Approaches to augment vascularisation and regeneration of the adult heart via the reactivated epicardium (original) (raw)

The epicardium as a candidate for heart regeneration

Future Cardiology, 2012

The mammalian heart loses its regenerative capacity during early postnatal stages; consequently, individuals surviving myocardial infarction (MI) are at risk of heart failure due to excessive fibrosis and maladaptive remodelling. There is an urgent need, therefore, to develop novel therapies for myocardial and coronary vascular regeneration. The epicardium-derived cells (EPDCs) present a tractable resident progenitor source with the potential to stimulate neovasculogenesis and contribute de novo cardiomyocytes. The ability to revive ordinarily dormant EPDCs lies in the identification of key stimulatory factors, such as Tβ4, and elucidation of the molecular cues used in the embryo to orchestrate cardiovascular development. MI injury signalling reactivates the adult epicardium; understanding the timing and magnitude of these signals will enlighten strategies for myocardial repair.

Cardiac Regeneration from Activated Epicardium

PLoS ONE, 2012

In contrast to lower vertebrates, the mammalian heart has a very limited regenerative capacity. Cardiomyocytes, lost after ischemia, are replaced by fibroblasts. Although the human heart is able to form new cardiomyocytes throughout its lifespan, the efficiency of this phenomenon is not enough to substitute sufficient myocardial mass after an infarction. In contrast, zebrafish hearts regenerate through epicardial activation and initiation of myocardial proliferation. With this study we obtain insights into the activation and cellular contribution of the mammalian epicardium in response to ischemia. In a mouse myocardial infarction model we analyzed the spatio-temporal changes in expression of embryonic epicardial, EMT, and stem cell markers and the contribution of cells of the Wt1-lineage to the infarcted area. Though the integrity of the epicardial layer overlaying the infarct is lost immediately after the induction of the ischemia, it was found to be regenerated at three days post infarction. In this regenerated epicardium, the embryonic gene program is transiently re-expressed as well as proliferation. Concomitant with this activation, Wt1-lineage positive subepicardial mesenchyme is formed until two weeks post-infarction. These mesenchymal cells replace the cardiomyocytes lost due to the ischemia and contribute to the fibroblast population, myofibroblasts and coronary endothelium in the infarct, and later also to the cardiomyocyte population. We show that in mice, as in lower vertebrates, an endogenous, epicardium-dependent regenerative response to injury is induced. Although this regenerative response leads to the formation of new cardiomyocytes, their number is insufficient in mice but sufficient in lower vertebrates to replace lost cardiomyocytes. These molecular and cellular analyses provide basic knowledge essential for investigations on the regeneration of the mammalian heart aiming at epicardiumderived cells.

Recapturing embryonic potential in the adult epicardium: Prospects for cardiac repair

Stem Cells Translational Medicine, 2020

Research into potential targets for cardiac repair encompasses recognition of tissue-resident cells with intrinsic regenerative properties. The adult vertebrate heart is covered by mesothelium, named the epicardium, which becomes active in response to injury and contributes to repair, albeit suboptimally. Motivation to manipulate the epicardium for treatment of myocardial infarction is deeply rooted in its central role in cardiac formation and vasculogenesis during development. Moreover, the epicardium is vital to cardiac muscle regeneration in lower vertebrate and neonatal mammalian-injured hearts. In this review, we discuss our current understanding of the biology of the mammalian epicardium in development and injury. Considering present challenges in the field, we further contemplate prospects for reinstating full embryonic potential in the adult epicardium to facilitate cardiac regeneration.

The ontogeny, activation and function of the epicardium during heart development and regeneration

Development

The epicardium plays a key role during cardiac development, homeostasis and repair, and has thus emerged as a potential target in the treatment of cardiovascular disease. However, therapeutically manipulating the epicardium and epicardium-derived cells (EPDCs) requires insights into their developmental origin and the mechanisms driving their activation, recruitment and contribution to both the embryonic and adult injured heart. In recent years, studies of various model systems have provided us with a deeper understanding of the microenvironment in which EPDCs reside and emerge into, of the crosstalk between the multitude of cardiovascular cell types that influence the epicardium, and of the genetic programmes that orchestrate epicardial cell behaviour. Here, we review these discoveries and discuss how technological advances could further enhance our knowledge of epicardium-based repair mechanisms and ultimately influence potential therapeutic outcomes in cardiovascular regenerative medicine.

