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1.
Cell ; 187(16): 4150-4175, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39121846

RESUMO

Cellular senescence is a cell fate triggered in response to stress and is characterized by stable cell-cycle arrest and a hypersecretory state. It has diverse biological roles, ranging from tissue repair to chronic disease. The development of new tools to study senescence in vivo has paved the way for uncovering its physiological and pathological roles and testing senescent cells as a therapeutic target. However, the lack of specific and broadly applicable markers makes it difficult to identify and characterize senescent cells in tissues and living organisms. To address this, we provide practical guidelines called "minimum information for cellular senescence experimentation in vivo" (MICSE). It presents an overview of senescence markers in rodent tissues, transgenic models, non-mammalian systems, human tissues, and tumors and their use in the identification and specification of senescent cells. These guidelines provide a uniform, state-of-the-art, and accessible toolset to improve our understanding of cellular senescence in vivo.


Assuntos
Senescência Celular , Humanos , Animais , Biomarcadores/metabolismo , Guias como Assunto , Neoplasias/patologia
2.
Cell ; 179(4): 813-827, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31675495

RESUMO

Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.


Assuntos
Envelhecimento/genética , Biomarcadores , Senescência Celular/genética , Doenças Genéticas Inatas/genética , Pontos de Checagem do Ciclo Celular/genética , Cromatina/genética , Regulação da Expressão Gênica/genética , Doenças Genéticas Inatas/terapia , Humanos
3.
Nat Rev Mol Cell Biol ; 22(2): 75-95, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33328614

RESUMO

Cellular senescence, first described in vitro in 1961, has become a focus for biotech companies that target it to ameliorate a variety of human conditions. Eminently characterized by a permanent proliferation arrest, cellular senescence occurs in response to endogenous and exogenous stresses, including telomere dysfunction, oncogene activation and persistent DNA damage. Cellular senescence can also be a controlled programme occurring in diverse biological processes, including embryonic development. Senescent cell extrinsic activities, broadly related to the activation of a senescence-associated secretory phenotype, amplify the impact of cell-intrinsic proliferative arrest and contribute to impaired tissue regeneration, chronic age-associated diseases and organismal ageing. This Review discusses the mechanisms and modulators of cellular senescence establishment and induction of a senescence-associated secretory phenotype, and provides an overview of cellular senescence as an emerging opportunity to intervene through senolytic and senomorphic therapies in ageing and ageing-associated diseases.


Assuntos
Envelhecimento , Senescência Celular , Telômero , Pesquisa Translacional Biomédica , Animais , Proliferação de Células , Dano ao DNA , Humanos , Fenótipo
4.
EMBO J ; 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39349844

RESUMO

Fibrosis and accumulation of senescent cells are common tissue changes associated with aging. Here, we show that the CDK inhibitor p21 (CDKN1A), known to regulate the cell cycle and the viability of senescent cells, also controls the expression of extracellular matrix (ECM) components in senescent and proliferating cells of the fibrotic lung, in a manner dependent on CDK4 and Rb phosphorylation. p21 knockout protects mice from the induction of lung fibrosis. Moreover, inducible p21 silencing during fibrosis development alleviates disease pathology, decreasing the inflammatory response and ECM accumulation in the lung, and reducing the amount of senescent cells. Furthermore, p21 silencing limits fibrosis progression even when introduced during disease development. These findings show that one common mechanism regulates both cell cycle progression and expression of ECM components, and suggest that targeting p21 might be a new approach for treating age-related fibrotic pathologies.

