Cardiac Regeneration by Statin-Polymer Nanoparticle-Loaded Adipose-Derived Stem Cell Therapy in Myocardial Infarction

Abstract

Clinical trials with autologous adipose‐derived stem cell (AdSC) therapy for ischemic heart diseases (IHDs) are ongoing. However, little is known about combinational therapeutic effect of AdSCs and statin poly(lactic‐co‐glycolic) acid (PLGA) nanoparticles on the ischemic myocardium. We investigated the hypothesis that statins, which have pleiotropic effects, augment the therapeutic potential of AdSCs and that AdSCs also act as drug delivery tools. Simvastatin‐conjugated nanoparticles (SimNPs) significantly promoted migration activity without changing proliferation activity and upregulated growth factor gene expression in vitro. A small number of intravenously administered SimNP‐loaded AdSCs (10,000 cells per mouse) improved cardiac function following myocardial infarction, inducing endogenous cardiac regeneration in the infarcted myocardium. The de novo regenerated myocardium was thought to be derived from epicardial cells, which were positive for Wilms' tumor protein 1 expression. These findings were attributed to the sustained, local simvastatin release from the recruited SimNP‐loaded AdSCs in the infarcted myocardium rather than to the direct contribution of recruited AdSCs to tissue regeneration. SimNP‐loaded AdSCs may lead to a novel somatic stem cell therapy for IHDs. Stem Cells Translational Medicine 2019;8:1055–1067

Polymers and Nanoparticles for Statin Delivery: Current Use and Future Perspectives in Cardiovascular Disease

“…Yokoyama et al [ 67 ], used a poly-lactic-co-glycolic acid (PLGA) nanoparticle to target simvastatin on the ischemic myocardium in mice. Simvastatin-loaded PLGA significantly enhanced cell migration and growth factor expression in vitro, and intravenous administration induced endogenous cardiac regeneration in their model of ischemic heart disease [ 67 ]. This regenerative ability was supposed to be related to adipose-derived stem cells, in which local simvastatin exerted a crucial effect.…”

“…This regenerative ability was supposed to be related to adipose-derived stem cells, in which local simvastatin exerted a crucial effect. The granulation tissue of chronic infarction was gradually and largely replaced with regenerated myocardium after 1 month, and this was paralleled with a reduction of fibrosis and scar [ 67 ]. Adipose-derived stem cells are extremely appealing for future research because of their plasticity [ 68 ], their easy harvesting with minimally invasive procedures [ 67 ], and their ability to differentiate into cardiomyocytes and secrete angiogenic factors [ 69 , 70 , 71 ].…”

“…The granulation tissue of chronic infarction was gradually and largely replaced with regenerated myocardium after 1 month, and this was paralleled with a reduction of fibrosis and scar [ 67 ]. Adipose-derived stem cells are extremely appealing for future research because of their plasticity [ 68 ], their easy harvesting with minimally invasive procedures [ 67 ], and their ability to differentiate into cardiomyocytes and secrete angiogenic factors [ 69 , 70 , 71 ]. Polymer-based methods require fewer stem cells for transplantation, thus minimizing the risks of thromboembolism, without increasing statin adverse side effects related to systemic concentrations [ 67 ].…”

Biomaterials Loaded with Growth Factors/Cytokines and Stem Cells for Cardiac Tissue Regeneration

“…Yet another advantageous effect of biomaterials on stem cell treatment is their ability to accommodate factors that could act synergistically with stem cells, thus, enhancing their therapeutic actions [ 119 , 120 ]. For instance, Yokoyama and colleagues tested the efficiency of statins and human ADSCs combinations incorporated into NPs [ 121 ]. The treatment was injected into the tail vein of mice with MI, and its therapeutic effects were assessed for four weeks after infarction.…”

“…The mechanism by which the treatment brought about these improvements is likely through stimulation of the sustained and localized release of the statins by ADSCs. This, in turn, resulted in the inhibition of local inflammation, promotion of circulating stem cell recruitment, and stimulation of their differentiation to cardiomyocytes and angiogenesis [ 121 ]. Importantly, in this study, treatment efficiency was achieved with a smaller cell number of ADSCs than has ever been reported.…”