Augmenting Mesenchymal Stem Cell-Based Therapy of the Infarcted Myocardium with Statins

Abstract

Preconditioning (PC) affords the most potent cytoprotective effects ever known in the physiological system. Since the publication of the first report that preconditioning by cyclical exposure to intermittent sublethal ischemia-reperfusion episodes is cardioprotective, the strategy has been extrapolated to sustain its beneficial effects at cellular and subcellular levels. The underlying principle of preconditioning is that exposure to sublethal episodes of a noxious stimulus triggers survival signaling pathways that render the cells resistant to subsequent exposure to the lethal stimulus. Diverging from the classical protocol involving treatment with ischemia-reperfusion, various preconditioning strategies have been developed and optimized to include physical, chemical, genetic, and pharmacological manipulation of cells to mimic the effects of ischemic preconditioning. Besides survival signaling, such manipulations significantly impact the stemness characteristics, paracrine behavior, angiogenic and differentiation potential, and various other aspects of cellular biology. Primarily used as cholesterol-lowering drugs, statins constitute a group of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors that have been effectively employed as preconditioning mimetics. Various members of the statin group, natural, semisynthetic, or synthetic, i.e., lovastatin, simvastatin, atorvastatin, rosuvastatin, etc., have been used to exploit their pleiotropic effects on the stem/progenitor cells as a part of the preconditioning strategy to enhance their stemness and functionality postengraftment. This book chapter provides a critical review of the advancements in pharmacological preconditioning of stem/progenitor cells in general and with the use of statin in particular. It highlights the mechanism that renders superiority in the use of statins as preconditioning mimetics.