How to Stimulate Myocardial Regeneration in Adult Mammalian Heart: Existing Views and New Approaches.

Galina Belostotskaya,Sergey Suchkov,Marc Hendrikx,Michael Galagudza

doi:10.1155/2020/7874109

Abstract

Stem cell-based therapy has been considered as a promising option in the treatment of ischemic heart disease. Although stem cell administration resulted in the temporary improvement of myocardial contractility in the majority of studies, the formation of new cardiomyocytes within the injured myocardium has not been conclusively demonstrated. Consequently, the focus of research in the field has since shifted to stem cell-derived paracrine factors, including cytokines, growth factors, mRNA, and miRNA. Notably, both mRNA and miRNA can enter into the extracellular space either in soluble form or packed into membrane vesicles. Stem cell-derived paracrine factors have been shown to suppress inflammation and apoptosis, stimulate angiogenesis, and amplify the proliferation and differentiation of resident cardiac stem cells (CSCs). Such features have led to exosomes being considered as potential drug candidates affording myocardial regeneration. The search for chemical signals capable of stimulating cardiomyogenesis is ongoing despite continuous debates regarding the ability of mature cardiomyocytes to divide or dedifferentiate, transdifferentiation of other cells into cardiomyocytes, and the ability of CSCs to differentiate into cardiomyocytes. Future research is aimed at identifying novel cell candidates capable of differentiating into cardiomyocytes. The observation that CSCs can undergo intracellular development with the formation of “cell-in-cell structure” and subsequent release of transitory amplifying cells with the capacity to differentiate into cardiomyocytes may provide clues for stimulating regenerative cardiomyogenesis.

Highlights

The idea of extending the lifetime of the human heart has been fuelled by a series of major advances in transplantation and drug therapies
By studying the behaviour of mammalian cardiac stem cells (CSCs), we showed that the formation of new CMs from resident CSCs occurs through colony formation [78] and consequent to their intracellular development inside the CMs, forming cell-in-cell structures (CICSs) [79]
It is important to highlight that intracellular CSC development is associated with partial cardiomyogenic differentiation of their progeny and by the decreased level of their stemness. This fact hampers the identification of daughter cells for transitory amplifying cells (TACs) and ignores that the small size of TACs may lead to their erroneous interpretation as proliferating CMs

Summary

Introduction

The idea of extending the lifetime of the human heart has been fuelled by a series of major advances in transplantation and drug therapies. By utilising a primitive cell-fate map for the generation of such progenitors, the possibility exists of regenerating the heart by transplanting specific progenitors derived from human SCs into patients with or at risk for cardiovascular disease Towards this end, a clinically useful tissueengineered graft needs to be designed to perform multiple different tasks including (i) reestablishment of the normal structure and function of injured myocardium across different size scales; (ii) functional integration with the host tissue; and (iii) remodelling in response to, e.g., environmental factors, growth, and aging. Our primary focus is on bioinspired strategies along with the knowledge gained to date regarding the challenges that remain to be addressed for engineered heart regeneration to become a clinical reality, within the framework of preventive and treatment strategies rooted in personalized and precision healthcare-based and translational resources This field still lacks sufficiently conclusive results to support full-scale implementation of such approaches, as exemplified by the poor survival and long-term engraftment of transplanted cells. These properties of exosomes support their likely utility as both biomarkers of cardiac damage and possible regulators of myocardium regeneration [46]

Innate Heart Regeneration

Conclusion

Findings

Conflicts of Interest