Power Is Nothing Without Control: The Enduring Search for the Best Cell in Cardiac Cell Therapy at a Crossroads.

Abstract

> A few observation and much reasoning lead to error; many observations and a little reasoning to truth. > > —Alexis Carrel, Medicine Nobel Prize 1912 Cardiac cell–based therapy, after a peak of untimely expectations of miraculous efficacy exceeding standard clinical practice, has faced the cardiological community and funding bodies with a predictable trough of disillusionment. In the light of more recent progresses, the field is by contrast moving toward a competitive differentiation phase, in which the resolution of the complex matching between potency of cell therapeutics and heart disease pathophysiology has the potential to make a difference for the most challenging unmet clinical needs in cardiovascular medicine. The exogenous administration of stem cells to repair the damaged heart has been clinically introduced on the basis of the revolutionary idea that by delivering cardiomyogenic potent cells, the substitution of dead or damaged myocardium with de novo cardiomyocytes able to directly contribute to contractile force generation would have been an achievable target. The confirmation that the heart possesses an intrinsic, although modest, self-renewal capacity1 has further fueled the clinical exploitation of such an innovative therapeutic strategy. However, from the progress in the field over the past 15 years, it has become evident that by means of available clinical-grade cell products, the salutary functional and clinical effects of cardiac cell therapy (CCT), when present, are more likely because of an indirect (paracrine) action exerted by cells nested in the myocardium through the release of a miscellany of largely unidentified molecules, which promote endogenous reparative processes. Such a paradigm shift from a cardiopoietic to a cardioreparative concept may have profound implications for forthcoming CCT clinical research. Notably, different classes of compounds with a cardioprotective action have been recently unsuccessfully tested in clinical trials with the aim to prevent ischemia–reperfusion injury or heart failure (HF) progression. …