Abstract
A variety of paracrine signals create networks within the myocardium and mediate intercellular communications. Indeed, paracrine stimulation of the endogenous regenerative program of the heart, mainly based on resident cardiac progenitor cell (CPC) activation together with cardiomyocyte proliferation, has become increasingly relevant for future cardiac medicine. In the last years, it has been shown that extracellular vesicles (EV), including exosomes (Ex), are powerful conveyors of relevant biological effects. EV have been proposed not only as promising therapeutic tool for triggering cardiac regeneration and improving repair, but also as means of better understanding the physiological and pathological relationships between specific cardiac components, including cardiomyocytes and fibroblasts. Actually, EV from different kinds of exogenous stem cells have been shown to mediate beneficial effects on the injured myocardium. Moreover, endogenous cells, like CPC can instruct cardiovascular cell types, including cardiomyocytes, while cardiac stromal cells, especially fibroblasts, secrete EV that modulate relevant aspects of cardiomyocyte biology, such as hypertrophy and electrophysiological properties. Finally, cardiomyocytes too may release EV influencing the function of other cardiac cell types. Therefore, EV-based crosstalk is thought to be important in both physiology and pathology, being involved in the responses of the heart to noxious stimuli. In this review we will discuss the role of EV in both regulating cardiac homeostasis and driving heart regeneration. In particular, we will address their role in: (i) providing cardio-protection and enhancing cardiac repair mechanisms; (ii) CPC biology; and (iii) influencing adult cardiomyocyte behavior.
Highlights
Full cardiac regeneration is well-established in lower vertebrates including amphibians and the teleost fish; in the zebrafish heart, responsive reactivation of resident cardiomyocyte proliferation can occur following severe myocardial injury, such as apex resection, with almost total reconstitution of viable tissue over a transient scar (Lepilina et al, 2006; Kikuchi et al, 2010; Zhao et al, 2014; González-Rosa et al, 2017)
The heart responds to an ischemic injury – such as the occlusion of a coronary artery causing the death of a consistent amount of cardiomyocytes – by promptly triggering an inflammatory response with activation of myofibroblasts, which rapidly lay down a collagen-enriched scar tissue to compensate the cardiomyocyte loss
A recent study from our group indicated that human amniotic fluid stem cell-extracellular vesicles (EV) are enriched with miRNAs over proteins or other soluble factors; notably direct trafficking of miR-210 and miR-199a-3p from hAFS-EV to responder cells were suggested to drive pro-survival and proliferative effects in recipient human dermal fibroblast and murine myoblasts, which showed significant increase of such putative molecular candidates (Balbi et al, 2017). This may lay the foundations for further studies to pinpoint specific signaling pathway/molecular targets with relevant therapeutic application for cardiac repair and regeneration; these miRNAs have been described to exert remarkable effects on the myocardium in vivo, as potent drivers of local angiogenesis and cardiomyocyte renewal (Eulalio et al, 2012; Arif et al, 2017)
Summary
Full cardiac regeneration is well-established in lower vertebrates including amphibians and the teleost fish; in the zebrafish heart, responsive reactivation of resident cardiomyocyte proliferation can occur following severe myocardial injury, such as apex resection, with almost total reconstitution of viable tissue over a transient scar (Lepilina et al, 2006; Kikuchi et al, 2010; Zhao et al, 2014; González-Rosa et al, 2017). A recent study from our group indicated that human amniotic fluid stem cell-EV (hAFS-EV) are enriched with miRNAs over proteins or other soluble factors; notably direct trafficking of miR-210 and miR-199a-3p from hAFS-EV to responder cells were suggested to drive pro-survival and proliferative effects in recipient human dermal fibroblast and murine myoblasts, which showed significant increase of such putative molecular candidates (Balbi et al, 2017) This may lay the foundations for further studies to pinpoint specific signaling pathway/molecular targets with relevant therapeutic application for cardiac repair and regeneration; these miRNAs have been described to exert remarkable effects on the myocardium in vivo, as potent drivers of local angiogenesis and cardiomyocyte renewal (Eulalio et al, 2012; Arif et al, 2017). Human ESC-derived MSC were shown to release Ex restoring the myocardium ATP production while decreasing oxidative stress via functional replenishment of glycolytic enzymes from their cargo into the injured myocardium in a preclinical mouse model of I/R injury (Arslan et al, 2013; Lai et al, 2013)
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