Background:Growth differentiation factor 11(GDF11),a transforming growth factor-beta superfamily member,is a crucial protein involved in many differentiation processes in embryogenesis and morphogenesis,and it has bee...Background:Growth differentiation factor 11(GDF11),a transforming growth factor-beta superfamily member,is a crucial protein involved in many differentiation processes in embryogenesis and morphogenesis,and it has been extensively characterized due to its capacity to target poorly differentiated cells,including transformed or cancer cells.Aim:In the present work,we aimed to describe the effects on migration,proliferation,and metabolism in the T-cell acute lymphoblastic leukemia-derived cell line Jurkat.Methods:Based on previous evidence,we analyzed metabolic changes exerted by GDF11 and its relationship with the aggressive phenotype.Results:We found a profound impact on mitochondrial metabolism and reactive oxygen species content;these were related to a decrement in the expression of the transcription factor forkhead-box-protein P3(FOXP3),which is highly involved in aggressiveness in leukemia cells;this was verified by a decrement in invasion capacity exhibited by the Jurkat cells under the GDF11 treatment.Conclusion:The results position the GDF11 response as a good alternative in the search for new therapeutic options for these 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
Objective:Our study aimed to assess the effects of Growth and differentiation factor 11(GDF11)on the function of endothelial progenitor cells in middle-age individuals(EPCs-MA)isolated from mouse bone marrow and to ex...Objective:Our study aimed to assess the effects of Growth and differentiation factor 11(GDF11)on the function of endothelial progenitor cells in middle-age individuals(EPCs-MA)isolated from mouse bone marrow and to explore the mechanistic relationship between GDF11 and age-related ALP impairment.Methods:Bone marrow-derived EPCs were isolated,culture and GDF11 treatment.In vivo,the mice model of myocardial ischemia(MI)was induced by permanent ligation of the left anterior descending coronary artery(LAD)and mice were randomly divided into MI group and EPCs transplantation group(EPCs-Y,EPCs-MA,EPCs-MA/GDF11).The positive effect of GDF11 treatment of EPCs-MA on MI was verified by echocardiography and the average ratio of fibrotic area to left ventricular(LV)area.In vitro,the effect of GDF11 on ameliorating EPCs aging by promoting autophagy was confirmed by transwell assay,immunofluorescence staining,characterization of EPCs ultrastructure through transmission electron microscope(TEM),lysosome imaging and Western blot.Result:Our findings demonstrate that GDF11 enhances the migration capacity of EPCs-MA and improves recovery of impaired cardiac function after myocardial infarction(MI)in mice,with EPCs isolated from young mice(EPCs-Y)as controls.Moreover,GDF11 restored functional phenotypes of EPCs-MA to levels akin to EPCs-Y,promoting the expression of CD31,endogenous NO synthase,and the restoration of von Willebrand factor(vWF)and CDH5 expression patterns,as well as the formation of Weibel-Palade bodies-key organelles for storage and secretion in endothelial cells and EPCs.Furthermore,GDF11 significantly enhanced the autophagic clearance capability of EPCs-MA by promoting ALP.Conclusions:Our results suggest that GDF11 ameliorates cardiac function impairment by restoring the activities of EPCs from aging mice through enhanced ALP.These findings suggest that GDF11 may hold therapeutic potential for improving aging-related conditions associated with declined autophagy.展开更多
生长分化因子11(Growth and differentiation factor-11,简称GDF11)是BMP/TGF-β超家族一员,编码一种在早期胚胎发育过程中起重要作用的骨形态发生蛋白,在确立骨骼模式中起重要作用。本研究旨在克隆里岔黑猪GDF11基因部分cDNA,并检测其...生长分化因子11(Growth and differentiation factor-11,简称GDF11)是BMP/TGF-β超家族一员,编码一种在早期胚胎发育过程中起重要作用的骨形态发生蛋白,在确立骨骼模式中起重要作用。本研究旨在克隆里岔黑猪GDF11基因部分cDNA,并检测其在不同组织中的表达差异。结果表明,所克隆的猪部分GDF11基因序列为1 161 bp(GenBank:HQ657211),编码332个氨基酸,与人、小鼠、大鼠、牛、马、兔、斑马鱼GDF11氨基酸序列同源性分别为99.10%,99.10%,99.10%,99.40%,99.10%,98.80%,78.82%。荧光定量PCR分析结果显示,GDF11基因mRNA在14种组织中均有表达,总体趋势为:脊椎>背膘>膀胱>肺>脾>胆囊>肾>大肠>心>骨骼肌>肝>小肠>眼肌>胃。这为进一步研究里岔黑猪GDF11基因的结构和功能及其脊椎数发生的机理奠定了基础。展开更多
Growth differentiation factor 11 （GDF11） is an important circulating factor that regulates aging. However, the role of GDF11 in bone metabolism remains unclear. The present study was undertaken to investigate the re...Growth differentiation factor 11 （GDF11） is an important circulating factor that regulates aging. However, the role of GDF11 in bone metabolism remains unclear. The present study was undertaken to investigate the relationship between serum GDF11 level, bone mass, and bone turnover markers in postmenopausal Chinese women. Serum GDF11 level, bone turnover biochemical markers, and bone mineral density （BMD） were determined in 169 postmenopausal Chinese women （47-78 years old）. GDF11 serum levels increased with aging. There were negative correlations between GDF11 and BMD at the various skeletal sites. After adjusting for age and body mass index （BMI）, the correlations remained statistically significant. In the multiple linear stepwise regression analysis, age or years since menopause, BMI, GDF11, and estradiol were independent predictors of BMD. A significant negative correlation between GDF11 and bone alkaline phosphatase （BAP） was identified and remained significant after adjusting for age and BMI. No significant correlation was noted between cross-linked N-telopeptides of type I collagen （NTX） and GDF11. In conclusion, GDF11 is an independent negative predictor of BMD and correlates with a biomarker of bone formation, BAP, in postmenopausal Chinese women. GDF11 potentially exerts a negative effect on bone mass by regulating bone formation.展开更多
基金funded by a grant from the Consejo Nacional de humanidades Ciencia y Tecnología(Conahcyt).Fronteras de la Ciencia 1320,Infra-2017280788Universidad Autónoma Metropolitana-Iztapalapa.