5.
Cell ; 155(5): 1119-30, 2013 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-24238961

RESUMO

Senescence is a form of cell-cycle arrest linked to tumor suppression and aging. However, it remains controversial and has not been documented in nonpathologic states. Here we describe senescence as a normal developmental mechanism found throughout the embryo, including the apical ectodermal ridge (AER) and the neural roof plate, two signaling centers in embryonic patterning. Embryonic senescent cells are nonproliferative and share features with oncogene-induced senescence (OIS), including expression of p21, p15, and mediators of the senescence-associated secretory phenotype (SASP). Interestingly, mice deficient in p21 have defects in embryonic senescence, AER maintenance, and patterning. Surprisingly, the underlying mesenchyme was identified as a source for senescence instruction in the AER, whereas the ultimate fate of these senescent cells is apoptosis and macrophage-mediated clearance. We propose that senescence is a normal programmed mechanism that plays instructive roles in development, and that OIS is an evolutionarily adapted reactivation of a developmental process.


Assuntos
Senescência Celular , Desenvolvimento Embrionário , Animais , Apoptose , Embrião de Galinha , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Embrião de Mamíferos/citologia , Embrião de Mamíferos/imunologia , Embrião de Mamíferos/metabolismo , Extremidades/embriologia , Fibroblastos/citologia , Humanos , Camundongos , Comunicação Parácrina
6.
Cell ; 153(2): 449-60, 2013 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-23562644

RESUMO

The p53 tumor suppressor can restrict malignant transformation by triggering cell-autonomous programs of cell-cycle arrest or apoptosis. p53 also promotes cellular senescence, a tumor-suppressive program that involves stable cell-cycle arrest and secretion of factors that modify the tissue microenvironment. In the presence of chronic liver damage, we show that ablation of a p53-dependent senescence program in hepatic stellate cells increases liver fibrosis and cirrhosis associated with reduced survival and enhances the transformation of adjacent epithelial cells into hepatocellular carcinoma. p53-expressing senescent stellate cells release factors that skew macrophage polarization toward a tumor-inhibiting M1-state capable of attacking senescent cells in culture, whereas proliferating p53-deficient stellate cells secrete factors that stimulate polarization of macrophages into a tumor-promoting M2-state and enhance the proliferation of premalignant cells. Hence, p53 can act non-cell autonomously to suppress tumorigenesis by promoting an antitumor microenvironment, in part, through secreted factors that modulate macrophage function.


Assuntos
Transformação Celular Neoplásica , Senescência Celular , Células Estreladas do Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Microambiente Celular , Fibrose/patologia , Células Estreladas do Fígado/citologia , Humanos , Inflamação/metabolismo , Células de Kupffer/metabolismo , Células de Kupffer/patologia , Fígado/citologia , Fígado/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , NF-kappa B
7.
Semin Cancer Biol ; 87: 214-219, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-33486077

RESUMO

Cellular senescence, a stable form of cell cycle arrest, accompanied by pronounced secretory activity, has functional roles in both physiological and pathological conditions. Although senescence has been linked for a long time with cancer and ageing, recent studies have revealed a functional role of senescence in development, regeneration and reprogramming. Notably, the transient presence of senescent cells may be beneficial, in contrast to the potential deleterious effects of persistent senescence in aged or chronically damaged tissues. We will discuss how senescence contributes to embryonic development, cell plasticity and tissue regeneration, as a highly coordinated and programmed cellular state.


Assuntos
Plasticidade Celular , Neoplasias , Humanos , Idoso , Senescência Celular/genética , Envelhecimento/genética , Pontos de Checagem do Ciclo Celular , Neoplasias/genética , Neoplasias/metabolismo
8.
EMBO J ; 38(18): e100849, 2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31424120

