Cells, Vol. 12, Pages 111: Cardiac Neural Crest and Cardiac Regeneration

1. IntroductionThe heart is a muscular and complex organ whose vital role includes the circulation of blood and nutrients throughout the biological system. In contrast to other species, the mammalian heart is composed of four chambers (right atria, left atria, right ventricle, and left ventricle), with various connecting vessels and arteries, including the aorta and pulmonary vessel. The mammalian heart is derived from numerous cell types, including the first heart field, second heart field, and neural crest (NC) population. The NC is an embryonic stem cell population known for its temporary migratory potential and multipotency, specific to vertebrate development. Neural crest cells (NCCs) are derived from the neural plate border during neurulation, while simultaneously undergoing epithelial-to-mesenchymal transition, a process that shifts cells into a mesenchymal state encompassed with enhanced migratory potential [1,2]. Based on the initial axial position and site of contribution, NCCs are divided into specific subpopulations: cranial, vagal, trunk, and sacral [3]. Although the vagal NC mainly contributes to the development of the enteric nervous system, a small number of cells, deemed the cardiac NC, contribute to the development of the cardiac system [4,5]. It is currently perceived that the first and second heart field contribute to the ventricles and atria, and the NC mainly contributes to the cardiac valves, interventricular septum, and both the aorta and pulmonary vessel [3,6,7]. However, recent investigations have focused on determining the contribution of cardiac NCCs to various portions and locations of the heart. Comparably, cardiac NC contribution, although varying between model systems, has shown promising results for contributing to the myocardium and assisting in the regenerative capacity of cardiac tissue in zebrafish (Danio rerio) [8,9]. This potential regenerative capacity to cardiac tissue in amniotes poses interesting avenues to advance the treatment of various cardiac diseases. Heart disease is currently the leading cause of death in the United States. Ranging in type and severity, the damage caused to the heart results in either death or irreplaceable damage to the function and/or structural integrity of the heart. Therefore, determining the contribution and regenerative capacity of the cardiac NC population in mammalian systems is of high clinical significance. 4. Cardiac Neural Crest in Cardiac Regeneration

During early mammalian development, the heart maintains its regenerative capacity; however, shortly after birth, this ability is lost. Postnatal cardiac progenitors remain a challenging and controversial issue in the cardiac field. Recent studies have begun to investigate the potential ability of the heart to re-activate regenerative ability, particularly through the NC, to assist in cardiac regeneration after injury.

It has previously been established that zebrafish maintain regenerative abilities throughout their systems, including the fins and retina [80,81,82,83]. Furthermore, it has been identified that adult zebrafish hearts are able to regenerate ventricular myocardium, without scarring, through cardiomyocyte dedifferentiation and proliferation [84,85]. However, until recently, it was unknown whether the NC population assists in this regeneration capacity of the heart. In addition to the established NCC contributions to cardiovascular development, numerous groups recently determined that NCCs in the zebrafish heart also contribute to the cardiomyocyte population [9,13,86]. Based on this, Tang and colleagues further investigated whether the NC population of the zebrafish heart also plays a role in cardiac regeneration. Using a sox10 promoter, expressing GFP (Tg(-4.9sox10:eGFP) to label embryonic NCCs, it was found that though sox10 expression is down-regulated after NCCs reach the heart, the removal of a portion of the adult ventricular apex stimulates sox10-GFP expression, along with the NC marker tfap2a, in cardiomyocytes near the injury site, suggesting the reactivation of a NC-like state for cardiac regeneration [13] (Figure 1). Furthermore, Sande-Melón et al. determined that pre-existing sox10-positive NCCs not only contributed to the zebrafish adult heart, but that after ventricular cryoinjury, the number of sox10-expressing cells significantly increased in the myocardium near the injured area [9] (Figure 1). Although regeneration in zebrafish has shown promising roles for NCCs in cardiac regeneration, less is known about the contribution of the NC during mammalian cardiac regeneration. Similar to zebrafish, it was identified that NCCs are present in the postnatal mouse heart and can differentiate into cardiomyocytes [17,18,19,20,21]. Tamura and colleagues found that after myocardial infarction in adult mice, GFP-expressed NCCs migrated to the border of the infarcted region and were able to differentiate into cardiomyocytes, contributing to the regeneration of the myocardium [19]. The authors suggest that this migration of NCCs after myocardial infarction is due to monocyte chemoattractant protein-1 (MCP-1) expression in the infarcted area that provides guidance cues to NCCs [19] (Figure 1). In contrast, although Hatzistergos and colleagues found that a population of NCCs generate cardiomyocytes postnatally, these cells were not proliferative and had lost their regenerative capacity [17]. 5. Conclusions and Future Perspectives

NCCs are a multipotent cell population that are active during vertebrate embryogenesis and can contribute to numerous portions of the developing system. It is well accepted that cardiac NCCs contribute to the OFT, great vessels, and septa of the heart. Furthermore, in mammals, it is understood that the heart loses its regenerative capacity shortly after birth. However, recent studies have begun to pose various insights into the regenerative capability of the heart and the contribution of the NC to such ability.

