Recently,some of the genetic mechanisms of heart specification have been elucidated in Drosophila .However,genes involved in early cardiogenesis of human remain to be identified.Since the pathways that regulate ear...Recently,some of the genetic mechanisms of heart specification have been elucidated in Drosophila .However,genes involved in early cardiogenesis of human remain to be identified.Since the pathways that regulate early cardiac fate determination are conserved between Drosophila and vertebrates,flies can be used as a model test system to explore the genetic basis of cardiogenesis in human.In this project,about 3000 reccieve lethal gene lines were produced by P or EMS mutagenesis.With staining of antibodies against heart precussor cells of Drosophila ,about 200 lines were observed to show heart phenotype.In pilot studies of their function with RNAi technique,the RNAi phenotypes of several genes tested were observed,which were very similar to that of their mutants,showing heart tube defects or no heart precursors formation.Taking advantage of the advanced genetic information available in the Drosophila and human systems,we have identified about 50 human transcripts homologous to the Drosophila heart related gene candidates.Northern blot analysis for some of the human candidates showed that several genes were expressed in both adult and early embryonic tissues,which may help in the evaluation of candidate genes for human cardiogenesis.Our further experiments with transgenic flies generated with wild type and mutant forms of these candidate genes to examine for defects in cardiogenesis or cardiac function are under way.The candidate genes producing cardiac specific defects suggestive of similarities to the heart disease syndromes can then be pursued further as likely disease gene candidates.Such an approach is likely to provide a dramatic reduction of possible candidate genes,or to screen and identify mutations that may generate the disease in human.展开更多
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 ...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.展开更多
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 unders...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.展开更多
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...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.展开更多
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...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.展开更多
We propose that locations of genes on chromosomes can contribute to the prediction of gene regulatory relationships. We constructed a time-based gene regulatory network of zebrafish cardiogenesis on the basis of a spa...We propose that locations of genes on chromosomes can contribute to the prediction of gene regulatory relationships. We constructed a time-based gene regulatory network of zebrafish cardiogenesis on the basis of a spatio-temporal neighborhood method. Through the network, specific regulatory pathways and order of gene expression during zebrafish cardiogenesis were obtained. By comparing the order with locations of these genes on chromosomes, we discovered that there exists a reversal phenomenon between the order and order of gene locations. The discovery provides an inherent rule to instruct exploration of gene regulatory relationships. Specifically, the discovery can help to predict if regulatory relationships between genes exist and contribute to evaluating the correctness of discovered gene regulatory relationships.展开更多
文摘Recently,some of the genetic mechanisms of heart specification have been elucidated in Drosophila .However,genes involved in early cardiogenesis of human remain to be identified.Since the pathways that regulate early cardiac fate determination are conserved between Drosophila and vertebrates,flies can be used as a model test system to explore the genetic basis of cardiogenesis in human.In this project,about 3000 reccieve lethal gene lines were produced by P or EMS mutagenesis.With staining of antibodies against heart precussor cells of Drosophila ,about 200 lines were observed to show heart phenotype.In pilot studies of their function with RNAi technique,the RNAi phenotypes of several genes tested were observed,which were very similar to that of their mutants,showing heart tube defects or no heart precursors formation.Taking advantage of the advanced genetic information available in the Drosophila and human systems,we have identified about 50 human transcripts homologous to the Drosophila heart related gene candidates.Northern blot analysis for some of the human candidates showed that several genes were expressed in both adult and early embryonic tissues,which may help in the evaluation of candidate genes for human cardiogenesis.Our further experiments with transgenic flies generated with wild type and mutant forms of these candidate genes to examine for defects in cardiogenesis or cardiac function are under way.The candidate genes producing cardiac specific defects suggestive of similarities to the heart disease syndromes can then be pursued further as likely disease gene candidates.Such an approach is likely to provide a dramatic reduction of possible candidate genes,or to screen and identify mutations that may generate the disease in human.
基金Supported by the National Research Foundation(NRF)funded by the Korean Government,(MEST Basic Science Research Program grant,No.NRF-2012R1A1B5000462 to D.-W.J+1 种基金the Korean Health Technology R&D Project,Ministry of Health and Welfare,South Korea,No.HI12C0275the Bioimaging Center,Gwangju Institute of Science and Technology
文摘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.
文摘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.
文摘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.
基金supposed by grants from National Natural Science Foundation of China(No.81100818,No.31100828 and No.81070342)the Fundamental Research Funds for the Central Universities(HUST:No.2012TS036)
文摘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.
基金Project supported by the National Natural Science Foundation of China(Nos.60574079,30872957,and 30572129)
文摘We propose that locations of genes on chromosomes can contribute to the prediction of gene regulatory relationships. We constructed a time-based gene regulatory network of zebrafish cardiogenesis on the basis of a spatio-temporal neighborhood method. Through the network, specific regulatory pathways and order of gene expression during zebrafish cardiogenesis were obtained. By comparing the order with locations of these genes on chromosomes, we discovered that there exists a reversal phenomenon between the order and order of gene locations. The discovery provides an inherent rule to instruct exploration of gene regulatory relationships. Specifically, the discovery can help to predict if regulatory relationships between genes exist and contribute to evaluating the correctness of discovered gene regulatory relationships.
