Abstract
BackgroundRecent evidence has demonstrated that cardiac progenitor cells play an essential role in the induction of angiomyogenesis in infarcted myocardium. We and others have shown that engraftment of c-kit+ cardiac stem cells (CSCs) into infarcted hearts led to myocardium regeneration and neovascularization, which was associated with an improvement of ventricular function. The purpose of this study is aimed at investigating the functional role of transcription factor (TF) Oct3/4 in facilitating CSCs to promote myocardium regeneration and preserve cardiac performance in the post-MI heart.Methodsc-kit+ CSCs were isolated from adult hearts and re-introduced into the infarcted myocardium in which the mouse MI model was created by permanent ligation of the left anterior descending artery (LAD). The Oct3/4 of CSCs was inhibited by transfection of Oct3/4 siRNA, and transfection of CSCs with control siRNA serves as control groups. Myocardial functions were evaluated by echocardiographic measurement. Histological analysis was employed to assess newly formed cardiogenesis, neovascularization, and cell proliferations. Terminal deoxynucleotidyltransferase (TdT) nick-end labeling (TUNEL) was carried out to assess apoptotic cardiomyocytes. Real time polymerase chain reaction and Western blot were carried out to evaluate the level of Oct 3/4 in CSCs.ResultsTwo weeks after engraftment, CSCs increased ventricular functional recovery as shown by a serial echocardiographic measurement, which is concomitant with the suppression of cardiac hypertrophy and attenuation of myocardial interstitial fibrosis. Suppression of Oct 3/4 of CSCs abrogated functional improvements and mitigated the hypertrophic response and cardiac remodeling. Transplantation of c-kit+ CSCs into MI hearts promoted cardiac regeneration and neovascularization, which were abolished with the knockdown of Oct3/4. Additionally, suppression of Oct3/4 abrogated myocyte proliferation in the CSC-engrafted myocardium.ConclusionOur results indicate that CSCs-derived cardiac regeneration improves the restoration of cardiac function and is mediated through Oct 3/4.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0252-5) contains supplementary material, which is available to authorized users.
Highlights
Recent evidence has demonstrated that cardiac progenitor cells play an essential role in the induction of angiomyogenesis in infarcted myocardium
An increase in left ventricular internal dimension (LVID) and a significant decrease in contractility were observed in myocardial infarction (MI)-phosphate-buffered saline (PBS) groups as compared with sham-operated mice, indicating a MIinduced LV dysfunction and myocardial remodeling. Both Left ventricular internal dimension in diastole (LVID;d) and Left ventricular internal dimension in systole (LVID;s) were depressed in mice receiving control small interfering RNA (siRNA)-treated cardiac stem cell (CSC) as compared with mice receiving PBS injection post MI (Fig. 2a, b, e), suggesting that CSC engraftment prevented left ventricular dilation in the MI heart, but the LV diameters were not reduced in mice receiving Oct3/ 4 siRNA-treated CSC injections
Successful engraftment of CSCs prevented systolic dysfunction in MI mice as evidenced by the decreases in ejection fraction and fraction shortening 2 weeks after surgery as compared with the PBStreated MI group, but in mice that received Oct3/4 siRNAtreated CSCs there was no significant difference observed in LV ejection fraction (LVEF) and LV fractional shortening (LVFS) as compared with MI-PBS mice (Fig. 2c, d), indicating that Oct3/4-deficient CSCs failed to preserve LV contractility post MI
Summary
Recent evidence has demonstrated that cardiac progenitor cells play an essential role in the induction of angiomyogenesis in infarcted myocardium. We and others have shown that engraftment of c-kit+ cardiac stem cells (CSCs) into infarcted hearts led to myocardium regeneration and neovascularization, which was associated with an improvement of ventricular function. Several studies have shown that these cardiac progenitor cells are capable of differentiating into cardiac tissue and improving cardiac function after myocardial injury. Cardiac progenitor cells have been found to have the capacity of differentiating into cardiac tissue and improving cardiac function after a myocardial injury. These new findings led to a novel understanding of both normal and pathologic cardiac developments and homeostasis, and foster a transition towards therapeutic goals for cardiac regenerative medicine. Studies have reported that genetically modified stem cells could repair the infarcted myocardium, prevent remodeling, and nearly normalize cardiac performance [11, 12]
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