Abstract
True cardiac regeneration of the injured heart has been broadly described in lower vertebrates by active replacement of lost cardiomyocytes to functionally and structurally restore the myocardial tissue. On the contrary, following severe injury (i.e., myocardial infarction) the adult mammalian heart is endowed with an impaired reparative response by means of meager wound healing program and detrimental remodeling, which can lead over time to cardiomyopathy and heart failure. Lately, a growing body of basic, translational and clinical studies have supported the therapeutic use of stem cells to provide myocardial regeneration, with the working hypothesis that stem cells delivered to the cardiac tissue could result into new cardiovascular cells to replenish the lost ones. Nevertheless, multiple independent evidences have demonstrated that injected stem cells are more likely to modulate the cardiac tissue via beneficial paracrine effects, which can enhance cardiac repair and reinstate the embryonic program and cell cycle activity of endogenous cardiac stromal cells and resident cardiomyocytes. Therefore, increasing interest has been addressed to the therapeutic profiling of the stem cell-derived secretome (namely the total of cell-secreted soluble factors), with specific attention to cell-released extracellular vesicles, including exosomes, carrying cardioprotective and regenerative RNA molecules. In addition, the use of cardiac decellularized extracellular matrix has been recently suggested as promising biomaterial to develop novel therapeutic strategies for myocardial repair, as either source of molecular cues for regeneration, biological scaffold for cardiac tissue engineering or biomaterial platform for the functional release of factors. In this review, we will specifically address the translational relevance of these two approaches with ad hoc interest in their feasibility to rejuvenate endogenous mechanisms of cardiac repair up to functional regeneration.
Highlights
Australian Regenerative Medicine Institute (ARMI), Australia Giovanni Vozzi, University of Pisa, Italy Anny Waloski Robert, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (Fiocruz), Brazil
True cardiac regeneration of the injured heart has been broadly described in lower vertebrates by active replacement of lost cardiomyocytes to functionally and structurally restore the myocardial tissue
On the contrary, following severe injury the adult mammalian heart is endowed with an impaired reparative response by means of meager wound healing program and detrimental remodeling, which can lead over time to cardiomyopathy and heart failure
Summary
Cardiovascular disorders significantly affect life expectancy; according to the World Health Organization (WHO), by 2030 about 23 million people annually will be severely affected by heart failure (Leone et al, 2015; Mozaffarian et al, 2015; Benjamin et al, 2018). Further in vitro investigation revealed that human epicardial CPC primed with human amniotic fluid stem cell-conditioned medium (containing EVs), produced a pro-angiogenic secretome driving tubulogenesis in HUVEC cells (Balbi et al, 2019) These results confirmed previous findings describing how severe myocardial injury can induce epicardial CPC proliferation, without differentiation into cardiomyocytes or endothelial cells, but with restoration of their paracrine activity on local de novo vascular network expansion (Zhou et al, 2011; Dube et al, 2017). In light of these evidences, endogenous CPC may represent an appealing therapeutic target for stem/progenitor cell-EVs for improving endogenous (paracrine) mechanisms of cardiac repair, as suggested by independent investigators (Alibhai et al, 2018). Systemic delivery of putative therapeutic paracrine factor(s), as the less invasive and more clinically compliant option, may be significantly restrained by the meager homing of the treatment to the cardiac tissue, as likely rapidly sequestered by off-target organs/tissues; optimization of local administration would offer significant improvements
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