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.
Highlights
Cardioprotection Versus Regeneration: Where do We Stand?1.1
MSCs derived from human term placenta, referred to as amniotic mesenchymal stromal cells (AMSCs), are well-known for theirmodulatory properties [202,203]; extracellular vesicles (EVs) released by human term placenta-MSCs have been recently demonstrated exertion of relevant therapeutic effects as supporting new vessel development in vitro and in vivo [204], with nitric oxide (NO)-releasing polymer stimulation as a functional trigger of exosomal enrichment of pro-angiogenic VEGF and miR-126 [205]
Functional readouts of biomedical applications of EV obtained by either cardiac progenitor cells (CPCs) or exogenous stromal cells of non-cardiac origin have revealed that both types may harbour therapeutic relevance for cardiovascular disease, questioning the rationale that CPCs could have superior cardio-active effects
Summary
The adult mammalian heart cannot withstand prolonged injury, such as severe ischaemia, being endowed with a defective repair programme as the one and only emergency and life-saving mechanism. Cell therapy has been effective in reducing cardiomyocyte apoptosis and tissue fibrosis, while promoting angiogenesis and immunomodulation of inflammation, likely via modulatory stimulation of the local microenvironment [33,34] This is leading to a paradigm shift, where the trophic molecules secreted by the transplanted cells are considered more critical than the differentiation potential of the cells. Modulation of paracrine cardiac endogenous mechanisms that exploit stem/progenitor cell secretory capacity has become an appealing strategy for future cardiovascular medicine In this scenario, cell-secreted factors could be envisioned to enhance and optimise defective cardiac repair programme, by means of supporting the survival of resident cardiomyocytes, activating therapeutic angiogenesis and modulation of inflammation, in order counteract excessive fibrosis
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