The heart is one of the first functional embryonic organs occurring during development. The fundamental developmental processes and genes involved in cardiogenesis are conserved between the invertebrates and vertebrat...The heart is one of the first functional embryonic organs occurring during development. The fundamental developmental processes and genes involved in cardiogenesis are conserved between the invertebrates and vertebrates. In the past fifteen years, one of signaling pathways that has been best characterized in heart development in both invertebrates and vertebrates is the Wg/Wnt signaling pathways. Since our discovery of the Wg signaling required for the early heart development in Drosophila, the past fifteen years have witnessed tremendous progress in the understanding of specific Wnt signaling pathways in vertebrate cardiogenesis. This review will summarize the current state of knowledge of Wg signaling transduction in Drosophila heart development, which will benefit our understanding of vertebrate cardiogenesis and human congenital malformations.展开更多
Gaining cellular and molecular insights into heart development and regeneration will likely provide new therapeutic targets and opportunities for cardiac regenerative medicine,one of the most urgent clinical needs for...Gaining cellular and molecular insights into heart development and regeneration will likely provide new therapeutic targets and opportunities for cardiac regenerative medicine,one of the most urgent clinical needs for heart failure.Here we present a review on zebrafish heart development and regeneration,with a particular focus on early cardiac progenitor development and their contribution to building embryonic heart,as well as cellular and molecular programs in adult zebrafish heart regeneration.We attempt to emphasize that the signaling pathways shaping cardiac progenitors in heart development may also be redeployed during the progress of adult heart regeneration.A brief perspective highlights several important and promising research areas in this exciting field.展开更多
The role of human ether a-go-go related gene(hERG) in electrically excitable cells has long been known.hERG currents IKr contribute to the re-polarisation phase 3 of the cardiac action potential. Mutations of this cha...The role of human ether a-go-go related gene(hERG) in electrically excitable cells has long been known.hERG currents IKr contribute to the re-polarisation phase 3 of the cardiac action potential. Mutations of this channel causes long QT syndrome. N629D hERG mutation(GFGN to GFGD) alters the pore selectivity signature sequence.N629D was over-expressed, via adenoviral gene transfer,in car-diomyocytes derived from mouse embryonic stem cells,the "IKr" showed outward rectification and an inward tail current,while WT IKr showed inward rectification and a positive tail current.N629D "IKr" phenotype also altered resting membrane potential and caused arrhythmia.Since hERG was reported to express in early stage of cardiogenesis,the role of the ERG potassium channel in cardiac development was elaborated in an in vivo model of a homozygous. The hERG N629D mutation was introduced into the orthologous mouse gene,mERG,by homologous recombination in mouse embryonic stem cells. N629D/N629D homozygous mutation results in embryonic lethality(died by E11.5).The mutation displayed defect cardiac morphogenesis including altered looping architecture,poorly developed bulbus cordis,and distorted aortic sac and branchial arches. N629D/N629D myocytes from embryonic day 9.5 embryos manifested complete loss of IKr function, depolarized resting potential,prolonged action potential duration(LQT),failure to repolarize,and propensity to oscillatory arrhythmias.Because deletion of transcription factor Hand2 produces apoptosis in similar regions and with a similar final developmental phenotype,Hand2 expression was evaluated. Robust decrease in Hand2 expression was observed in the secondary heart field in N629D/N629D embryos. mERG protein expression in the developing embryonic heart is not homogeneous.The protein expression is exaggerated in the right ventricle and in the outflow tract.N629D/N629D embryos manifest extensive apoptosis particularly in the first branchial arch and the facial region.Given that cells from the branchial arch populate the outflow tract,the early apoptosis,in the