Cardiac-resident macrophages(CRMs)play important roles in homeostasis,cardiac function,and remodeling.Although CRMs play critical roles in cardiac regeneration of neonatal mice,their roles are yet to be fully elucidat...Cardiac-resident macrophages(CRMs)play important roles in homeostasis,cardiac function,and remodeling.Although CRMs play critical roles in cardiac regeneration of neonatal mice,their roles are yet to be fully elucidated.Therefore,this study aimed to investigate the dynamic changes of CRMs during cardiac ontogeny and analyze the phenotypic and functional properties of CRMs in the promotion of cardiac regeneration.During mouse cardiac ontogeny,four CRM subsets exist successively:CX3CR1+CCR2-Ly6C-MHCII-(MP1),CX3CR1lowCCR2lowLy6C-MHCII-(MP2),CX3CR1-CCR2+Ly6C+MHCII-(MP3),and CX3CR1+CCR2-Ly6C-MHCII+(MP4).MP1 cluster has different derivations(yolk sac,fetal liver,and bone marrow)and multiple functions population.Embryonic and neonatal-derived-MP1 directly promoted cardiomyocyte proliferation through Jagged-1-Notch1 axis and significantly ameliorated cardiac injury following myocardial infarction.MP2/3 subsets could survive throughout adulthood.MP4,the main population in adult mouse hearts,contributed to inflammation.During ontogeny,MP1 can convert into MP4 triggered by changes in the cellular redox state.These findings delineate the evolutionary dynamics of CRMs under physiological conditions and found direct evidence that embryonic and neonatal-derived CRMs regulate cardiomyocyte proliferation.Our findings also shed light on cardiac repair following injury.展开更多
The heart has been considered a post-mitotic organ without regenerative capacity for most of the last century.We review the evidence that led to this hypothesis in the early 1900s and how it was progressively modified...The heart has been considered a post-mitotic organ without regenerative capacity for most of the last century.We review the evidence that led to this hypothesis in the early 1900s and how it was progressively modified,culminating with the report that we renew 50% of our cardiomyocytes during our lifetime.The future of cardiac regenerative therapies is discussed,presenting the difficulties to overcome before repair of the diseased heart can come into clinical practice.展开更多
In the mammalian heart,cardiomyocytes are forced to withdraw from the cell cycle shortly after birth,limiting the ability of the heart to regenerate and repair.The development of multimodal regulation of cardiac proli...In the mammalian heart,cardiomyocytes are forced to withdraw from the cell cycle shortly after birth,limiting the ability of the heart to regenerate and repair.The development of multimodal regulation of cardiac proliferation has verified that pre-existing cardiomyocyte proliferation is an essential driver of cardiac renewal.With the continuous development of genetic lineage tracking technology,it has been revealed that cell cycle activity produces polyploid cardiomyocytes during the embryonic,juvenile,and adult stages of cardiogenesis,but newly formed mononucleated diploid cardiomyocytes also elevated sporadically during myocardial infarction.It implied that adult cardiomyocytes have a weak regenerative capacity under the condition of ischemia injury,which offers hope for the clinical treatment of myocardial infarction.However,the regeneration frequency and source of cardiomyocytes are still low,and the mechanism of regulating cardiomyocyte proliferation remains further explained.It is noteworthy to explore what force triggers endogenous cardiomyocyte proliferation and heart regeneration.Here,we focused on summarizing the recent research progress of emerging endogenous key modulators and crosstalk with other signaling pathways and furnished valuable insights into the internal mechanism of heart regeneration.In addition,myocardial transcription factors,non-coding RNAs,cyclins,and cell cycle-dependent kinases are involved in the multimodal regulation of pre-existing cardiomyocyte proliferation.Ultimately,awakening the myocardial proliferation endogenous modulator and regeneration pathways may be the final battlefield for the regenerative therapy of cardiovascular diseases.展开更多