Myocardial regeneration: role of epicardium and implicated genes

Molecular Biology Reports, 2019

Lower invertebrates' hearts such as those of zebrafish have the capacity for scarless myocardial regeneration which is lost by mammalian hearts as they form a fibrotic scar tissue instead of regenerating the injured area. However, neonatal mammalian hearts have a remarkable capacity for regeneration highlighting conserved evolutionary mechanisms underlying such a process. Studies investigated the underlying mechanism of myocardial regeneration in species capable to do so, to see its applicability on mammals. The epicardium, the mesothelial outer layer of the vertebrate heart, has proven to play an important role in the process of repair and regeneration. It serves as an important source of smooth muscle cells, cardiac fibroblasts, endothelial cells, stem cells, and signaling molecules that are involved in this process. Here we review the role of the epicardium in myocardial regeneration focusing on the different involved; Activation, epithelial to mesenchymal transition, and differentiation. In addition, we will discuss its contributory role to different aspects that support myocardial regeneration. Of these we will discuss angiogenesis and the formation of a regenerate extracellular matrix. Moreover, we will discuss several factors that act on the epicardium to affect regeneration. Finally, we will highlight the utility of the epicardium as a mode of cell therapy in the treatment of myocardial injury.

The epicardium signals the way towards heart regeneration

Stem Cell Research, 2014

From historical studies of developing chick hearts to recent advances in regenerative injury models, the epicardium has arisen as a key player in heart genesis and repair. The epicardium provides paracrine signals to nurture growth of the developing heart from mid-gestation, and epicardium-derived cells act as progenitors of numerous cardiac cell types. Interference with either process is terminal for heart development and embryogenesis. In adulthood, the dormant epicardium reinstates an embryonic gene programme in response to injury. Furthermore, injury-induced epicardial signalling is essential for heart regeneration in zebrafish. Given these critical roles in development, injury response and heart regeneration, the application of epicardial signals following adult heart injury could offer therapeutic strategies for the treatment of ischaemic heart disease and heart failure.

The arterial and cardiac epicardium in development, disease and repair

Differentiation, 2012

The importance of the epicardium covering the heart and the intrapericardial part of the great arteries has reached a new summit. It has evolved as a major cellular component with impact both in development, disease and more recently also repair potential. The role of the epicardium in development, its differentiation from a proepicardial organ at the venous pole (vPEO) and the differentiation capacities of the vPEO initiating cardiac epicardium (cEP) into epicardium derived cells (EPDCs) have been extensively described in recent reviews on growth and transcription factor pathways. In short, the epicardium is the source of the interstitial, the annulus fibrosus and the adventitial fibroblasts, and differentiates into the coronary arterial smooth muscle cells. Furthermore, EPDCs induce growth of the compact myocardium and differentiation of the Purkinje fibers. This review includes an arterial pole located PEO (aPEO) that provides the epicardium covering the intrapericardial great vessels. In avian and mouse models disturbance of epicardial outgrowth and maturation leads to a broad spectrum of cardiac anomalies with main focus on non-compaction of the myocardium, deficient annulus fibrosis, valve malformations and coronary artery abnormalities. The discovery that in disease both arterial and cardiac epicardium can again differentiate into EPDCs and thus reactivate its embryonic program and potential has highly broadened the scope of research interest. This reactivation is seen after myocardial infarction and also in aneurysm formation of the ascending aorta. Use of EPDCs for cell therapy show their positive function in paracrine mediated repair processes which can be additive when combined with the cardiac progenitor stem cells that probably share the same embryonic origin with EPDCs. Research into the many cell-autonomous and cell-cell-based capacities of the adult epicardium will open up new realistic therapeutic avenues.

