RESUMO
Aging poses a major risk factor for cardiovascular diseases, the leading cause of death in the aged population. However, the cell type-specific changes underlying cardiac aging are far from being clear. Here, we performed single-nucleus RNA-sequencing analysis of left ventricles from young and aged cynomolgus monkeys to define cell composition changes and transcriptomic alterations across different cell types associated with age. We found that aged cardiomyocytes underwent a dramatic loss in cell numbers and profound fluctuations in transcriptional profiles. Via transcription regulatory network analysis, we identified FOXP1, a core transcription factor in organ development, as a key downregulated factor in aged cardiomyocytes, concomitant with the dysregulation of FOXP1 target genes associated with heart function and cardiac diseases. Consistently, the deficiency of FOXP1 led to hypertrophic and senescent phenotypes in human embryonic stem cell-derived cardiomyocytes. Altogether, our findings depict the cellular and molecular landscape of ventricular aging at the single-cell resolution, and identify drivers for primate cardiac aging and potential targets for intervention against cardiac aging and associated diseases.
Assuntos
Idoso , Animais , Humanos , Envelhecimento/genética , Fatores de Transcrição Forkhead/metabolismo , Miócitos Cardíacos/metabolismo , Primatas/metabolismo , Proteínas Repressoras/metabolismo , Transcriptoma , Macaca fascicularis/metabolismoRESUMO
Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtype-specific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Envelhecimento , Genética , Alergia e Imunologia , Betacoronavirus , Linfócitos T CD4-Positivos , Metabolismo , Linhagem da Célula , Montagem e Desmontagem da Cromatina , Infecções por Coronavirus , Alergia e Imunologia , Síndrome da Liberação de Citocina , Alergia e Imunologia , Citocinas , Genética , Suscetibilidade a Doenças , Citometria de Fluxo , Métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Rearranjo Gênico , Sistema Imunitário , Biologia Celular , Alergia e Imunologia , Imunocompetência , Genética , Inflamação , Genética , Alergia e Imunologia , Espectrometria de Massas , Métodos , Pandemias , Pneumonia Viral , Alergia e Imunologia , Análise de Sequência de RNA , Análise de Célula Única , TranscriptomaRESUMO
Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtype-specific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Envelhecimento , Genética , Alergia e Imunologia , Betacoronavirus , Linfócitos T CD4-Positivos , Metabolismo , Linhagem da Célula , Montagem e Desmontagem da Cromatina , Infecções por Coronavirus , Alergia e Imunologia , Síndrome da Liberação de Citocina , Alergia e Imunologia , Citocinas , Genética , Suscetibilidade a Doenças , Citometria de Fluxo , Métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Rearranjo Gênico , Sistema Imunitário , Biologia Celular , Alergia e Imunologia , Imunocompetência , Genética , Inflamação , Genética , Alergia e Imunologia , Espectrometria de Massas , Métodos , Pandemias , Pneumonia Viral , Alergia e Imunologia , Análise de Sequência de RNA , Análise de Célula Única , TranscriptomaRESUMO
Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtype-specific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Envelhecimento , Genética , Alergia e Imunologia , Betacoronavirus , Linfócitos T CD4-Positivos , Metabolismo , Linhagem da Célula , Montagem e Desmontagem da Cromatina , Infecções por Coronavirus , Alergia e Imunologia , Síndrome da Liberação de Citocina , Alergia e Imunologia , Citocinas , Genética , Suscetibilidade a Doenças , Citometria de Fluxo , Métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Rearranjo Gênico , Sistema Imunitário , Biologia Celular , Alergia e Imunologia , Imunocompetência , Genética , Inflamação , Genética , Alergia e Imunologia , Espectrometria de Massas , Métodos , Pandemias , Pneumonia Viral , Alergia e Imunologia , Análise de Sequência de RNA , Análise de Célula Única , TranscriptomaRESUMO
Werner syndrome (WS) is a premature aging disorder that mainly affects tissues derived from mesoderm. We have recently developed a novel human WS model using WRN-deficient human mesenchymal stem cells (MSCs). This model recapitulates many phenotypic features of WS. Based on a screen of a number of chemicals, here we found that Vitamin C exerts most efficient rescue for many features in premature aging as shown in WRN-deficient MSCs, including cell growth arrest, increased reactive oxygen species levels, telomere attrition, excessive secretion of inflammatory factors, as well as disorganization of nuclear lamina and heterochromatin. Moreover, Vitamin C restores in vivo viability of MSCs in a mouse model. RNA sequencing analysis indicates that Vitamin C alters the expression of a series of genes involved in chromatin condensation, cell cycle regulation, DNA replication, and DNA damage repair pathways in WRN-deficient MSCs. Our results identify Vitamin C as a rejuvenating factor for WS MSCs, which holds the potential of being applied as a novel type of treatment of WS.
Assuntos
Animais , Humanos , Camundongos , Ácido Ascórbico , Farmacologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular , Senescência Celular , Dano ao DNA , Reparo do DNA , Replicação do DNA , Modelos Animais de Doenças , Heterocromatina , Metabolismo , Patologia , Células-Tronco Mesenquimais , Metabolismo , Patologia , Lâmina Nuclear , Metabolismo , Patologia , Espécies Reativas de Oxigênio , Metabolismo , Homeostase do Telômero , Síndrome de Werner , Tratamento Farmacológico , Genética , MetabolismoRESUMO
AIM: To investigate the effect of dihydroartemisinin (DHA) on the proliferation of murine T lymphocytes stimulated by Con A in vitro and its related immunosuppressive mechanism. METHODS: Murine T lymphocytes were stimulated by Con A and treated with different concentrations of DHA. Cell proliferation was measured by carboxyl fluoresce in diacetate succinmidyl ester (CFDA-SE) staining. The expression of CD69, CD25 and CD71,which was the marker of early, middle, later activation of CD3~+ T lymphocytes, was measured by flow cytometry (FCM) combined with two-color immunofluorescent staining of cell surface antigen. Fluorescence calcium indicator fluo-4/AM was used to measure the change of the intracellular calcium concentration ([Ca~(2+)]_i) of murine T lymphocytes. The distribution of the cell cycle was analyzed by PI staining. The expression of CD69, the early activation antigen on CD4~+CD25~(high) Treg was also measured by FCM combined with three-color immunofluorescent staining. RESULTS: The result of CFDA-SE staining showed that DHA efficiently inhibited the Con A-induced proliferation of T-lymphocytes in a time-and dose-dependent manners. DHA showed modestly increased proportions of CD69 and CD25 on Con A-stimulated CD3~+T cells, but inhibited the expression of CD25 in a dose dependent manner. DHA with Con A, but not DHA alone, caused an increase in intracellular calcium concentration of T cells. The results of FCM analysis with PI staining showed that DHA imposed a total cell cycle arrest in G_0/G_1 and prevented cells entering S phase and G_2/M phase. Furthermore, DHA reduced the expression of CD69 on CD4~+CD25~(high) Treg. CONCLUSION: DHA, which exhibits immunosuppressive effect on the proliferation of murine T-lymphocytes, is promising to be developed as an immunosuppressive reagent.