Hyaluronan and proteoglycan link protein 1(Hapln1)supports active cardiomyogenesis in zebrafish hearts,but its regulation in mammal cardiomyocytes is unclear.This study aimed to explore the potential regulation of Hap...Hyaluronan and proteoglycan link protein 1(Hapln1)supports active cardiomyogenesis in zebrafish hearts,but its regulation in mammal cardiomyocytes is unclear.This study aimed to explore the potential regulation of Hapln1 in the dedifferentiation and proliferation of cardiomyocytes and its therapeutic value in myocardial infarction with human induced pluripotent stem cell(hiPSC)-derived cardiomyocytes(CMs)and an adult mouse model of myocardial infarction.HiPSC-CMs and adult mice with myocardial infarction were used as in vitro and in vivo models,respectively.Previous single-cell RNA sequencing data were retrieved for bioinformatic exploration.The results showed that recombinant human Hapln1(rhHapln1)promotes the proliferation of hiPSC-CMs in a dose-dependent manner.As a physical binding protein of Hapln1,versican interacted with Nodal growth differentiation factor(NODAL)and growth differentiation factor 11(GDF11).GDF11,but not NODAL,was expressed by hiPSC-CMs.GDF11 expression was unaffected by rhHapln1 treatment.However,this molecule was required for rhHapln1-mediated activation of the transforming growth factor(TGF)-β/Drosophila mothers against decapentaplegic protein(SMAD)2/3 signaling in hiPSC-CMs,which stimulates cell dedifferentiation and proliferation.Recombinant mouse Hapln1(rmHapln1)could induce cardiac regeneration in the adult mouse model of myocardial infarction.In addition,rmHapln1 induced hiPSC-CM proliferation.In conclusion,Hapln1 can stimulate the dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping and subsequent activation of the TGF-β/SMAD2/3 signaling pathway.Hapln1 might be an effective hiPSC-CM dedifferentiation and proliferation agent and a potential reagent for repairing damaged hearts.展开更多
Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes(CMs).However,the signaling mechanisms by which injury induces CM renewal remain incompletely understood.Here,we find that...Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes(CMs).However,the signaling mechanisms by which injury induces CM renewal remain incompletely understood.Here,we find that cardiac injury in zebrafish induces expression of the secreted Wnt inhibitors,including Dickkopf 1(Dkkl),Dkk3,secreted Frizzled-related protein 1(sFrpl),and sFrp2,in cardiac tissue adjacent to injury sites.Experimental blocking of Wnt activity via Dkkl overexpression enhances CM proliferation and heart regeneration,whereas ectopic activation of Wnt8 signaling blunts injury-induced CM dedifferentiation and proliferation.Although Wnt signaling is dampened upon injury,the cytoplasmic β-catenin is unexpectedly increased at disarrayed CM sarcomeres in myocardial wound edges.Our analyses indicated that p21-activated kinase 2(Pak2)is induced at regenerating CMs,where it phosphorylates cytoplasmic β-catenin at Ser 675 and increases its stability at disassembled sarcomeres.Myocardial-specific induction of the phospho-mimeticβ-catenin(S675E)enhances CM dedifferentiation and sarcomere disassembly in response to injury.Conversely,inactivation of Pak2 kinase activity reduces the Ser 675-phosphorylatedβ-catenin(pS675-β-catenin)and attenuates CM sarcomere disorganization and dedifferentiation・Taken together,these findings demonstrate that coordination of Wnt signaling inhibition and Pak2/pS675-βYatenin signaling enhances zebrafish heart regeneration by supporting CM dedifferentiation and proliferation.展开更多
Ischemic heart disease is one of the main causes of morbidity and mortality in the world. In adult mammalianhearts, most cardiomyocytes are terminally differentiated and have extremely limited capacity of proliferatio...Ischemic heart disease is one of the main causes of morbidity and mortality in the world. In adult mammalianhearts, most cardiomyocytes are terminally differentiated and have extremely limited capacity of proliferation,making it impossible to regenerate the heart after injuries such as myocardial infarction. MicroRNAs (miRNAs), aclass of non-coding single-stranded RNA, which are involved in mRNA silencing and the regulation of posttranscriptionalgene expression, have been shown to play a crucial role in cardiac development and cardiomyocyteproliferation. Muscle specific miRNAs such as miR-1 are key regulators of cardiomyocyte maturation and growth,while miR-199-3p and other miRNAs display potent activity to induce proliferation of cardiomyocytes. Given theirsmall size and relative pleiotropic effects, miRNAs have gained significant attraction as promising therapeutic targetsor tools in cardiac regeneration. Increasing number of studies demonstrated that overexpression or inhibition ofspecific miRNAs could induce cardiomyocyte proliferation and cardiac regeneration. Some common targets of proproliferationmiRNAs, such as the Hippo-Yap signaling pathway, were identified in multiple species, highlighting thepower of miRNAs as probes to dissect core regulators of biological processes. A number of miRNAs have beenshown to improve heart function after myocardial infarction in mice, and one trial in swine also demonstratedpromising outcomes. However, technical difficulties, especially in delivery methods, and adverse effects, such asuncontrolled proliferation, remain. In this review, we summarize the recent progress in miRNA research in cardiacdevelopment and regeneration, examine the mechanisms of miRNA regulating cardiomyocyte proliferation, anddiscuss its potential as a new strategy for cardiac regeneration therapy.展开更多
