Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

Abstract

Ischaemic cardiac disease is associated with a loss of cardiomyocytes and an intrinsic lack of myocardial renewal. Recent work has shown that the heart retains limited cardiomyocyte proliferation, which remains inefficient when facing pathological conditions. While broadly active in the neonatal mammalian heart, this mechanism becomes quiescent soon after birth, suggesting loss of regenerative potential with maturation into adulthood. A key question is whether this temporary regenerative window can be enhanced via appropriate stimulation and further extended. Recently the search for novel therapeutic approaches for heart disease has centred on stem cell biology. The "paracrine effect" has been proposed as a promising strategy to boost endogenous reparative and regenerative mechanisms from within the cardiac tissue by exploiting the modulatory potential of soluble stem cell-secreted factors. As such, growing interest has been specifically addressed towards stem/progenitor cell-secreted extracellular vesicles (EVs), which can be easily isolated in vitro from cell-conditioned medium. This review will provide a comprehensive overview of the current paradigm on cardiac repair and regeneration, with a specific focus on the role and mechanism(s) of paracrine action of EVs from cardiac stromal progenitors as compared to exogenous stem cells in order to discuss the optimal choice for future therapy. In addition, the challenges to overcoming translational EV biology from bench to bedside for future cardiac regenerative medicine will be discussed.

Comprehensive Profiling of Secretome Formulations from Fetal- and Perinatal Human Amniotic Fluid Stem Cells

“…EVs include very small (<200 nm) exosomes, medium-sized (200–500 nm) microvesicles or shedding vesicles, and larger-sized apoptotic bodies (>500 nm); they operate as critical biological conveyors of inter-cellular signaling by delivering their molecular cargo from a parental cell to a responder/target one [ 5 , 6 ]. Given that their peculiar paracrine potential in exerting beneficial effects are comparable to their cells of origin, stem cell-EVs have arisen as appealing therapeutic options in preclinical models of diseases, such as ischemia, inflammation or injury, as extensively reviewed in [ 7 , 8 , 9 ]. From a translational perspective, on top of cell modulatory potential, isolation feasibility and elevated self-renewal are key aspects for the ideal source of therapeutic EVs and soluble factors.…”

The Cellular Stress Response Interactome and Extracellular Matrix Cross-Talk during Fibrosis: A Stressed Extra-Matrix Affair

“…Delineating the subtle mechanisms and cellular, molecular, and extracellular matrix players implicated in regenerative and non-regenerative hearts can provide insights into the homeostasisrepair-fibrosis continuum, which remains the most vexing challenge in developing successful regenerative/anti-fibrotic approaches for fibrotic disorders. Further, the refractory response of cardiomyocytes to complete cell-cycle progression through mitosis limits their self-renewal, therefore, cardiomyogenic approaches to treat heart failure remain practically intractable [38][39][40][41][42][43][44][45][46][47][48].…”

Unravelling the Biology of Adult Cardiac Stem Cell-Derived Exosomes to Foster Endogenous Cardiac Regeneration and Repair

“…It appears that exosomes derived from CPCs may have a central role in maintaining the balance between self-renewal and differentiation of CPCs themselves, the two main characteristics that characterize stem cells [54,114,115,121] (Figure 2). Thus, exosomes derived from CPCs may improve the activation of the regenerative potential of the endogenous pool of cardiac tissue-specific stem/progenitor cells by transferring signal molecules directly within their niche and the myocardial microenvironment [121,122]. Moreover, exosomes derived from CPCs may release in the extracellular environment genetic information, modulating endogenous stem cell plasticity and tissue regeneration after damage [119,123,124] (Figure 3).…”

“…Thus, thanks to the repertoire of macromolecules that they contain, exosomes derived from the CPCs may improve cardiac function and may reduce fibrosis after myocardial damage [119,[121][122][123][124]127].…”

“…Another important evidence is correlated to the pro-regenerative effect of miRNAs released from CPC-derived exosomes, in response to differential myocardial stress and damage [39][40][41][117][118][119][121][122][123][124]127,128]. To date, this evidence that exosomes contain miRNAs has acquired a growing interest in the scientific community because it seems that these small RNA molecules may have a significant impact on cell and tissue homeostasis as well as in cellular phenotype specification [128,129].…”