RESUMO

The placenta is an autonomous organ that maintains fetal growth and development. Its multinucleated syncytiotrophoblast layer, providing fetal nourishment during gestation, exhibits characteristics of cellular senescence. We show that in human placentas from pregnancies with intrauterine growth restriction, these characteristics are decreased. To elucidate the functions of pathways regulating senescence in syncytiotrophoblast, we used dynamic contrast-enhanced MRI in mice with attenuated senescence programs. This approach revealed an altered dynamics in placentas of p53-/- , Cdkn2a-/- , and Cdkn2a-/- ;p53-/- mice, accompanied by histopathological changes in placental labyrinths. Human primary syncytiotrophoblast upregulated senescence markers and molecular pathways associated with cell-cycle inhibition and senescence-associated secretory phenotype. The pathways and components of the secretory phenotype were compromised in mouse placentas with attenuated senescence and in human placentas from pregnancies with intrauterine growth restriction. We propose that molecular mediators of senescence regulate placental structure and function, through both cell-autonomous and non-autonomous mechanisms.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Retardo do Crescimento Fetal/genética , Redes Reguladoras de Genes , Placenta/diagnóstico por imagem , Proteína Supressora de Tumor p53/genética , Animais , Senescência Celular , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Imageamento por Ressonância Magnética , Camundongos , Fenótipo , Placenta/metabolismo , Gravidez , Transdução de Sinais , Trofoblastos/metabolismo
9.
Cell ; 134(4): 657-67, 2008 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-18724938

RESUMO

Cellular senescence acts as a potent mechanism of tumor suppression; however, its functional contribution to noncancer pathologies has not been examined. Here we show that senescent cells accumulate in murine livers treated to produce fibrosis, a precursor pathology to cirrhosis. The senescent cells are derived primarily from activated hepatic stellate cells, which initially proliferate in response to liver damage and produce the extracellular matrix deposited in the fibrotic scar. In mice lacking key senescence regulators, stellate cells continue to proliferate, leading to excessive liver fibrosis. Furthermore, senescent activated stellate cells exhibit gene expression profile consistent with cell-cycle exit, reduced secretion of extracellular matrix components, enhanced secretion of extracellular matrix-degrading enzymes, and enhanced immune surveillance. Accordingly natural killer cells preferentially kill senescent activated stellate cells in vitro and in vivo, thereby facilitating the resolution of fibrosis. Therefore, the senescence program limits the fibrogenic response to acute tissue damage.


Assuntos
Senescência Celular , Cirrose Hepática/imunologia , Fígado/citologia , Animais , Tetracloreto de Carbono , Células Cultivadas , Feminino , Fibroblastos/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Fígado/fisiologia , Cirrose Hepática/metabolismo , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/imunologia , Cirrose Hepática Experimental/metabolismo , Camundongos
10.
Genes Dev ; 29(8): 791-802, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25854920

RESUMO

Mammalian cells mostly rely on extracellular molecules to transfer signals to other cells. However, in stress conditions, more robust mechanisms might be necessary to facilitate cell-cell communications. Cellular senescence, a stress response associated with permanent exit from the cell cycle and the development of an immunogenic phenotype, limits both tumorigenesis and tissue damage. Paradoxically, the long-term presence of senescent cells can promote tissue damage and aging within their microenvironment. Soluble factors secreted from senescent cells mediate some of these cell-nonautonomous effects. However, it is unknown whether senescent cells impact neighboring cells by other mechanisms. Here we show that senescent cells directly transfer proteins to neighboring cells and that this process facilitates immune surveillance of senescent cells by natural killer (NK) cells. We found that transfer of proteins to NK and T cells is increased in the murine preneoplastic pancreas, a site where senescent cells are present in vivo. Proteomic analysis and functional studies of the transferred proteins revealed that the transfer is strictly dependent on cell-cell contact and CDC42-regulated actin polymerization and is mediated at least partially by cytoplasmic bridges. These findings reveal a novel mode of intercellular communication by which senescent cells regulate their immune surveillance and might impact tumorigenesis and tissue aging.


