Cardiac Repair With Echocardiography-Guided Multiple Percutaneous Left Ventricular Intramyocardial Injection of hiPSC-CMs After Myocardial Infarction

Abstract

Objective: We investigated the potency of cardiac repair based on echocardiography-guided multiple percutaneous left ventricular intramyocardial injection of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) after myocardial infarction (MI).Methods: Mice with surgically induced MI were randomly divided into three groups (n = 8 in each group) and subjected to echocardiography-guided percutaneous left ventricular infarcted border injection of hiPSC-CMs (single dose; 10 μl 3 × 105 cells) or repeated injections of hiPSC-CMs at post-MI weeks 1 and 2 (multiple doses). The sham group of animals underwent all surgical procedures necessary for MI induction except for ligation. Then 4 weeks after MI, heart function was measured with transthoracic echocardiography. Engraftment was evaluated through the detection of human-specific cardiac troponin T. Infarct size and collagen volume were calculated with Sirius Red/Fast Green staining. Angiogenesis was evaluated with isolectin B4 staining. Cardiac remodeling was evaluated from the cardiomyocyte minimal fiber diameter in the infarcted border zone. Apoptosis was detected via TdT-mediated dUTP Nick-End Labeling (TUNEL) staining in cardiomyocytes from the infarcted border zone.Results: No mice died after echocardiography-guided percutaneous left ventricular intramyocardial injection. hiPSC-CMs were about nine-fold higher in the multiple-dose group at week 4 compared to the single-dose group. Multiple-dose transplantation was associated with significant improvement in left ventricular function, infarct size, angiogenesis, cardiac remodeling, and cardiomyocyte apoptosis.Conclusion: Echocardiography-guided multiple percutaneous left ventricular intramyocardial injection is a feasible, satisfactory, repeatable, relatively less invasive, and effective method of delivering cell therapy. The delivery of hiPSC-CMs indicates a novel therapy for MI.

Magnesium lithospermate B enhances the potential of human-induced pluripotent stem cell-derived cardiomyocytes for myocardial repair

“…Cardiomyocyte transplantation can improve cardiac function after MI via paracrine-induced suppression of cardiomyocyte apoptosis, promotion of angiogenesis, and functional integration. [2,3,5,7,16] Extremely high mortality of cells after transplantation is a major factor limiting ischemic heart disease-related cell therapy. [6] The survival rate of transplanted cells was reported to be lower in both ischemia-reperfusion and MI models in large part owing to the local microenvironment.…”

“…Transplanted hiPSC-CMs were quantified, as previously described. [5] Briefly, following the serial sectioning of the whole heart, one section out of every 50 was chosen to be stained with fluorescence. Randomly selected high-magnification images at a scale of five were taken from each section.…”

“…[2][3][4] However, restricted engraftment ability and the inflammatory microenvironment are major barriers to conventional cardiac cell therapies, including transplantation. [5][6][7] The infiltration of inflammatory cells results in the secretion of proteolytic enzymes and reactive oxygen species (ROS), which increases the damage at the infarct site. [8] Accordingly, ischemic heart disease therapy that focuses on suppressing the body's hyperactive inflam-matory response is regarded as a feasible scheme.…”