Cardiac development: from current understanding to new regenerative concepts

Journal of Thoracic Disease, 2017

In recent years, innovative and significant progress has been made in cardiac developmental biology, cardiovascular genetics, and stem cell research. The 3 rd Munich Conference on Cardiac Development focused on our current understanding of the mechanisms that underlie heart development, cardiac disease, and cardiac ageing and ways to develop new regenerative concepts to foster future therapeutic regenerative treatment strategies. The paradigm of an entirely postmitotic mammalian heart was recently challenged, offering perspectives for the development of new regenerative strategies. Adult mammalian hearts are able to regenerate, even if at a markedly lower rate than the hearts of zebrafish and newts (1,2). However, there is ongoing debate about the source of this homeostatic cardiac turnover in mammals. One possible source is cardiomyocytes that pass through a phase of dedifferentiation, in which they reenter the cell cycle and start to divide again (3). Cardiomyocyte proliferation is well described in the zebrafish heart as being fundamental to their tremendous heart regeneration capacity (4). Another possibility that is still under debate is that resident cardiac progenitor/stem cells are reactivated from their niches and then contribute to cardiomyocyte proliferation or even differentiate directly into cardiomyocytes (5). Few scientists have discussed the contribution of circulating cells to cardiomyocyte regeneration after injury (6). Current regenerative approaches include the transplantation of various cell types [ideally combined with tissue engineering; e.g., (7)], the stimulation of endogenous repair mechanisms [e.g., the induction of cardiomyocyte proliferation (8-11)], and the direct reprogramming of fibrotic parts of the failing heart back to a functional myocardium [e.g., (12,13)]. For the development and improvements of such innovative therapies, a detailed understanding of cardiac development and the processes by which cardiac progenitor cell populations mature into cardiomyocytes is essential (14,15). However, the highly complex temporal and spatial interactions between transcription factors, growth factors, and non-coding RNAs that act in various progenitor cell populations during cardiac development are not completely understood. Alexanian et al. (16) review the knowledge about how long-non-coding (lnc)-RNAs contribute to mesoderm specification. New omics techniques, combined with single-cell analysis tools, will help shed light on above mentioned mechanisms and offer the possibility to expand our knowledge of the cardiac developmental network [reviewed by (17)]. Furthermore, the processes and factors that are involved in cardiac aging have become increasingly important because the world's population is aging, and aging itself is a major cardiovascular risk factor (18). A thorough understanding of the underlying mechanisms may provide novel targets for regenerative strategies. In this issue, Cannatà et al. review the role of circulating humoral factors in cardiovascular aging (19). A true understanding of the cell types that are involved in cardiac injury, disease mechanisms, and cardiac remodeling [e.g., inflammatory cells (20) and cardiac fibroblasts (21)] and their mechanisms of action is mandatory. This may also foster new ideas and identify new options for improving current therapeutic strategies. Following tissue injury by myocardial infarction the immune system and its cellular protagonists (i.e., monocytes and macrophages) substantially contribute to the initial inflammatory response and subsequent regenerative response. The specific role of monocytes and macrophages during homeostasis and after cardiac ischemic injury is reviewed by Sager et al. (22). Cardiac fibroblasts were long an underestimated cell population. However, they have gained more attention in recent years (23). Following the inflammatory phase after myocardial infarction, cardiac fibroblasts proliferate and undergo myofibroblast transdifferentiation to maintain the structural integrity of the impaired ventricle. The role of transforming growth factor-β in this process is reviewed by Frangogiannis (24). Cardiac fibroblasts and their activated forms after injury also represent an interesting novel target population for direct reprogramming techniques (13). Alternative targets after cardiac injury include non-coding RNAs, e.g., microRNAs and long-non-coding RNAs (25,26). Recent studies have provided additional insights into the roles of non-coding RNAs in heart development and disease [e.g., (27)].

Underlying mechanisms and prospects of heart regeneration

TURKISH JOURNAL OF BIOLOGY, 2016

Using electron microscopy in 1974, Oberpriler et al. (1974) demonstrated the prospect of cardiac regeneration in newts. Later, Witman et al. (2011) reported that the adult newt is able to completely regenerate its heart after a basal resection (Witman et al., 2011). Zebrafish (Danio rerio) is a tropical freshwater fish Abstract: Findings in the last decade suggest that there is a considerable amount of cardiomyocyte turnover in the human heart throughout life, albeit not sufficient for heart regeneration following myocardial infarctions. Only a few species are known to be remarkably efficient in cardiac regeneration. They restore lost cardiomyocytes via a process of cardiomyocyte dedifferentiation, which is followed by robust proliferation of cardiomyocytes and incorporation into the myocardium. Similarly, neonatal mice have been recently shown to regenerate their heart following myocardial injuries. Studies with a neonatal cardiac regeneration mouse model suggest that the major source of new cardiomyocytes is likely to be of cardiomyocyte origin, with the possibility of involvement of cardiac stem cells. To this end, numerous studies have been conducted on the induction of cardiac regeneration to shed light on the underlying mechanisms. This review covers studies on the renewal of cardiomyocytes, the utilization of stem cells in myocardial therapies, and their future applications.