branchial arch and facial region would prevent those cells from contributing to the development of the outflow tract in N629D/N629D hearts.The working model is that the Hand2 expres- sion is down regulated in N629D/N629D embryonic right ventricle and outflow tract because progenitor cells that populate the outflow tract undergo apoptosis while in the facial region and branchial arch. Thus tissues that would be expected to express Hand2 are absent,simply because those structures fail to develop.N629D/N629D embryos also displayed defects in both extraembryonic and intraem-bryonic vasculature.Yolk sac from N629D/N629D homozygous embryos revealed primary vascular networks formed,while they failed to remodel into more complex vascular structures,unlike wild-type yolk sacs at E9.5 N629D/N629D embryo yolk sacs at E9.5 display absence of visible vessels.Intraembry-onic vessels in the mutant showed less complex branching in comparison with the normal vessels structure in WT embryo,dorsal aorta exhibited abnormally formation and small lumens.Whole mount in situ hybridization displayed hERG was also expressed in E9.5 yolk sac and dorsal aorta.Immunofluorescence showed the co-localization of hERG and Cd31 and smooth muscle actin in E10.5. The role of hERG protein in the development of vasculature is further evaluated by using Cre-loxP-based mouse model for tissue specific hERG mutation expression.展开更多
Heart rate variaty (HRV) of 85cases with AMI was observed in the early phase after onset and rehabilitation phase at first month and sixth month, and was contrasted with six time threshold indices of 111 cases with co...Heart rate variaty (HRV) of 85cases with AMI was observed in the early phase after onset and rehabilitation phase at first month and sixth month, and was contrasted with six time threshold indices of 111 cases with coronary heart disease and that of 35 normal control. We found the HRV of AMI was apperantly lower in the acute phase than that of coronary heart disease and normal controls. HRV recovered gradually with inclining to be stable after half a year, but it was still lower than that of controls. Low HRV in early phase of AMI suggested the poor prognosis.展开更多
目的研究简单先天性心脏病(congenital heart disease,CHD)患儿的运动功能发育特征及其合并运动发育迟缓的情况。方法选择357例0~6岁的简单CHD患儿作为研究对象。采用Peabody运动发育量表(第2版)对所有患儿的运动功能发育水平进行评定,...目的研究简单先天性心脏病(congenital heart disease,CHD)患儿的运动功能发育特征及其合并运动发育迟缓的情况。方法选择357例0~6岁的简单CHD患儿作为研究对象。采用Peabody运动发育量表(第2版)对所有患儿的运动功能发育水平进行评定,分别计算精细运动发育商(fine motor quotient,FMQ)、粗大运动发育商(gross motor quotient,GMQ)和总运动发育商(total motor quotient,TMQ)。GMQ<90分为粗大运动发育迟缓,FMQ<90分为精细运动发育迟缓,TMQ<90分为总运动发育迟缓。结果CHD不同类型患儿FMQ、GMQ和TMQ的差异均有统计学意义(均P<0.05);女性CHD患儿GMQ低于男性CHD患儿,差异有统计学意义(P=0.003)。粗大运动发育迟缓率为37.5%,精细运动发育迟缓率为11.8%,总运动发育迟缓率为29.1%。结论0~6岁简单CHD患儿合并运动发育迟缓的发生率较高,不同性别、不同类型患儿的运动功能发育水平不同。展开更多
As an increasingly used alternative to perfluorooctanoic acid(PFOA),hexafluoropropylene oxide trimer acid(HFPO-TA)has been widely detected in global water environments.However,little is known regarding its toxic effec...As an increasingly used alternative to perfluorooctanoic acid(PFOA),hexafluoropropylene oxide trimer acid(HFPO-TA)has been widely detected in global water environments.However,little is known regarding its toxic effects on cardiovascular development.Here,zebrafish embryos were treated with egg water containing 0,60,120,or 240 mg/L HFPO-TA.Results showed that HFPO-TA treatment led to a significant reduction in both larval survival percentage and heart rate.Furthermore,HFPO-TA exposure caused severe pericardial edema and elongation of the sinus venous to bulbus arteriosus distance(SV-BA)in Tg(myl7:GFP)transgenic larvae,disrupting the expression of genes involved in heart development and thus causing abnormal heart looping.Obvious sprouting angiogenesis was observed in the 120 and 240 mg/L exposed Tg(fli:GFP)transgenic larvae.HFPO-TA treatment also impacted the mRNA levels of genes involved in the vascular endothelial growth factor(VEGF)pathway and embryonic vascular development.HFPO-TA exposure significantly decreased erythrocyte number in Tg(gata1:DsRed)transgenic embryos and influenced gene expression associated with the heme metabolism pathway.HFPO-TA also induced oxidative stress and altered the transcriptional levels of genes related to cell cycle and apoptosis,inhibiting cell proliferation while promoting apoptosis.Therefore,HFPO-TA exposure may induce abnormal development of the cardiovascular and hematopoietic systems in zebrafish embryos,suggesting it may not be a suitable or safe alternative for PFOA.展开更多
