Cardiac development and regeneration

The conflicting results of cell therapy clinical trials for heart regeneration have led to some confusion over the efficacy of this approach. This Review summarizes the main outcomes of these studies and gives perspectives for future cell-based regenerative trials largely based on the primary therapeutic target: regeneration of lost myocardium by exogenous cells or promotion of intrinsic repair though paracrine signalling.

This Review discusses the advances in therapeutic approaches for cardiac repair and regeneration, including cell-based therapies as well as the use of secretory factors, such as microRNAs and exosomes, direct reprogramming strategies, and gene editing to control cardiac remodelling and redirect the adult heart to a regenerative state, and highlights the future prospects of preclinical and clinical trials of heart regeneration.

Research on cardiac repair and regeneration is shifting from a stem cell focus towards the dynamic interplay of stromal and immune cells of the cardiac interstitium. This Review provides new insights into the immunoregulatory functions of cardiac interstitial cells and their complex network of interactions, highlighting the therapeutic potential for cardiac disease.

This Review summarizes the current understanding on the roles of the Hippo–YAP pathway in cardiac development, growth, homeostasis, disease, and regeneration, with a particular focus on the roles of the Hippo–YAP pathway in endogenous cardiac muscle renewal, including the pivotal role of this pathway in regulating cardiomyocyte proliferation, differentiation, stress response, and mechanical signalling.

The epicardium is a multipotent cardiac progenitor tissue that serves as a crucial signalling centre for heart development and repair. This Review describes recent advances in our understanding of the biology of the epicardium and discusses the potential to harness the properties of the epicardium to develop therapeutic strategies for heart repair and regeneration.

In this Review, de la Pompa and colleagues describe the role of the Notch pathway during the differentiation and patterning of cardiac tissues and in valve and ventricular chamber development, discussing the crosstalk with other signalling pathways, how defective Notch signalling is linked to congenital heart diseases, and the relevance of the Notch pathway in heart regeneration and repair.

In this Review, Meilhac and Buckingham discuss the origin of cardiac cell populations, their lineage relationships and the genes that regulate their behaviour and differentiation. Characterizing the progenitor cells that form the heart and the gene regulatory networks controlling their deployment is of major importance for understanding the origin of congenital heart malformations and for developing cardiac regeneration therapies.

In this Review, Christoffels and colleagues detail the transcriptional networks that control development and homeostasis of the cardiac conduction system. The pathophysiological consequences of aberrations in these networks are also discussed, with potential insights into the generation of biological pacemakers.

Despite substantial advances, bona fide regeneration of the damaged human heart is still an unmet ambition. By extracting our current knowledge from developmental biology, animal models of heart regeneration, and clinical observations, we propose five hallmarks of cardiac regeneration and suggest a holistic approach to reconstituting human heart function.

Early studies showing that KIT⁺ cardiac progenitor cells (CPCs) could differentiate into cardiomyocytes generated excitement regarding their potential therapeutic application. Subsequent studies called their functional relevance into question, and while claims for a contribution of KIT⁺ CPCs to myocardial regeneration continue, two new studies confirm the doubts about their relevance to cardiomyogenesis and provide unexpected new insights.

The immaturity of stem cell-derived cardiomyocytes has impeded their use for in vitro disease modelling, cardiotoxicity assays, and cell-replacement therapy. Ronaldson-Bouchard and colleagues report unparalleled in vitro maturation of stem cell-derived cardiomyocytes. This advance promises to unlock the translational potential of these cells.

Important milestones in cardiac regenerative medicine that will define future research were reached in 2017: demonstration of adult cardiomyocyte renewal capacity, recognition of the importance of the extracellular matrix and the higher regenerative efficacy of repetitive dose protocols, and the publication of human data supporting paracrine effects of stem cell therapies and guidelines from TACTICS, the first international alliance on cardiac regenerative medicine.

Type V collagen, a minor constituent of the myocardial scar that forms after ischaemic injury, is an important regulator of scar size via a previously unrecognized role in limiting integrin-dependent fibrosis.

An ‘off-the-shelf’, cell-free, artificial cardiac patch has been created that is easy to store and improves outcomes in rat and pig models of myocardial infarction.

Inhibition of fatty acid metabolism to promote oxidation of glycolysis-derived pyruvate promotes cardiomyocyte proliferation and improves left ventricular function after myocardial infarction.

Macrophages directly contribute collagen to scar formation as part of heart regeneration in zebrafish and heart repair in mice; this finding develops the current paradigm of collagen deposition for scar formation being generated exclusively via macrophage-mediated activation of cardiac fibroblasts to myofibroblasts.

Intravenous infusion of a platelet-derived growth factor promoted wound healing and increased survival in a pig model of myocardial infarction.

Stem cell therapy does not promote the regeneration or production of new cardiomyocytes in the injured heart but induces a wound healing response that contributes to improved cardiac function.

A new study reveals a developmental basis for mitral valve prolapse, caused by altered primary cilia-mediated regulation of extracellular matrix deposition during development, and suggests that mutations in primary cilia genes can be the cause of mitral valve prolapse in some patients.

Placental stem cells expressing caudal-type homeobox 2 can differentiate into cardiomyocytes and vascular cells, improving cardiac function in the infarcted hearts of mice.

Viral vector delivery of microRNA-199a after myocardial infarction in pigs can stimulate endogenous myocardial repair mechanisms and improve cardiac function; however, persistent expression of the miRNA leads to sudden arrhythmic death.

The polyploidy of mammalian cardiomyocytes is a barrier to heart regeneration, but modification of the cardiomyocyte cell cycle can boost their regenerative potential.

Ischaemic cardiomyopathy leads to destruction of cardiomyocytes beyond the regenerative potential of the adult human heart. The murine heart can regenerate in utero and shortly after birth, but oxidative stress eventually arrests cardiomyocyte division. Chronic hypoxia in mice has now been shown to induce the cell cycle in cardiomyocytes, resulting in cardiac regeneration.