Assuntos
Senescência Celular/fisiologia , Pâncreas/citologia , Actinas/metabolismo , Animais , Comunicação Celular/fisiologia , Fibroblastos/citologia , Fibroblastos/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária , Camundongos , Pâncreas/fisiologia , Polimerização , Transporte Proteico , Linfócitos T/citologia , Linfócitos T/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo
11.
Gut ; 71(2): 345-355, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33649045

RESUMO

OBJECTIVE: Cellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised. It is currently unknown whether senolytic drugs, aimed at eliminating senescent cells from lesions, could be beneficial in blocking tumour development. DESIGN: To uncover the functions of senescent cells and their potential contribution to early pancreatic tumourigenesis, we isolated and characterised senescent cells from PanINs formed in a Kras-driven mouse model, and tested the consequences of their targeted elimination through senolytic treatment. RESULTS: We found that senescent PanIN cells exert a tumour-promoting effect through expression of a proinflammatory signature that includes high Cox2 levels. Senolytic treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent cells, and an intermittent short-duration treatment course dramatically reduced PanIN development and progression to pancreatic ductal adenocarcinoma. CONCLUSIONS: These findings reveal that senescent PanIN cells support tumour growth and progression, and provide a first indication that elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions.


Assuntos
Adenocarcinoma/patologia , Senescência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Neoplasias Pancreáticas/patologia , Lesões Pré-Cancerosas/patologia , Senoterapia/uso terapêutico , Adenocarcinoma/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Neoplasias Pancreáticas/metabolismo , Lesões Pré-Cancerosas/metabolismo
12.
EMBO J ; 36(15): 2280-2295, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28607003

RESUMO

Cellular senescence is a permanent state of cell cycle arrest that protects the organism from tumorigenesis and regulates tissue integrity upon damage and during tissue remodeling. However, accumulation of senescent cells in tissues during aging contributes to age-related pathologies. A deeper understanding of the mechanisms regulating the viability of senescent cells is therefore required. Here, we show that the CDK inhibitor p21 (CDKN1A) maintains the viability of DNA damage-induced senescent cells. Upon p21 knockdown, senescent cells acquired multiple DNA lesions that activated ataxia telangiectasia mutated (ATM) and nuclear factor (NF)-κB kinase, leading to decreased cell survival. NF-κB activation induced TNF-α secretion and JNK activation to mediate death of senescent cells in a caspase- and JNK-dependent manner. Notably, p21 knockout in mice eliminated liver senescent stellate cells and alleviated liver fibrosis and collagen production. These findings define a novel pathway that regulates senescent cell viability and fibrosis.


Assuntos
Caspases/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Dano ao DNA , Regulação da Expressão Gênica , Sistema de Sinalização das MAP Quinases , Animais , Linhagem Celular , Sobrevivência Celular , Humanos , Camundongos
13.
Genes Dev ; 27(21): 2356-66, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24186980

RESUMO

Cellular senescence limits proliferation of potentially detrimental cells, preventing tumorigenesis and restricting tissue damage. However, the function of senescence in nonpathological conditions is unknown. We found that the human placental syncytiotrophoblast exhibited the phenotype and expressed molecular markers of cellular senescence. During embryonic development, ERVWE1-mediated cell fusion results in formation of the syncytiotrophoblast, which serves as the maternal/fetal interface at the placenta. Expression of ERVWE1 caused cell fusion in normal and cancer cells, leading to formation of hyperploid syncytia exhibiting features of cellular senescence. Infection by the measles virus, which leads to cell fusion, also induced cellular senescence in normal and cancer cells. The fused cells activated the main molecular pathways of senescence, the p53- and p16-pRb-dependent pathways; the senescence-associated secretory phenotype; and immune surveillance-related proteins. Thus, fusion-induced senescence might be needed for proper syncytiotrophoblast function during embryonic development, and reuse of this senescence program later in life protects against pathological expression of endogenous fusogens and fusogenic viral infections.


