, and finally to the design of therapeutic tools to heal the damaged heart.

3. Perspectives

Over the last decades, our understanding of the cellular and molecular processes involved in cardiac morphogenesis has greatly increased. A large number of studied in different species have identified several growth factors and transcription factors with pivotal roles in the cardiogenic lineage commitment. Importantly, several of these factors contribute to multiple facets of cardiac development beyond just the early stages, such as for example chamber formation and valvulogenesis as reported for Nxk2.5 and Gata4 ([11,12,13]), respectively. Furthermore, the functional roles of these early cardiogenic lineage transcription factors are also associated to adult cardiac structural pathologies, such as dilated cardiomyopathy [420,421,422,423,424,425,426] or bicuspid aortic valves [427,428] and electrophysiological pathologies such as atrial fibrillation [429,430,431,432]. Manipulation of these core transcription factors have provided new tools to convert differentiated cells such as fibroblasts into cardiomyocytes [91], opening new therapeutic opportunities to heal the damaged heart. Importantly, a novel layer of gene regulation is emerging with the identification and functional characterization of non-coding RNAs that are important for cardiomyogenic commitment [462,463,464,465], broadening thus the therapeutic tools to provide novel approaches for cardiac repair.
The embryonic heart is the first organ to display morphological left–right asymmetry. Impairment of sidedness leads to severe body plan abnormalities, including herein cardiac defects. Our knowledge of the molecular and cellular bases of left-right symmetry break has considerably increased over the last decade, providing novel links between early molecular events and impaired sidedness [222]. Such discoveries have served to unravel the genetic bases of heterotaxia and thus as guiding tools for genetic screening and counseling in these human conditions. The discovery of non-coding RNAs involved in early cardiac looping events [252] also exemplify that the final picture of left–right signaling is still incomplete and it would anticipate novel discoveries in the front in the near future.
As cardiac looping takes place, the heart is progressively externally covered by the embryonic epicardium. Importantly, such embryonic epicardium will migrate and deepen into the embryonic myocardium leading to the formation of the cardiac fibroskeleton and part of the coronary vasculature [290,291,292,293]. Failure on the formation of the embryonic epicardium or its progenitor cells in the proepicardium is incompatible with life since the ventricular walls are thinner and the coronary vasculature failed to properly form [299]. Curiously, neither the proepicardium or the epicardium leads to significant contribution to the embryonic myocardium in vivo, but if isolated and cultured in vitro, they can do so [290]. Such properties can be used to unlock the cardiomyogenic potential of the epicardium and thus to sever as a source of myocardial differentiation to heal the heart, as previously reported [300,466]. Unlocking these events with non-coding RNAs have been recently reported [321], opening new strategies to heal the damaged heart.
The formation of the cardiac chambers and the cardiac conduction system is an intricated developmental process that is initiated right after left–right symmetry break and thus cardiac looping. Subsequently, the heart displays a complex septation process that provide morphogenetic cues to form a four-chambered organ with distinct inlet and outlet connections. A multitude of different growth factors such as Bmp, Fgf and Wnt family members, and of transcription factors participate on this cardiac developmental orchestra [44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60], and similarly as in the earlier events of heart formation, non–coding RNAs, including herein microRNAs and lncRNAs also participate [61,315,462,463,464], although our understanding of their functional role is still scarce. Deciphering the molecular cascades involved in these developmental processes have provided candidate genes to test and identify genetic culprits of congenital cardiac anomalies in humans, and thus to design strategies for genetic screening and counseling.

Author Contributions

Conceptualization, D.F.; data curation, D.F.; writing—original draft preparation, D.F.; and E.L.-V.; writing—review and editing, C.G.-P., J.N.D., E.L.-V., A.A. and D.F.; funding acquisition, A.A. and D.F. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Consejeria de Transformación Económica, Industria, Conocimiento y Universidades of the Junta de Andalucia Regional Council, grant number CTS-446.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

List of Abbreviations

AAAAortic arch anomalies
ASDAtrial septal defects
AVCAtrioventricular canal
AVSDAtrioventricular septal defects
BmpBone morphogenetic protein
CCSCardiac conduction system
DORVDouble outlet right ventricle
EMTEpithelial to mesenchymal transition
EPDCsEpicardial derived cells
ESCEmbryonic stem cells
FgfFibroblast growth factor
FHFFirst heart field
iPSInduced pluripotent stem cells
IVSInterventricular septum
LPMLateral plate mesoderm
PTAPermanent truncus arteriosus
SHFSecond heart field
ShhSonic hedghog
TGATransposition of the great arteries
TOFTetralogy of Fallot
VSDVentricular septal defects

