Abstract
Background: The roots of Codonopsis pilosula (Franch.) Nannf. have been used in traditional Chinese medicine for treating cardiovascular disease. In the current study, we aimed to discover herbal extracts from C. pilosula that are capable of improving cardiac function of infarcted hearts to develop a potential therapeutic approach. Methods: A mouse embryonic stem (ES) cell-based model with an enhanced green fluorescent protein (eGFP) reporter driven by a cardiomyocyte-specific promoter, the α-myosin heavy chain, was constructed to evaluate the cardiogenic activity of herbal extracts. Then, herbal extracts from C. pilosula with cardiogenic activity based on an increase in eGFP expression during ES cell differentiation were further tested in a rat myocardial infarction model with left anterior descending artery (LAD) ligation. Cardiac function assessments were performed using echocardiography, 1, 3, and 6 weeks post LAD ligation. Results: The herbal extract 417W from C. pilosula was capable of enhancing cardiogenic differentiation in mouse ES cells in vitro. Echocardiography results in the LAD-ligated rat model revealed significant improvements in the infarcted hearts at least 6 weeks after 417W treatment that were determined based on left ventricle fractional shortening (FS), fractional area contraction (FAC), and ejection fraction (EF). Conclusions: The herbal extract 417W can enhance the cardiogenic differentiation of ES cells and improve the cardiac function of infarcted hearts.
Highlights
To use the spontaneous differentiation of EMG8 cells directly, without embryoid bodies (EBs) formation, as the cell-based model for evaluating cardiogenic activity of herbal extracts, in this study, we examined whether EMG8 cells could undergo cardiogenic differentiation without the EB formation stage
417W showed functional improvements in fractional shortening (FS), fractional area contraction (FAC), and ejection fraction (EF), whether these gesting it has potential for promoting cardiac differentiation of embryonic stem (ES) cells in vitro. Consistent with this result, the infarcted hearts of the left anterior descending artery (LAD)-ligated rat model treated with 417W showed functional improvements in FS, FAC, and EF, whether these improvements were due to the replenishment of cardiomyocytes derived from stem cells in the circulation, resident cardiac stem cells, or other mechanisms requires further investigation
Cardiac differentiation in the embryo originates from the anterolateral mesoderm that receives instructive guidance from the adjacent endoderm [28,29]. Both bone morphogenetic protein and fibroblast growth factor families of signaling molecules expressed in the endoderm of the cardiogenic region are involved in the determination of cardiac fate [30,31], while Nkx2.5, MEF-C, and the GATA family are responsible for initiating cardiomyocyte differentiation [32,33,34]
Summary
Heart failure (HF) is a frequent complication of myocardial infarction (MI) [1]. We aimed to discover herbal extracts from C. pilosula that are capable of improving cardiac function of infarcted hearts to develop a potential therapeutic approach. Methods: A mouse embryonic stem (ES) cell-based model with an enhanced green fluorescent protein (eGFP) reporter driven by a cardiomyocyte-specific promoter, the α-myosin heavy chain, was constructed to evaluate the cardiogenic activity of herbal extracts. Herbal extracts from C. pilosula with cardiogenic activity based on an increase in eGFP expression during ES cell differentiation were further tested in a rat myocardial infarction model with left anterior descending artery (LAD) ligation. Results: The herbal extract 417W from C. pilosula was capable of enhancing cardiogenic differentiation in mouse ES cells in vitro
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