Clonal hematopoiesis(CH)is a clonally expanded population of hematopoietic stem cells carrying somatic mutations that differentiate through multilineage hematopoiesis to form terminally differentiated mature hematopoi...Clonal hematopoiesis(CH)is a clonally expanded population of hematopoietic stem cells carrying somatic mutations that differentiate through multilineage hematopoiesis to form terminally differentiated mature hematopoietic cells carrying markers of the clonal mutation.Genes integral to critical cellular processes such as epigenetic regulation,DNA damage response,and inflammation frequently carry these mutations.Clonal hematopoiesis becomes increasingly prevalent with age and is associated with an increased risk of hematological tumors and some nonhematological conditions.Recent insights have revealed that the mutations driving CH are not only implicated in hematologic neoplasms but also possess the potential to influence cardiovascular pathogenesis.Here,we reviewed up-to-date findings about the roles of CH in cardiovascular diseases and tumors and explored the clinical significance of CH,as well as look forward to future related studies,so as to provide valuable references for future research and clinical practice.展开更多
Atherosclerosis(AS)is the main underlyingpathology of atherosclerotic cardiovascular disease(ASCVD),which is the leading cause of mortality inthe worldwide[1,2].Since the 19th century,Virchowhas already stated that AS...Atherosclerosis(AS)is the main underlyingpathology of atherosclerotic cardiovascular disease(ASCVD),which is the leading cause of mortality inthe worldwide[1,2].Since the 19th century,Virchowhas already stated that AS is a chronic inflammatorystate induced by cholesterol.After that,it took at leastthree decades’worth of study to establish the multipleinflammatory pathways related to AS.展开更多
Objective Vascular smooth muscle cell(VSMC)differentiation from stem cells is one source of the increasing number of VSMCs that are involved in vascular remodeling-related diseases such as hypertension,atherosclerosis...Objective Vascular smooth muscle cell(VSMC)differentiation from stem cells is one source of the increasing number of VSMCs that are involved in vascular remodeling-related diseases such as hypertension,atherosclerosis,and restenosis.MicroRNA-146a(miR-146a)has been proven to be involved in cell proliferation,migration,and tumor metabolism.However,little is known about the functional role of miR-146a in VSMC differentiation from embryonic stem cells(ESCs).This study aimed to determine the role of miR-146a in VSMC differentiation from ESCs.Methods Mouse ESCs were differentiated into VSMCs,and the cell extracts were analyzed by Western blotting and RT-qPCR.In addition,luciferase reporter assays using ESCs transfected with miR-146a/mimic and plasmids were performed.Finally,C57BL/6J female mice were injected with mimic or miR-146a-overexpressing ESCs,and immunohistochemistry,Western blotting,and RT-qPCR assays were carried out on tissue samples from these mice.Results miR-146a was significantly upregulated during VSMC differentiation,accompanied with the VSMC-specific marker genes smooth muscle-alpha-actin(SMαA),smooth muscle 22(SM22),smooth muscle myosin heavy chain(SMMHC),and h1-calponin.Furthermore,overexpression of miR-146a enhanced the differentiation process in vitro and in vivo.Concurrently,the expression of Kruppel-like factor 4(KLF4),predicted as one of the top targets of miR-146a,was sharply decreased in miR-146a-overexpressing ESCs.Importantly,inhibiting KLF4 expression enhanced the VSMC-specific gene expression induced by miR-146a overexpression in differentiating ESCs.In addition,miR-146a upregulated the mRNA expression levels and transcriptional activity of VSMC differentiation-related transcription factors,including serum response factor(SRF)and myocyte enhancer factor 2c(MEF-2c).Conclusion Our data support that miR-146a promotes ESC-VSMC differentiation through regulating KLF4 and modulating the transcription factor activity of VSMCs.展开更多
基金Supported by a grant from the National Natural Science Founda-tion of China(no.82200319).
文摘Clonal hematopoiesis(CH)is a clonally expanded population of hematopoietic stem cells carrying somatic mutations that differentiate through multilineage hematopoiesis to form terminally differentiated mature hematopoietic cells carrying markers of the clonal mutation.Genes integral to critical cellular processes such as epigenetic regulation,DNA damage response,and inflammation frequently carry these mutations.Clonal hematopoiesis becomes increasingly prevalent with age and is associated with an increased risk of hematological tumors and some nonhematological conditions.Recent insights have revealed that the mutations driving CH are not only implicated in hematologic neoplasms but also possess the potential to influence cardiovascular pathogenesis.Here,we reviewed up-to-date findings about the roles of CH in cardiovascular diseases and tumors and explored the clinical significance of CH,as well as look forward to future related studies,so as to provide valuable references for future research and clinical practice.
文摘Atherosclerosis(AS)is the main underlyingpathology of atherosclerotic cardiovascular disease(ASCVD),which is the leading cause of mortality inthe worldwide[1,2].Since the 19th century,Virchowhas already stated that AS is a chronic inflammatorystate induced by cholesterol.After that,it took at leastthree decades’worth of study to establish the multipleinflammatory pathways related to AS.
基金funded by the National Natural Science Foundation of China(No.82070376 and No.81873491)the Natural Science Foundation of Zhejiang Province(No.LY21H020005)+1 种基金the Zhejiang Medical Science and Technology Project(No.2019KY376 and No.2018KY071)a Ningbo Science and Technology Project(No.202002N3173).
文摘Objective Vascular smooth muscle cell(VSMC)differentiation from stem cells is one source of the increasing number of VSMCs that are involved in vascular remodeling-related diseases such as hypertension,atherosclerosis,and restenosis.MicroRNA-146a(miR-146a)has been proven to be involved in cell proliferation,migration,and tumor metabolism.However,little is known about the functional role of miR-146a in VSMC differentiation from embryonic stem cells(ESCs).This study aimed to determine the role of miR-146a in VSMC differentiation from ESCs.Methods Mouse ESCs were differentiated into VSMCs,and the cell extracts were analyzed by Western blotting and RT-qPCR.In addition,luciferase reporter assays using ESCs transfected with miR-146a/mimic and plasmids were performed.Finally,C57BL/6J female mice were injected with mimic or miR-146a-overexpressing ESCs,and immunohistochemistry,Western blotting,and RT-qPCR assays were carried out on tissue samples from these mice.Results miR-146a was significantly upregulated during VSMC differentiation,accompanied with the VSMC-specific marker genes smooth muscle-alpha-actin(SMαA),smooth muscle 22(SM22),smooth muscle myosin heavy chain(SMMHC),and h1-calponin.Furthermore,overexpression of miR-146a enhanced the differentiation process in vitro and in vivo.Concurrently,the expression of Kruppel-like factor 4(KLF4),predicted as one of the top targets of miR-146a,was sharply decreased in miR-146a-overexpressing ESCs.Importantly,inhibiting KLF4 expression enhanced the VSMC-specific gene expression induced by miR-146a overexpression in differentiating ESCs.In addition,miR-146a upregulated the mRNA expression levels and transcriptional activity of VSMC differentiation-related transcription factors,including serum response factor(SRF)and myocyte enhancer factor 2c(MEF-2c).Conclusion Our data support that miR-146a promotes ESC-VSMC differentiation through regulating KLF4 and modulating the transcription factor activity of VSMCs.