文摘Background:Growth differentiation factor 11(GDF11),a transforming growth factor-beta superfamily member,is a crucial protein involved in many differentiation processes in embryogenesis and morphogenesis,and it has been extensively characterized due to its capacity to target poorly differentiated cells,including transformed or cancer cells.Aim:In the present work,we aimed to describe the effects on migration,proliferation,and metabolism in the T-cell acute lymphoblastic leukemia-derived cell line Jurkat.Methods:Based on previous evidence,we analyzed metabolic changes exerted by GDF11 and its relationship with the aggressive phenotype.Results:We found a profound impact on mitochondrial metabolism and reactive oxygen species content;these were related to a decrement in the expression of the transcription factor forkhead-box-protein P3(FOXP3),which is highly involved in aggressiveness in leukemia cells;this was verified by a decrement in invasion capacity exhibited by the Jurkat cells under the GDF11 treatment.Conclusion:The results position the GDF11 response as a good alternative in the search for new therapeutic options for these 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the National Natural Science Foundation of China(81421063)China Postdoctoral Science Foundation(2016M591556)+2 种基金Natural Science Foundation of Heilongjiang Province of China(H2016008)Postdoctoral Science Foundation of Heilongjiang Province of China(LBH-Z15146)Research Project of the Health and Family Planning Commission of Heilongjiang Province(2016-166).
文摘Objective:Our study aimed to assess the effects of Growth and differentiation factor 11(GDF11)on the function of endothelial progenitor cells in middle-age individuals(EPCs-MA)isolated from mouse bone marrow and to explore the mechanistic relationship between GDF11 and age-related ALP impairment.Methods:Bone marrow-derived EPCs were isolated,culture and GDF11 treatment.In vivo,the mice model of myocardial ischemia(MI)was induced by permanent ligation of the left anterior descending coronary artery(LAD)and mice were randomly divided into MI group and EPCs transplantation group(EPCs-Y,EPCs-MA,EPCs-MA/GDF11).The positive effect of GDF11 treatment of EPCs-MA on MI was verified by echocardiography and the average ratio of fibrotic area to left ventricular(LV)area.In vitro,the effect of GDF11 on ameliorating EPCs aging by promoting autophagy was confirmed by transwell assay,immunofluorescence staining,characterization of EPCs ultrastructure through transmission electron microscope(TEM),lysosome imaging and Western blot.Result:Our findings demonstrate that GDF11 enhances the migration capacity of EPCs-MA and improves recovery of impaired cardiac function after myocardial infarction(MI)in mice,with EPCs isolated from young mice(EPCs-Y)as controls.Moreover,GDF11 restored functional phenotypes of EPCs-MA to levels akin to EPCs-Y,promoting the expression of CD31,endogenous NO synthase,and the restoration of von Willebrand factor(vWF)and CDH5 expression patterns,as well as the formation of Weibel-Palade bodies-key organelles for storage and secretion in endothelial cells and EPCs.Furthermore,GDF11 significantly enhanced the autophagic clearance capability of EPCs-MA by promoting ALP.Conclusions:Our results suggest that GDF11 ameliorates cardiac function impairment by restoring the activities of EPCs from aging mice through enhanced ALP.These findings suggest that GDF11 may hold therapeutic potential for improving aging-related conditions associated with declined autophagy.
基金supported by Grant 81570806 from the National Natural Science Foundation of China
文摘Growth differentiation factor 11 （GDF11） is an important circulating factor that regulates aging. However, the role of GDF11 in bone metabolism remains unclear. The present study was undertaken to investigate the relationship between serum GDF11 level, bone mass, and bone turnover markers in postmenopausal Chinese women. Serum GDF11 level, bone turnover biochemical markers, and bone mineral density （BMD） were determined in 169 postmenopausal Chinese women （47-78 years old）. GDF11 serum levels increased with aging. There were negative correlations between GDF11 and BMD at the various skeletal sites. After adjusting for age and body mass index （BMI）, the correlations remained statistically significant. In the multiple linear stepwise regression analysis, age or years since menopause, BMI, GDF11, and estradiol were independent predictors of BMD. A significant negative correlation between GDF11 and bone alkaline phosphatase （BAP） was identified and remained significant after adjusting for age and BMI. No significant correlation was noted between cross-linked N-telopeptides of type I collagen （NTX） and GDF11. In conclusion, GDF11 is an independent negative predictor of BMD and correlates with a biomarker of bone formation, BAP, in postmenopausal Chinese women. GDF11 potentially exerts a negative effect on bone mass by regulating bone formation.
