Induced Pluripotent Stem Cell (iPSC)-Derived Exosomes for Precision Medicine in Heart Failure.

Abstract

In the United States, heart failure (HF) is the leading cause of hospital admission and a major public health problem.1 Ischemic cardiomyopathy is the primary pathogenesis of advanced HF.1 More than 5 million people experience HF, with an annual incidence of 300 000 patients.1 Despite significant therapeutic advances during the past 3 decades, the 5-year survival remains at a dismal 50%.2 Clinical studies have confirmed that the high morbidity and mortality of HF are because of left ventricular arrhythmias and dilatation.1,2 Patients with a history of acute myocardial infarction and left ventricular dysfunction have a 6-month mortality of >10% of which one third is attributed to sudden cardiac death.3 Although implantable cardioverter defibrillators reduced mortality from left ventricular arrhythmia, patients with acute myocardial infarction do not qualify under the current guideline. An important trigger for ventricular arrhythmias and dilatation is the tissue heterogeneity in the peri-infarct region (PIR), which is independent of the actual infarct size.4–7 An effective targeted therapy to salvage the injured and vulnerable myocardium in the PIR is urgently needed to reduce the high mortality of patients with HF.7,8 Promising discoveries of induced pluripotent stem cell (iPSC) biology may restore the PIR.9,10 The initial theory for the regeneration of the myocardium hypothesized that the transplanted stem cells would differentiate into cardiomyocytes, engraft into the host myocardium, and augment the cardiac function through synchronized electromechanical integration. However, de novo cardiac differentiation of transplanted stem cells was rare and mostly led to teratoma.9,10 Similarly, ex vivo differentiated cardiac stem cells demonstrate transient in vivo engraftment and functional restoration.9,10 Other controversial studies examined the cardiac progenitor cells, a multipotent population of cardiac, vascular, and endothelial cells in the …