Making cardiomyocytes with your chemistry set:Small molecule-induced cardiogenesis in somatic cells

Cell transplantation is an attractive potential therapy for heart diseases. For example, myocardial infarction(MI) is a leading cause of mortality in many countries. Numerous medical interventions have been developed to stabilize patients with MI and, although this has increased survival rates, there is currently no clinically approved method to reverse the loss of cardiac muscle cells(cardiomyocytes) that accompanies this disease. Cell transplantation has been proposed as a method to replace cardiomyocytes, but a safe and reliable source of cardiogenic cells is required. An ideal source would be the patients' own somatic tissue cells, which could be converted into cardiogenic cells and transplanted into the site of MI. However, these are difficult to produce in large quantities and standardized protocols to produce cardiac cells would be advantageous for the research community. To achieve these research goals, small molecules represent attractive tools to control cell behavior. In this editorial, we introduce the use of small molecules in stem cell research and summarize their application to the induction of cardiogenesis in noncardiac cells. Exciting new developments in this field are discussed, which we hope will encourage cardiac stem cell biologists to further consider employing small molecules in their culture protocols.

ATP-dependent chromatin remodeling complex SWI/SNF in cardiogenesis and cardiac progenitor cell development

The recent identification of cardiac progenitor cells （CPCs） provides a new paradigm for studying and treating heart disease. To realize the full potential of CPCs for therapeutic purposes, it is essential to understand the genetic and epigenetic mechanisms guiding CPC differentiation into cardiomyocytes, smooth muscle, or endothelial cells. ATP-dependent chromatin remodelers mediate one critical epigenetic mechanism. These large multiprotein complexes open up chromatin to modulate transcription factor access to DNA. SWI/SNF, one of the major types of chromatin remodelers, plays a key role in various aspects of development （de la Serna et al., 2006; Wu et al., 2009）, including heart development and disease （Lickert et al., 2004; Wang et al., 2004; Huang et al., 2008; Stankunas et al., 2008; Hang et al., 2010）. In this review, we describe the specific function of various SWI/SNF components in cardiogenesis and cardiac progenitor cell （CPC） self-renewal and differentiation. We envision that a detailed understanding of the SWI/SNF in heart development and CPC formation and differentiation will generate novel insights into epigenetic mechanisms that govern CPC differentiation and may have significant implications in understanding and treating heart disease.

Cynodon dactylon andSida acuta extracts impact on the function of the cardiovascular system in zebrafish embryos

The aim of the present study was to screen cardioactive herbs from Western Ghats of India. The heart beat rate （HBR） and blood flow during systole and diastole were tested in zebrafish embryos. We found that Cynodon dactylon （C. dactylon） induced increases in the HBR in zebrafish embryos with a HBR of （3.968±0.344） beats/ s, which was significantly higher than that caused by betamethosone [（3.770±0.344） beats/s]. The EC50 value of C. dactylon was 3.738 μg/mL. The methanolic extract of Sida acuta （S. acuta） led to decreases in the HBR in zebrafish embryos [（1.877 ±0.079） beats/s], which was greater than that caused by nebivolol （positive control）. The EC50 value of Sida acuta was 1.195 μg/mL. The untreated embryos had a HBR of （2.685±0.160） beats/s at 3 d post fertilization （dpf）. The velocities of blood flow during the cardiac cycle were （2,291.667 ±72.169） μm/s for the control, （4,250± 125.000） μm/s for C. dactylon and （1,083.333±72.169） μm/s for S. acuta. The LC50 values were 32.6 μg/mL for C. dactylon and 20.9 μg/mL for S. acuta. In addition, the extracts exhibited no chemical genetic effects in the drug dosage range tested. In conclusion, we developed an assay that can measure changes in cardiac function in response to herbal small molecules and determine the cardiogenic effects by microvideography.

Thymosinβ4 Impeded Murine Stem Cell Proliferation with an Intact Cardiovascular Differentiation

Thymosin β4（Tβ4） is a key factor in cardiac development, growth, disease, epicardial integrity, blood vessel formation and has cardio-protective properties. However, its role in murine embryonic stem cells（m ESCs） proliferation and cardiovascular differentiation remains unclear. Thus we aimed to elucidate the influence of Tβ4 on m ESCs. Target genes during m ESCs proliferation and differentiation were detected by real-time PCR or Western blotting, and patch clamp was applied to characterize the m ESCs-derived cardiomyocytes. It was found that Tβ4 decreased m ESCs proliferation in a partial dose-dependent manner and the expression of cell cycle regulatory genes c-myc, c-fos and c-jun. However, m ESCs self-renewal markers Oct4 and Nanog were elevated, indicating the maintenance of self-renewal ability in these m ESCs. Phosphorylation of STAT3 and Akt was inhibited by Tβ4 while the expression of RAS and phosphorylation of ERK were enhanced. No significant difference was found in BMP2/BMP4 or their downstream protein smad. Wnt3 and Wnt11 were remarkably decreased by Tβ4 with upregulation of Tcf3 and constant ？-catenin. Under m ESCs differentiation, Tβ4 treatment did not change the expression of cardiovascular cell markers α-MHC, PECAM, and α-SMA. Neither the electrophysiological properties of m ESCs-derived cardiomyocytes nor the hormonal regulation by Iso/Cch was affected by Tβ4. In conclusion, Tβ4 suppressed m ESCs proliferation by affecting the activity of STAT3, Akt, ERK and Wnt pathways. However, Tβ4 did not influence the in vitro cardiovascular differentiation.