Mammals exhibit limited heart regeneration ability,which can lead to heart failure after myocardial infarction.In contrast,zebrafish exhibit remarkable cardiac regeneration capacity.Several cell types and signaling pa...Mammals exhibit limited heart regeneration ability,which can lead to heart failure after myocardial infarction.In contrast,zebrafish exhibit remarkable cardiac regeneration capacity.Several cell types and signaling pathways have been reported to participate in this process.However,a comprehensive analysis of how different cells and signals interact and coordinate to regulate cardiac regeneration is unavailable.We collected major cardiac cell types from zebrafish and performed high-precision single-cell transcriptome analyses during both development and post-injury regeneration.We revealed the cellular heterogeneity as well as the molecular progress of cardiomyocytes during these processes,and identified a subtype of atrial cardiomyocyte exhibiting a stem-like state which may transdifferentiate into ventricular cardiomyocytes during regeneration.Furthermore,we identified a regeneration-induced cell(RIC)population in the epicardium-derived cells(EPDC),and demonstrated Angiopoietin 4(Angpt4)as a specific regulator of heart regeneration.angpt4 expression is specifically and transiently activated in RIC,which initiates a signaling cascade from EPDC to endocardium through the Tie2-MAPK pathway,and further induces activation of cathepsin K in cardiomyocytes through RA signaling.Loss of angpt4 leads to defects in scar tissue resolution and cardiomyocyte proliferation,while overexpression of angpt4 accelerates regeneration.Furthermore,we found that ANGPT4 could enhance proliferation of neonatal rat cardiomyocytes,and promote cardiac repair in mice after myocardial infarction,indicating that the function of Angpt4 is conserved in mammals.Our study provides a mechanistic understanding of heart regeneration at single-cell precision,identifies Angpt4 as a key regulator of cardiomyocyte proliferation and regeneration,and offers a novel therapeutic target for improved recovery after human heart injuries.展开更多
Wound healing requires abundant nutrition and blood supply, thus angiogenesis is a vital stage in this process. Angiogenesis involves diverse kinds of immune cells, growth factors, cytokines and inhibitors. ADSCs, esp...Wound healing requires abundant nutrition and blood supply, thus angiogenesis is a vital stage in this process. Angiogenesis involves diverse kinds of immune cells, growth factors, cytokines and inhibitors. ADSCs, especially ADSCs cultured in hypoxic condition, are reported to be able to facilitate angiogenesis and promote wound healing process. Significant efforts have been made on the development of ADSCs-based therapies with wound-healing applications. Here the results showed that expression of Angiopoietin-2 (ANGPT2) in ADSCs was up-regulated in the hypoxic condition.展开更多
基金the National Key Research and Development Program of China and the National Natural Science Foundation of China(NSFC)(Grant Nos.2018YFA0801001,32070824,31871458,2019YFA0802800,2016YFA0100500,31671500,81371264,31671177,and 2018YFA0800501).
文摘Mammals exhibit limited heart regeneration ability,which can lead to heart failure after myocardial infarction.In contrast,zebrafish exhibit remarkable cardiac regeneration capacity.Several cell types and signaling pathways have been reported to participate in this process.However,a comprehensive analysis of how different cells and signals interact and coordinate to regulate cardiac regeneration is unavailable.We collected major cardiac cell types from zebrafish and performed high-precision single-cell transcriptome analyses during both development and post-injury regeneration.We revealed the cellular heterogeneity as well as the molecular progress of cardiomyocytes during these processes,and identified a subtype of atrial cardiomyocyte exhibiting a stem-like state which may transdifferentiate into ventricular cardiomyocytes during regeneration.Furthermore,we identified a regeneration-induced cell(RIC)population in the epicardium-derived cells(EPDC),and demonstrated Angiopoietin 4(Angpt4)as a specific regulator of heart regeneration.angpt4 expression is specifically and transiently activated in RIC,which initiates a signaling cascade from EPDC to endocardium through the Tie2-MAPK pathway,and further induces activation of cathepsin K in cardiomyocytes through RA signaling.Loss of angpt4 leads to defects in scar tissue resolution and cardiomyocyte proliferation,while overexpression of angpt4 accelerates regeneration.Furthermore,we found that ANGPT4 could enhance proliferation of neonatal rat cardiomyocytes,and promote cardiac repair in mice after myocardial infarction,indicating that the function of Angpt4 is conserved in mammals.Our study provides a mechanistic understanding of heart regeneration at single-cell precision,identifies Angpt4 as a key regulator of cardiomyocyte proliferation and regeneration,and offers a novel therapeutic target for improved recovery after human heart injuries.
文摘Wound healing requires abundant nutrition and blood supply, thus angiogenesis is a vital stage in this process. Angiogenesis involves diverse kinds of immune cells, growth factors, cytokines and inhibitors. ADSCs, especially ADSCs cultured in hypoxic condition, are reported to be able to facilitate angiogenesis and promote wound healing process. Significant efforts have been made on the development of ADSCs-based therapies with wound-healing applications. Here the results showed that expression of Angiopoietin-2 (ANGPT2) in ADSCs was up-regulated in the hypoxic condition.