To form fully functional four-chambered structure,mammalian heart development undergoes a transient finger-shaped trabeculae,crucial for efficient contraction and exchange for gas and nutrient.Although its development...To form fully functional four-chambered structure,mammalian heart development undergoes a transient finger-shaped trabeculae,crucial for efficient contraction and exchange for gas and nutrient.Although its developmental origin and direct relevance to congenital heart disease has been studied extensively,the time-resolved cellular mechanism underlying hypotrabeculation remains elusive.Here,we employed in toto live imaging and reconstructed the holistic cell lineages and cellular behavior landscape of control and hypotrabeculed hearts of mouse embryos from E9.5 for up to 24 h.Compared to control,hypotrabeculation in ErbB2 mutants arose mainly through dual mechanisms:both reduced proliferation of trabecular cardiomyocytes from early cell fate segregation and markedly impaired oriented cell division and migration.Further examination of mosaic mutant hearts confirmed alterations in cellular behaviors in a cell autonomous manner.Thus,our work offers a framework for continuous live imaging and digital cell lineage analysis to better understand subtle pathological alterations in congenital heart disease.展开更多
Background Cellular senescence,an irreversible state of cell-cycle arrest triggered by multiple stress factors,plays a key role in organ development and wound healing.Accumulated senescent cells also promote tissue in...Background Cellular senescence,an irreversible state of cell-cycle arrest triggered by multiple stress factors,plays a key role in organ development and wound healing.Accumulated senescent cells also promote tissue inflammation and involve in various diseases including myocardial infarction,atherosclerosis,diabetes and nonalcoholic steatohepatitis.Understanding the mechanism and consequences of cellular senescence is crucial to develop new therapies for diseases.Here,we describe the characteristics of senescent cells and involvement of senescent cardiac cells in heart development,regeneration and diseases.We summarize the work in this area and provide directions and clues for future studies.展开更多
基金supported in part by the National Basic Research Program of China (No.2005CB522505)the National Natural Science Foundation of China (No.30930054)
文摘The heart is one of the first functional embryonic organs occurring during development. The fundamental developmental processes and genes involved in cardiogenesis are conserved between the invertebrates and vertebrates. In the past fifteen years, one of signaling pathways that has been best characterized in heart development in both invertebrates and vertebrates is the Wg/Wnt signaling pathways. Since our discovery of the Wg signaling required for the early heart development in Drosophila, the past fifteen years have witnessed tremendous progress in the understanding of specific Wnt signaling pathways in vertebrate cardiogenesis. This review will summarize the current state of knowledge of Wg signaling transduction in Drosophila heart development, which will benefit our understanding of vertebrate cardiogenesis and human congenital malformations.
基金supported by the grants from the National Basic Research Program of China(Nos.2010CB529503 and 2012CB944501)the National Science Foundation of China(Nos.30971662 and 31000644)
文摘Gaining cellular and molecular insights into heart development and regeneration will likely provide new therapeutic targets and opportunities for cardiac regenerative medicine,one of the most urgent clinical needs for heart failure.Here we present a review on zebrafish heart development and regeneration,with a particular focus on early cardiac progenitor development and their contribution to building embryonic heart,as well as cellular and molecular programs in adult zebrafish heart regeneration.We attempt to emphasize that the signaling pathways shaping cardiac progenitors in heart development may also be redeployed during the progress of adult heart regeneration.A brief perspective highlights several important and promising research areas in this exciting field.