The use of various model organisms has provided vital information on how NCCs contribute to cardiac formation, and more recently, these have been providing insight into the possible contribution of this cell population beyond that which was previously accepted. Although progress has been made in understanding the function of the NC between species, cardiac formation, and correspondingly, NC contribution, varies between model systems, which poses questions as to the evolutionarily conserved abilities of the NC. For example, the finding that NCCs differentiate into cardiomyocytes and assist in the reformation of the ventricular myocardium has been clearly shown in adult zebrafish [9,13,86]. However, the confirmation of this ability in mammalian species has proved more challenging, but recent advances have shown potential corroboration of such ability [17,19,20,21,87]. This variation in the capacity of NCCs in different species may be due to the variation in how NCCs contribute to cardiac formation. The location of NCCs in the heart during embryogenesis could pose an advantage in certain species, as the recruitment of NCCs to the injured area may lead them to be able to receive certain cues from surrounding cells to re-instate stem cell-like properties. Furthermore, the axolotl should be additionally investigated into the NC’s role in regeneration. The axolotl is a type of salamander with an astounding capacity for regeneration of its system, including the tail and limbs, along with portions of its spinal cord and brain [88,89,90,91,92,93]. As NCCs contribute to a large portion of various developmental processes, it only raises the question as to whether NCCs contribute to the regenerative ability of the axolotl. Multiple groups have reported the ability of the axolotl to regenerate cardiac tissue without scarring after partial ventricular amputation assisted by cardiomyocyte proliferation [94,95], with Cano-Martinez et al. further indicating that the axolotl is also able to restore cardiac function after injury [94]. To date, little is known about the NC’s contribution to the development of the axolotl heart [35,96]. However, the current data pose an interesting avenue into the potential abilities of the NC regarding such regenerative capacity, which could lead to advances in cardiac NC regeneration in mammalian species and advances in cardiac disease therapies. As the contribution of NCCs to the heart varies between model systems, it should be further investigated whether regulatory networks controlling NC response to injury and tissue regeneration also differ. For example, in zebrafish, it was identified that sox10 is potentially a vital component in cardiac NC reactivation and cardiomyocyte proliferation [13,86]. However, this role for sox10 has yet to be investigated and corroborated in other vertebrate systems, such as the mouse or chick. Although there are various genes and networks that are staples in cardiac mechanism studies, such as BMP and Wnt [44,97,98,99], one signaling pathway that warrants further investigation regarding the NC’s contribution to cardiac regeneration is the Hippo signaling pathway. The Hippo signaling pathway is a highly conserved regulator of organ size and tissue growth. Previous studies have reported that during mouse embryogenesis, the deletion of Hippo pathway core kinases promotes cardiomyocyte proliferation, and that constitutively active Yap, a downstream effector of the Hippo pathway, increases cardiomyocyte proliferation and heart size both in the embryonic and postnatal mouse [100,101]. To date, numerous studies have identified Yap as a vital factor in regulating cardiomyocytes and neonatal cardiac regeneration, and deficiencies in Yap or its downstream targets, such as Wntless, result in increased scar size and fibrosis after myocardial infarction [98,102]. Furthermore, it was identified that overexpression of Yap (YapS112A) after injury at postnatal day 28 reduced fibrosis, increased myocardial tissue, enhanced cardiac function, and promoted cardiomyocyte proliferation and survival, indicating that Yap is vital for postnatal-cardiac regeneration after injury in mice [102]. As NCCs have been shown to give rise to cardiomyocytes among various species, further investigation into the Hippo signaling pathway’s role in regulating NC-derived cardiac tissue regeneration could pose a novel mechanism and role for both Hippo signaling and cardiac regeneration. To enhance current therapies for patients with heart injuries, numerous studies have begun investigating the ability of NC-derived stem cell models. As discussed, both human embryonic stem cells and iPSCs are currently at the forefront of regeneration strategies [61,69,70]. Although results are promising, further investigations are needed into the potential of NC-like stem cells in specific tissues to contribute to regeneration. Promising results have been shown in the ENS [44,45], but similar abilities of NCCs in the cardiac system have not yet been identified. Further investigations should include whether NCCs from embryonic stages remain multipotent in a dormant stage, or whether such cells maintain specialized fates and later dedifferentiate to contribute to regeneration upon injury.

This review summarizes the contribution of the cardiac NC to the heart between species and the possible contribution to regenerative capacity. Furthermore, we have discussed recent advances in the field of cardiac regeneration, with emphasis on the investigation into how NCCs may be a pivotal cell population that could provide novel information regarding tissue regeneration therapies. Despite the recent advances in understanding NC-derived cardiac regeneration, many questions still persist regarding the regenerative capacity of the adult mammalian heart and the respective mechanisms. Research is also needed to determine the evolutionarily conserved elements of NCs in the cardiac system in order to better understand the abilities and functional contributions of the NC.

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