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Figure 1. Early steps of cardiogenesis. Schematic representation of the early steps of cardiac development, initiated at the primitive streak stage with the formation of the cardiogenic precursors (panel A) that soon migrate anteriorly and constitute a horse-shoe cardiac crescent (panel B), and, subsequently, the cardiac straight tube (panel C). Contribution of the FHF and SHF can already be identified at the cardiac crescent stage (panel B). During these morphogenetic events, cardiac specification and determination takes place with the contribution of distinct growth factors and transcription factors, as exemplified in panel A. Impaired expression of these factors is observed in adult cardiac pathologies such as dilated cardiomyopathy or hypertrophic cardiomyopathy (panel D) providing target genes for drug discovery and therapy of these physiopathological conditions [72,73,74,75,76,77]. Manipulation and implementation of sequential protocols of these growth factors played an important role for directing embryonic stem cells (ESCs) and induced pluripotent stem cells (iPS) cell determination into the cardiomyogenic lineage and thus providing tools for cellular therapy, novel gene discoveries and drug/pharmacological treatments (panel E) [78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93].
Figure 1. Early steps of cardiogenesis. Schematic representation of the early steps of cardiac development, initiated at the primitive streak stage with the formation of the cardiogenic precursors (panel A) that soon migrate anteriorly and constitute a horse-shoe cardiac crescent (panel B), and, subsequently, the cardiac straight tube (panel C). Contribution of the FHF and SHF can already be identified at the cardiac crescent stage (panel B). During these morphogenetic events, cardiac specification and determination takes place with the contribution of distinct growth factors and transcription factors, as exemplified in panel A. Impaired expression of these factors is observed in adult cardiac pathologies such as dilated cardiomyopathy or hypertrophic cardiomyopathy (panel D) providing target genes for drug discovery and therapy of these physiopathological conditions [72,73,74,75,76,77]. Manipulation and implementation of sequential protocols of these growth factors played an important role for directing embryonic stem cells (ESCs) and induced pluripotent stem cells (iPS) cell determination into the cardiomyogenic lineage and thus providing tools for cellular therapy, novel gene discoveries and drug/pharmacological treatments (panel E) [78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93].
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Figure 2. Left-right symmetry break and epicardium development. Schematic representation of the conserved left–right symmetry break molecular cascade, emanating from the node and leading to Nodal and Pitx2 activation in the left lateral plate mesoderm (panel A) [253,254,255,256,257,258,259,260,261]. As a consequence, cardiac looping takes place (panel A) and the heart display distinct left and right cardiac components that, if impaired, leads to heterotaxia (panel C). Understanding of the molecular cascades directing left–right symmetry break has allowed genetic screening and counseling in these pathophysiological conditions (panel C) [262,263,264,265,266,267,268,269,270,271,272,273,274]. In addition, soon after rightward bending of the heart, the proepicardium starts externally covering the naked embryonic myocardium (panel B) and subsequently contributes to distinct cardiac cell types such as vascular endothelial and smooth muscle cells as well as fibroblasts (panel D) [275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297,298,299]. Manipulation of the epicardium cell fate can be envisioned as a therapeutic strategy to generate novel cardiomyocytes [300]. Understanding the molecular cascades involved in proepicardium to embryonic epicardium conversion and subsequently to epicardial derived cells (EPCD) will provide soon novel candidate genes for genetic screening and counseling in devastating defects such as left ventricular non compaction and thin ventricular myocardium phenotypes.
Figure 2. Left-right symmetry break and epicardium development. Schematic representation of the conserved left–right symmetry break molecular cascade, emanating from the node and leading to Nodal and Pitx2 activation in the left lateral plate mesoderm (panel A) [253,254,255,256,257,258,259,260,261]. As a consequence, cardiac looping takes place (panel A) and the heart display distinct left and right cardiac components that, if impaired, leads to heterotaxia (panel C). Understanding of the molecular cascades directing left–right symmetry break has allowed genetic screening and counseling in these pathophysiological conditions (panel C) [262,263,264,265,266,267,268,269,270,271,272,273,274]. In addition, soon after rightward bending of the heart, the proepicardium starts externally covering the naked embryonic myocardium (panel B) and subsequently contributes to distinct cardiac cell types such as vascular endothelial and smooth muscle cells as well as fibroblasts (panel D) [275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297,298,299]. Manipulation of the epicardium cell fate can be envisioned as a therapeutic strategy to generate novel cardiomyocytes [300]. Understanding the molecular cascades involved in proepicardium to embryonic epicardium conversion and subsequently to epicardial derived cells (EPCD) will provide soon novel candidate genes for genetic screening and counseling in devastating defects such as left ventricular non compaction and thin ventricular myocardium phenotypes.