基金supported by National Natural Science Foundation of China(Grant No.81871244)Primary Research&Development Plan of Jiangsu Province(BE2019700,China)+4 种基金Jiangsu Province“333”project(BRA2018016,China)six talent peaks project in Jiangsu Province(2019-WSN-122,China)Projects of International Cooperation from Jiangsu(BX2019100,China)international cooperation and exchange from Zhenjiang(GJ2020010,China)key funds from health commission of jiangsu(ZD2021009,China)。
文摘Cardiac-resident macrophages(CRMs)play important roles in homeostasis,cardiac function,and remodeling.Although CRMs play critical roles in cardiac regeneration of neonatal mice,their roles are yet to be fully elucidated.Therefore,this study aimed to investigate the dynamic changes of CRMs during cardiac ontogeny and analyze the phenotypic and functional properties of CRMs in the promotion of cardiac regeneration.During mouse cardiac ontogeny,four CRM subsets exist successively:CX3CR1+CCR2-Ly6C-MHCII-(MP1),CX3CR1lowCCR2lowLy6C-MHCII-(MP2),CX3CR1-CCR2+Ly6C+MHCII-(MP3),and CX3CR1+CCR2-Ly6C-MHCII+(MP4).MP1 cluster has different derivations(yolk sac,fetal liver,and bone marrow)and multiple functions population.Embryonic and neonatal-derived-MP1 directly promoted cardiomyocyte proliferation through Jagged-1-Notch1 axis and significantly ameliorated cardiac injury following myocardial infarction.MP2/3 subsets could survive throughout adulthood.MP4,the main population in adult mouse hearts,contributed to inflammation.During ontogeny,MP1 can convert into MP4 triggered by changes in the cellular redox state.These findings delineate the evolutionary dynamics of CRMs under physiological conditions and found direct evidence that embryonic and neonatal-derived CRMs regulate cardiomyocyte proliferation.Our findings also shed light on cardiac repair following injury.
文摘The heart has been considered a post-mitotic organ without regenerative capacity for most of the last century.We review the evidence that led to this hypothesis in the early 1900s and how it was progressively modified,culminating with the report that we renew 50% of our cardiomyocytes during our lifetime.The future of cardiac regenerative therapies is discussed,presenting the difficulties to overcome before repair of the diseased heart can come into clinical practice.
基金supported by the National Natural Science Foundation of China(No.82070314,81600244)the Natural Science Foundation of Shandong Province,China(No.ZR2021MC189).
文摘In the mammalian heart,cardiomyocytes are forced to withdraw from the cell cycle shortly after birth,limiting the ability of the heart to regenerate and repair.The development of multimodal regulation of cardiac proliferation has verified that pre-existing cardiomyocyte proliferation is an essential driver of cardiac renewal.With the continuous development of genetic lineage tracking technology,it has been revealed that cell cycle activity produces polyploid cardiomyocytes during the embryonic,juvenile,and adult stages of cardiogenesis,but newly formed mononucleated diploid cardiomyocytes also elevated sporadically during myocardial infarction.It implied that adult cardiomyocytes have a weak regenerative capacity under the condition of ischemia injury,which offers hope for the clinical treatment of myocardial infarction.However,the regeneration frequency and source of cardiomyocytes are still low,and the mechanism of regulating cardiomyocyte proliferation remains further explained.It is noteworthy to explore what force triggers endogenous cardiomyocyte proliferation and heart regeneration.Here,we focused on summarizing the recent research progress of emerging endogenous key modulators and crosstalk with other signaling pathways and furnished valuable insights into the internal mechanism of heart regeneration.In addition,myocardial transcription factors,non-coding RNAs,cyclins,and cell cycle-dependent kinases are involved in the multimodal regulation of pre-existing cardiomyocyte proliferation.Ultimately,awakening the myocardial proliferation endogenous modulator and regeneration pathways may be the final battlefield for the regenerative therapy of cardiovascular diseases.
基金Shaanxi Province Natural Science Foundation,China(Grant No.:2021JM-568).