文摘The role of human ether a-go-go related gene(hERG) in electrically excitable cells has long been known.hERG currents IKr contribute to the re-polarisation phase 3 of the cardiac action potential. Mutations of this channel causes long QT syndrome. N629D hERG mutation(GFGN to GFGD) alters the pore selectivity signature sequence.N629D was over-expressed, via adenoviral gene transfer,in car-diomyocytes derived from mouse embryonic stem cells,the "IKr" showed outward rectification and an inward tail current,while WT IKr showed inward rectification and a positive tail current.N629D "IKr" phenotype also altered resting membrane potential and caused arrhythmia.Since hERG was reported to express in early stage of cardiogenesis,the role of the ERG potassium channel in cardiac development was elaborated in an in vivo model of a homozygous. The hERG N629D mutation was introduced into the orthologous mouse gene,mERG,by homologous recombination in mouse embryonic stem cells. N629D/N629D homozygous mutation results in embryonic lethality(died by E11.5).The mutation displayed defect cardiac morphogenesis including altered looping architecture,poorly developed bulbus cordis,and distorted aortic sac and branchial arches. N629D/N629D myocytes from embryonic day 9.5 embryos manifested complete loss of IKr function, depolarized resting potential,prolonged action potential duration(LQT),failure to repolarize,and propensity to oscillatory arrhythmias.Because deletion of transcription factor Hand2 produces apoptosis in similar regions and with a similar final developmental phenotype,Hand2 expression was evaluated. Robust decrease in Hand2 expression was observed in the secondary heart field in N629D/N629D embryos. mERG protein expression in the developing embryonic heart is not homogeneous.The protein expression is exaggerated in the right ventricle and in the outflow tract.N629D/N629D embryos manifest extensive apoptosis particularly in the first branchial arch and the facial region.Given that cells from the branchial arch populate the outflow tract,the early apoptosis,in the branchial arch and facial region would prevent those cells from contributing to the development of the outflow tract in N629D/N629D hearts.The working model is that the Hand2 expres- sion is down regulated in N629D/N629D embryonic right ventricle and outflow tract because progenitor cells that populate the outflow tract undergo apoptosis while in the facial region and branchial arch. Thus tissues that would be expected to express Hand2 are absent,simply because those structures fail to develop.N629D/N629D embryos also displayed defects in both extraembryonic and intraem-bryonic vasculature.Yolk sac from N629D/N629D homozygous embryos revealed primary vascular networks formed,while they failed to remodel into more complex vascular structures,unlike wild-type yolk sacs at E9.5 N629D/N629D embryo yolk sacs at E9.5 display absence of visible vessels.Intraembry-onic vessels in the mutant showed less complex branching in comparison with the normal vessels structure in WT embryo,dorsal aorta exhibited abnormally formation and small lumens.Whole mount in situ hybridization displayed hERG was also expressed in E9.5 yolk sac and dorsal aorta.Immunofluorescence showed the co-localization of hERG and Cd31 and smooth muscle actin in E10.5. The role of hERG protein in the development of vasculature is further evaluated by using Cre-loxP-based mouse model for tissue specific hERG mutation expression.
文摘Heart rate variaty (HRV) of 85cases with AMI was observed in the early phase after onset and rehabilitation phase at first month and sixth month, and was contrasted with six time threshold indices of 111 cases with coronary heart disease and that of 35 normal control. We found the HRV of AMI was apperantly lower in the acute phase than that of coronary heart disease and normal controls. HRV recovered gradually with inclining to be stable after half a year, but it was still lower than that of controls. Low HRV in early phase of AMI suggested the poor prognosis.
