Cardiac muscle regeneration: lessons from development

Mammalian heart formation is a complex morphogenetic event that depends on the correct temporal and spatial contribution of distinct cell sources. During cardiac formation, cellular specification, differentiation, and rearrangement are tightly regulated by an intricate signaling network. Over the last years, many aspects of this network have been uncovered not only due to advances in cardiac development comprehension but also due to the use of embryonic stem cells (ESCs) in vitro model system. Additionally, several of these pathways have been shown to be functional or reactivated in the setting of cardiac disease. Knowledge withdrawn from studying heart development, ESCs differentiation, and cardiac pathophysiology may be helpful to envisage new strategies for improved cardiac repair/regeneration. In this review, we provide a comparative synopsis of the major signaling pathways required for cardiac lineage commitment in the embryo and murine ESCs. The involvement and possible reactivation of these pathways following heart injury and their role in tissue recovery will also be discussed. BioMed Research International, Volume 2014, http://dx.doi.org/10.1155/2014/679168

Cell Stem Cell, 2020

Heart regeneration, a relatively new field of biology, is one of the most active and controversial areas of biomedical research. The potential impact of successful human heart regeneration therapeutics cannot be overstated, given the magnitude and prognosis of heart failure. However, the regenerative process is highly complex, and premature claims of successful heart regeneration have both fueled interest and created controversy. The field as a whole is now in the process of course correction, and a clearer picture is beginning to emerge. Despite the challenges, fundamental principles in developmental biology have provided a framework for hypothesis-driven approaches toward the ultimate goal of adult heart regeneration and repair. In this review, we discuss the current state of the field and outline the potential paths forward toward regenerating the human myocardium.

Heart disease is the number one cause of morbidity and mortality in the world and is a major health and economic burden costing the United States Health Care System more than $200 billion annually. A major cause of heart disease is the massive loss or dysfunction of cardiomyocytes caused by myocardial infarctions and hypertension. Due to the limited regenerative capacity of the heart, much research has focused on better understanding the process of differentiation towards cardiomyocytes. This review will highlight what is currently known about cardiac cell specification during mammalian development, areas of controversy, cellular sources of cardiomyocytes, and current and potential uses of stem cell derived cardiomyocytes for cardiac therapies.

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)].

Journal of Molecular and Cellular Cardiology, 2016

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Cell Reports, 2020

The adult mammalian heart has limited capacity for regeneration following injury, whereas the neonatal heart can readily regenerate within a short period after birth. Neonatal heart regeneration is orchestrated by multiple cell types intrinsic to the heart, as well as immune cells that infiltrate the heart after injury. To elucidate the transcriptional responses of the different cellular components of the mouse heart following injury, we perform single-cell RNA sequencing on neonatal hearts at various time points following myocardial infarction and couple the results with bulk tissue RNA-sequencing data collected at the same time points. Concomitant single-cell ATAC sequencing exposes underlying dynamics of open chromatin landscapes and regenerative gene regulatory networks of diverse cardiac cell types and reveals extracellular mediators of cardiomyocyte proliferation, angiogenesis, and fibroblast activation. Together, our data provide a transcriptional basis for neonatal heart regeneration at single-cell resolution and suggest strategies for enhancing cardiac function after injury.

Current Opinion in Cell Biology, 2019

Ischemic heart disease is one of the leading causes of mortality. Myocardial infarction causes loss of cardiomyocytes in the injury area accompanied by formation of a fibrotic scar. This initiates a cascade of events including further loss of myocyte, increased fibrosis, and pathological cardiac hypertrophy, eventually leading to the heart failure. Cardiomyocytes in mammals have limited regenerative potential due to post mitotic nature of cardiomyocytes. Recently, multiple studies have provided substantial insights in to the molecular pathways governing this block in adult cardiomyocyte proliferation, and successfully employed that understanding to achieve cardiac regeneration. These strategies include directly reprograming the cardiomyocytes or manipulating the cardiac interstitium to repair the injured heart. In this review, we discuss the recent advances made in the field in the past two years.

American Journal of Physiology-Heart and Circulatory Physiology, 2020

The adult mammalian cardiomyocyte has a very limited capacity to reenter the cell cycle and advance into mitosis. Therefore, diseases characterized by lost contractile tissue usually evolve into myocardial remodeling and heart failure. Analyzing the cardiac transcriptome at different developmental stages in a large mammal closer to the human than laboratory rodents may serve to disclose positive and negative cardiomyocyte cell cycle regulators potentially targetable to induce cardiac regeneration in the clinical setting. Thus we aimed at characterizing the transcriptomic profiles of the early fetal, late fetal, and adult sheep heart by employing RNA-seq technique and bioinformatic analysis to detect protein-encoding genes that in some of the stages were turned off, turned on, or differentially expressed. Genes earlier proposed as positive cell cycle regulators such as cyclin A, cdk2, meis2, meis3, and PCNA showed higher expression in fetal hearts and lower in AH, as expected. In con...

Circulation Research, 2013

Frontiers in Cardiovascular Medicine, 2021

Despite considerable efforts carried out to develop stem/progenitor cell-based technologies aiming at replacing and restoring the cardiac tissue following severe damages, thus far no strategies based on adult stem cell transplantation have been demonstrated to efficiently generate new cardiac muscle cells. Intriguingly, dedifferentiation, and proliferation of pre-existing cardiomyocytes and not stem cell differentiation represent the preponderant cellular mechanism by which lower vertebrates spontaneously regenerate the injured heart. Mammals can also regenerate their heart up to the early neonatal period, even in this case by activating the proliferation of endogenous cardiomyocytes. However, the mammalian cardiac regenerative potential is dramatically reduced soon after birth, when most cardiomyocytes exit from the cell cycle, undergo further maturation, and continue to grow in size. Although a slow rate of cardiomyocyte turnover has also been documented in adult mammals, both in ...