文摘Hyaluronan and proteoglycan link protein 1(Hapln1)supports active cardiomyogenesis in zebrafish hearts,but its regulation in mammal cardiomyocytes is unclear.This study aimed to explore the potential regulation of Hapln1 in the dedifferentiation and proliferation of cardiomyocytes and its therapeutic value in myocardial infarction with human induced pluripotent stem cell(hiPSC)-derived cardiomyocytes(CMs)and an adult mouse model of myocardial infarction.HiPSC-CMs and adult mice with myocardial infarction were used as in vitro and in vivo models,respectively.Previous single-cell RNA sequencing data were retrieved for bioinformatic exploration.The results showed that recombinant human Hapln1(rhHapln1)promotes the proliferation of hiPSC-CMs in a dose-dependent manner.As a physical binding protein of Hapln1,versican interacted with Nodal growth differentiation factor(NODAL)and growth differentiation factor 11(GDF11).GDF11,but not NODAL,was expressed by hiPSC-CMs.GDF11 expression was unaffected by rhHapln1 treatment.However,this molecule was required for rhHapln1-mediated activation of the transforming growth factor(TGF)-β/Drosophila mothers against decapentaplegic protein(SMAD)2/3 signaling in hiPSC-CMs,which stimulates cell dedifferentiation and proliferation.Recombinant mouse Hapln1(rmHapln1)could induce cardiac regeneration in the adult mouse model of myocardial infarction.In addition,rmHapln1 induced hiPSC-CM proliferation.In conclusion,Hapln1 can stimulate the dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping and subsequent activation of the TGF-β/SMAD2/3 signaling pathway.Hapln1 might be an effective hiPSC-CM dedifferentiation and proliferation agent and a potential reagent for repairing damaged hearts.
基金This research was supported by grants from the Ministry of Science and Technology of China(2018YFA0801004 and 2018YFA0800103)National Science Foundation of China(NSFC31530044 and NSFC31970780)We acknowledge Guozhen Wu for invaluable assistanee with fish care.We are grateful to Mark Mercola and members of TPZ laboratory for comments on the manuscript and helpful discussions.
文摘Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes(CMs).However,the signaling mechanisms by which injury induces CM renewal remain incompletely understood.Here,we find that cardiac injury in zebrafish induces expression of the secreted Wnt inhibitors,including Dickkopf 1(Dkkl),Dkk3,secreted Frizzled-related protein 1(sFrpl),and sFrp2,in cardiac tissue adjacent to injury sites.Experimental blocking of Wnt activity via Dkkl overexpression enhances CM proliferation and heart regeneration,whereas ectopic activation of Wnt8 signaling blunts injury-induced CM dedifferentiation and proliferation.Although Wnt signaling is dampened upon injury,the cytoplasmic β-catenin is unexpectedly increased at disarrayed CM sarcomeres in myocardial wound edges.Our analyses indicated that p21-activated kinase 2(Pak2)is induced at regenerating CMs,where it phosphorylates cytoplasmic β-catenin at Ser 675 and increases its stability at disassembled sarcomeres.Myocardial-specific induction of the phospho-mimeticβ-catenin(S675E)enhances CM dedifferentiation and sarcomere disassembly in response to injury.Conversely,inactivation of Pak2 kinase activity reduces the Ser 675-phosphorylatedβ-catenin(pS675-β-catenin)and attenuates CM sarcomere disorganization and dedifferentiation・Taken together,these findings demonstrate that coordination of Wnt signaling inhibition and Pak2/pS675-βYatenin signaling enhances zebrafish heart regeneration by supporting CM dedifferentiation and proliferation.
基金This work was supported by Key Research and Development Program,Ministry of Science and Technology of China(2017YFA0105601,2018YFA0800104)National Natural Science Foundation of China(31771613,32070823)Fundamental Research Funds for the Central Universities(22120200411).
文摘Ischemic heart disease is one of the main causes of morbidity and mortality in the world. In adult mammalianhearts, most cardiomyocytes are terminally differentiated and have extremely limited capacity of proliferation,making it impossible to regenerate the heart after injuries such as myocardial infarction. MicroRNAs (miRNAs), aclass of non-coding single-stranded RNA, which are involved in mRNA silencing and the regulation of posttranscriptionalgene expression, have been shown to play a crucial role in cardiac development and cardiomyocyteproliferation. Muscle specific miRNAs such as miR-1 are key regulators of cardiomyocyte maturation and growth,while miR-199-3p and other miRNAs display potent activity to induce proliferation of cardiomyocytes. Given theirsmall size and relative pleiotropic effects, miRNAs have gained significant attraction as promising therapeutic targetsor tools in cardiac regeneration. Increasing number of studies demonstrated that overexpression or inhibition ofspecific miRNAs could induce cardiomyocyte proliferation and cardiac regeneration. Some common targets of proproliferationmiRNAs, such as the Hippo-Yap signaling pathway, were identified in multiple species, highlighting thepower of miRNAs as probes to dissect core regulators of biological processes. A number of miRNAs have beenshown to improve heart function after myocardial infarction in mice, and one trial in swine also demonstratedpromising outcomes. However, technical difficulties, especially in delivery methods, and adverse effects, such asuncontrolled proliferation, remain. In this review, we summarize the recent progress in miRNA research in cardiacdevelopment and regeneration, examine the mechanisms of miRNA regulating cardiomyocyte proliferation, anddiscuss its potential as a new strategy for cardiac regeneration therapy.
