Myocardial regeneration protocols towards the routine clinical scenario: An unseemly path from bench to bedside

Figures

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  Figure 1. Potential approaches for successful myocardial remuscularization. The cartoon depicts the main approaches tested pre-clinically and clinically to obtain cardiac remuscularization. Two main approaches have been pursued: (1, top) the exogenous approach has been based on the injection of pluripotent/multipotent ex vivo expanded stem cells (ESCs, iPSCs, CSCs and their derivatives) capable to form new cardiac tissue (including new cardiomyocytes), either directly administered to the injured myocardium or through the use of engineered materials; (2, bottom) the endogenous approach has been based on the injection of cells or factors able to ‘boost’ the endogenous regeneration potential of the adult heart to form new cardiac muscle: the latter has been tested by the paracrine potential of allogenic/autologous stem cells or directly by regenerating factors able to activate (i) the endogenous cardiac stem progenitor cells (CSCs), (ii) the claimed proliferative potential of adult cardiomyocytes or (iii) to reprogram somatic cells like fibroblasts to acquire cardiomyocyte identity.

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  Figure 2. Proposed mechanisms of action of (stem) cell therapy. The cartoon summarizes the main mechanisms claimed to underline the potential benefits of (stem) cell therapy. While cardiac regeneration was the stated goal of (stem) cell therapy, the realization that many clinical attempts of so-called stem cell therapy did not contain actual stem cells with cardiac remuscularization potential shifted the interest on the paracrine ability of the injected cells. This paracrine potential includes the ability of the injected cells to stimulate the repair of the endogenous myocardium through (i) boosting new cardiomyocytes formation either from the endogenous CSCs or from the unexpected division of pre-existing cardiomyocytes, (ii) fostering cardiac protection (reducing hypertrophy, cell death and fibrosis), (iii) improving new vessel formation (angiogenesis) and (iv) overall ameliorating pathologic cardiac remodeling.