Abstract
BackgroundIschemic heart diseases are still a threat to human health. Human pluripotent stem cell-based transplantation exhibits great promise in cardiovascular disease therapy, including heart ischemia. The purpose of this study was to compare the efficacy of human embryonic stem cell-derived cardiomyocyte (ESC-CM) therapy in two heart ischemia models, namely, permanent ischemia (PI) and myocardial ischemia reperfusion (IR).MethodsHuman embryonic stem cell-derived cardiomyocytes were differentiated from engineered human embryonic stem cells (ESC-Rep) carrying green fluorescent protein (GFP), herpes simplex virus-1 thymidine kinase (HSVtk), and firefly luciferase (Fluc). Two different heart ischemia models were generated by the ligation of the left anterior descending artery (LAD), and ESC-Rep-derived cardiomyocytes (ESC-Rep-CMs) were transplanted into the mouse hearts. Cardiac function was analyzed to evaluate the outcomes of ESC-Rep-CM transplantation. Bioluminescence signal analysis was performed to assess the cell engraftment. Finally, the inflammation response was analyzed by real-time PCR and ELISA.ResultsCardiac function was significantly improved in the PI group with ESC-Rep-CM injection compared to the PBS-injected control, as indicated by increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), as well as reduced fibrotic area. However, minimal improvement by ESC-Rep-CM injection was detected in the IR mouse model. We observed similar engraftment efficiency between PI and IR groups after ESC-Rep-CM injection. However, the restricted inflammation was observed after the injection of ESC-Rep-CMs in the PI group, but not in the IR group. Transplantation of ESC-Rep-CMs can partially preserve the heart function via regulating the inflammation response in the PI model, while little improvement of cardiac function in the IR model may be due to the less dynamic inflammation response by the mild heart damage.ConclusionsOur findings identified the anti-inflammatory effect of ESC-CMs as a possible therapeutic mechanism to improve cardiac function in the ischemic heart.
Highlights
Ischemic heart diseases are still a threat to human health
To provide evidence for optimizing cell transplantation strategy, this study investigated the efficacy of embryonic stem cells (ESC)-CM therapy in the two different heart ischemia models
Generation and identification of ESC-derived cardiomyocytes Three reporter genes, namely, green fluorescent protein (GFP), Herpes Simplex Virus-1 Thymidine Kinase (HSVtk), and firefly luciferase (Fluc), were successfully engineered into human embryonic stem cells (ESC), and the engineered cells were named as ESC-Rep (Additional file 1: Figure S1)
Summary
Ischemic heart diseases are still a threat to human health. Human pluripotent stem cell-based transplantation exhibits great promise in cardiovascular disease therapy, including heart ischemia. The purpose of this study was to compare the efficacy of human embryonic stem cell-derived cardiomyocyte (ESC-CM) therapy in two heart ischemia models, namely, permanent ischemia (PI) and myocardial ischemia reperfusion (IR). Due to the limited regenerative capacity of the heart [2], most patients who suffered from permanent ischemia (PI) will develop into heart failure. Reperfusion strategies, such as thrombolytic therapy or primary percutaneous coronary intervention, are still the standard and most effective therapeutic treatment for acute myocardial infarction [3]. In contrast to IR, permanent ischemia significantly changes heart structure and function [6] It remains uncertain whether transplantation outcomes are correlated with the ischemic microenvironment in the heart. Preclinical studies in animal models of heart ischemia are necessary to fully evaluate the cell therapeutic efficacy
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