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Figure 3. Forming a four-chambered heart. Schematic representation of the fully septated heart (panel A), a process that requires multiple players. Impaired expression and or function of any of them leads to congenital heart diseases (CHD) such as atrial septal defects (ASDs), ventricular septal defects (VSDs), atrioventricular ventricular septal defects (AVSDs), conotruncal abnormalities such as double outlet right ventricle (DORV) or transposition of the great arteries (TGA), aortic arch abnormalities (AAA) or even more complex CHD such as Tetralogy of Fallot (TOF) (panel C). Understanding of the causative genes have provide tools for genetic screening and counseling (panel C) [402,403,404,405,406,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422,423,424,425,426,427,428,429,430,431,432]. Similarly, our understanding of the cellular and molecular cascades leading to the formation of the cardiac conduction system (CCS) has enormously increased (panel B), providing also tools for genetic screening and counseling of CCS abnormalities (panel D).
Figure 3. Forming a four-chambered heart. Schematic representation of the fully septated heart (panel A), a process that requires multiple players. Impaired expression and or function of any of them leads to congenital heart diseases (CHD) such as atrial septal defects (ASDs), ventricular septal defects (VSDs), atrioventricular ventricular septal defects (AVSDs), conotruncal abnormalities such as double outlet right ventricle (DORV) or transposition of the great arteries (TGA), aortic arch abnormalities (AAA) or even more complex CHD such as Tetralogy of Fallot (TOF) (panel C). Understanding of the causative genes have provide tools for genetic screening and counseling (panel C) [402,403,404,405,406,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422,423,424,425,426,427,428,429,430,431,432]. Similarly, our understanding of the cellular and molecular cascades leading to the formation of the cardiac conduction system (CCS) has enormously increased (panel B), providing also tools for genetic screening and counseling of CCS abnormalities (panel D).
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Table 1. List of distinct transcription factors involved in cardiogenesis and they main functional contribution to heart development.
Table 1. List of distinct transcription factors involved in cardiogenesis and they main functional contribution to heart development.
TFFunctionReferences
BrachyuryMesodermal commitment[1]
Mesp1Cardiogenic mesoderm commitment[2,3,4,5,6,7,8,9]
Mesp2Cardiogenic mesoderm commitment[2,3,4,5,6,7,8,9]
Gata4Early cardiac specification, proepicardium development, chamber formation, atrial and atrioventricular septation, cardiomyocyte proliferation, cardiac hypertrophy[10,11,12,13,14,27,35,36,37,38,94,95,97,98,99,100,125,126,127]
Gata5Early cardiac specification, cardiomyocyte proliferation[10,11,12,13,14,16,26,105]
Gata6Early cardiac specification, cardiac hypertrophy[10,11,12,13,14,16,25,41]
Nkx2.3Early cardiac specification[15]
Nkx2.5Early cardiac specification, FHF development, cardiac looping, chamber formation, cardiac conduction system specification, atrial septation[15,31,32,33,34,68,96,97,98,99,100,128,129,130,131,132,133,134,135]
Nkx2.6Early cardiac specification[24,29]
Nkx2.7Early cardiac specification[15]
Nkx2.8Early cardiac specification[18,19,20]
Foxh1Anterior heart field development[28,35]
Mef2cEarly cardiac specification, chamber formation[35,36,37,38,39,40,41,42,43,136]
Islet-1Second heart field specification[69]
Tbx5Early cardiac specification, chamber formation, cardiac conduction system specification, atrial and ventricular septation[101,102,103,104,128,137,138,139,140,141,142]
Pitx2left right signalling, heterotaxia, chamber formation, cardiac conduction system development[143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167]
Prrx1cardiac looping[168]
Wt1proepicardium and epicardial development[169,170]
Tcf21proepicardium and epicardial development[171,172]
Tbx18proepicardium and epicardial development[169]
Tbx2primary myocardium and cardiac conduction system development[173,174,175,176,177,178]
Tbx3primary myocardium and cardiac conduction system development[179,180,181,182]
Tbx20chamber formation, atrioventricular canal development, cardiomyocyte cell proliferation[183,184,185,186,187,188,189,190]
Irx3ventricular trabecular and cardiac conduction system development[191,192]
Irx4ventricular chamber development[191,193]
Irx5cardiac conduction system development[191,192]
Hey1ventricular chamber development[194,195,196]
Hey2ventricular chamber development[194,195,196,197]
Coup-TFIIatrial development[198]
eHandventricular development[199,200,201,202]
dHandventricular development[199,202]
Foxm1ventricular trabecular and compact layers development[203]
Hopventricular trabecular and compact layers development[204]
Klf13ventricular trabecular and compact layers development[205]
Srfventricular trabecular and compact layers development[206,207]
Shox2cardiac conduction development[208,209,210,211,212,213]
Odd1atrial septation[214]
Klf2atrioventricular septation[215]
Sox9atrioventricular septation[216]
Smad4atrioventricular septation[217]
Tbx1outflow tract and aortic arch development[218]
Foxc1aortic arch development[219]
Foxc2aortic arch development[219]
Prx1aortic arch development[220]
Prx2aortic arch development[220]
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