文摘目的研究简单先天性心脏病(congenital heart disease,CHD)患儿的运动功能发育特征及其合并运动发育迟缓的情况。方法选择357例0~6岁的简单CHD患儿作为研究对象。采用Peabody运动发育量表(第2版)对所有患儿的运动功能发育水平进行评定,分别计算精细运动发育商(fine motor quotient,FMQ)、粗大运动发育商(gross motor quotient,GMQ)和总运动发育商(total motor quotient,TMQ)。GMQ<90分为粗大运动发育迟缓,FMQ<90分为精细运动发育迟缓,TMQ<90分为总运动发育迟缓。结果CHD不同类型患儿FMQ、GMQ和TMQ的差异均有统计学意义(均P<0.05);女性CHD患儿GMQ低于男性CHD患儿,差异有统计学意义(P=0.003)。粗大运动发育迟缓率为37.5%,精细运动发育迟缓率为11.8%,总运动发育迟缓率为29.1%。结论0~6岁简单CHD患儿合并运动发育迟缓的发生率较高,不同性别、不同类型患儿的运动功能发育水平不同。
基金supported by the Ministry of Science and Technology of China(Nos.2021YFA1101300 and 2020YFA0112500)the National Key R&D Program of China(2018YFA0801000)the National Natural Science Foundation of China(No.32170853)。
文摘As an increasingly used alternative to perfluorooctanoic acid(PFOA),hexafluoropropylene oxide trimer acid(HFPO-TA)has been widely detected in global water environments.However,little is known regarding its toxic effects on cardiovascular development.Here,zebrafish embryos were treated with egg water containing 0,60,120,or 240 mg/L HFPO-TA.Results showed that HFPO-TA treatment led to a significant reduction in both larval survival percentage and heart rate.Furthermore,HFPO-TA exposure caused severe pericardial edema and elongation of the sinus venous to bulbus arteriosus distance(SV-BA)in Tg(myl7:GFP)transgenic larvae,disrupting the expression of genes involved in heart development and thus causing abnormal heart looping.Obvious sprouting angiogenesis was observed in the 120 and 240 mg/L exposed Tg(fli:GFP)transgenic larvae.HFPO-TA treatment also impacted the mRNA levels of genes involved in the vascular endothelial growth factor(VEGF)pathway and embryonic vascular development.HFPO-TA exposure significantly decreased erythrocyte number in Tg(gata1:DsRed)transgenic embryos and influenced gene expression associated with the heme metabolism pathway.HFPO-TA also induced oxidative stress and altered the transcriptional levels of genes related to cell cycle and apoptosis,inhibiting cell proliferation while promoting apoptosis.Therefore,HFPO-TA exposure may induce abnormal development of the cardiovascular and hematopoietic systems in zebrafish embryos,suggesting it may not be a suitable or safe alternative for PFOA.
基金the National Basic Research Program of China(Grants No.2019YFA0801802 and 2017YFA0103402)the National Natural Science Foundation of China(Grants No.32025015 and 31771607)the Peking-Tsinghua Center for Life Sciences,and the 1000 Youth Talents Program of China.We thank the Confocal LSM 710 Core at National Center for Protein Sciences at Peking University for technical help.
文摘To form fully functional four-chambered structure,mammalian heart development undergoes a transient finger-shaped trabeculae,crucial for efficient contraction and exchange for gas and nutrient.Although its developmental origin and direct relevance to congenital heart disease has been studied extensively,the time-resolved cellular mechanism underlying hypotrabeculation remains elusive.Here,we employed in toto live imaging and reconstructed the holistic cell lineages and cellular behavior landscape of control and hypotrabeculed hearts of mouse embryos from E9.5 for up to 24 h.Compared to control,hypotrabeculation in ErbB2 mutants arose mainly through dual mechanisms:both reduced proliferation of trabecular cardiomyocytes from early cell fate segregation and markedly impaired oriented cell division and migration.Further examination of mosaic mutant hearts confirmed alterations in cellular behaviors in a cell autonomous manner.Thus,our work offers a framework for continuous live imaging and digital cell lineage analysis to better understand subtle pathological alterations in congenital heart disease.
基金sponsored by grants from the National key R&D Program of China(No.2018YFA0108700,No.2017YFA0105602,No.2018YFA0108100)National Natural Science Foundation of China(No.81720108004,No.81974019,No.31871474)+4 种基金the Research Team Project of Natural Science Foundation of Guangdong Province of China(No.2017A030312007)Science and Technology Planning Project of Guangdong Province(No.2022B1212010010)the Key Program of Guangzhou Science Research Plan(No.201904020047)The Special Project of Dengfeng Program of Guangdong Provincial People’s Hospital(No.DFJH201812,No.KJ012019119,No.KJ012019423)the Shanghai Tech University start-up fund。
文摘Background Cellular senescence,an irreversible state of cell-cycle arrest triggered by multiple stress factors,plays a key role in organ development and wound healing.Accumulated senescent cells also promote tissue inflammation and involve in various diseases including myocardial infarction,atherosclerosis,diabetes and nonalcoholic steatohepatitis.Understanding the mechanism and consequences of cellular senescence is crucial to develop new therapies for diseases.Here,we describe the characteristics of senescent cells and involvement of senescent cardiac cells in heart development,regeneration and diseases.We summarize the work in this area and provide directions and clues for future studies.