Assuntos
Senescência Celular/fisiologia , Produtos do Gene env/metabolismo , Vírus do Sarampo/fisiologia , Proteínas da Gravidez/metabolismo , Fusão Celular , Linhagem Celular , Linhagem Celular Tumoral , Senescência Celular/genética , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibroblastos/virologia , Regulação da Expressão Gênica , Produtos do Gene env/genética , Humanos , Sarampo/fisiopatologia , Placenta/citologia , Gravidez , Proteínas da Gravidez/genética , Trofoblastos/metabolismo
15.
Nat Genet ; 39(7): 914-21, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17572676

RESUMO

Genetically engineered mice provide powerful tools for understanding mammalian gene function. These models traditionally rely on gene overexpression from transgenes or targeted, irreversible gene mutation. By adapting the tetracycline (tet)-responsive system previously used for gene overexpression, we have developed a simple transgenic system to reversibly control endogenous gene expression using RNA interference (RNAi) in mice. Transgenic mice harboring a tet-responsive RNA polymerase II promoter driving a microRNA-based short hairpin RNA targeting the tumor suppressor Trp53 reversibly express short hairpin RNA when crossed with existing mouse strains expressing general or tissue-specific 'tet-on' or 'tet-off' transactivators. Reversible Trp53 knockdown can be achieved in several tissues, and restoring Trp53 expression in lymphomas whose development is promoted by Trp53 knockdown leads to tumor regression. By leaving the target gene unaltered, this approach permits tissue-specific, reversible regulation of endogenous gene expression in vivo, with potential broad application in basic biology and drug target validation.


Assuntos
Especificidade de Órgãos/genética , Animais , Sistemas de Liberação de Medicamentos , Camundongos , Camundongos Transgênicos , Regiões Promotoras Genéticas , Interferência de RNA/fisiologia , Tetraciclina
16.
Cell Mol Life Sci ; 71(22): 4373-86, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25080110

RESUMO

Cellular senescence, a permanent state of cell cycle arrest accompanied by a complex phenotype, is an essential mechanism that limits tumorigenesis and tissue damage. In physiological conditions, senescent cells can be removed by the immune system, facilitating tumor suppression and wound healing. However, as we age, senescent cells accumulate in tissues, either because an aging immune system fails to remove them, the rate of senescent cell formation is elevated, or both. If senescent cells persist in tissues, they have the potential to paradoxically promote pathological conditions. Cellular senescence is associated with an enhanced pro-survival phenotype, which most likely promotes persistence of senescent cells in vivo. This phenotype may have evolved to favor facilitation of a short-term wound healing, followed by the elimination of senescent cells by the immune system. In this review, we provide a perspective on the triggers, mechanisms and physiological as well as pathological consequences of senescent cells.


Assuntos
Senescência Celular , Transformação Celular Neoplásica , Dano ao DNA , Matriz Extracelular/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Progéria/metabolismo , Progéria/fisiopatologia , Transdução de Sinais , Síndrome de Werner/metabolismo , Síndrome de Werner/fisiopatologia
17.
Biogerontology ; 15(6): 627-42, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25217383

RESUMO

The progression of physiological ageing is driven by intracellular aberrations including telomere attrition, genomic instability, epigenetic alterations and loss of proteostasis. These in turn damage cells and compromise their functionality. Cellular senescence, a stable irreversible cell-cycle arrest, is elicited in damaged cells and prevents their propagation in the organism. Under normal conditions, senescent cells recruit the immune system which facilitates their removal from tissues. Nevertheless, during ageing, tissue-residing senescent cells tend to accumulate, and might negatively impact their microenvironment via profound secretory phenotype with pro-inflammatory characteristics, termed senescence-associated secretory phenotype (SASP). Indeed, senescent cells are mostly abundant at sites of age-related pathologies, including degenerative disorders and malignancies. Interestingly, studies on progeroid mice indicate that selective elimination of senescent cells can delay age-related deterioration. This suggests that chronic inflammation induced by senescent cells might be a main driver of these pathologies. Importantly, senescent cells accumulate as a result of deficient immune surveillance, and their removal is increased upon the use of immune stimulatory agents. Insights into mechanisms of senescence surveillance could be combined with current approaches for cancer immunotherapy to propose new preventive and therapeutic strategies for age-related diseases.


Assuntos
Envelhecimento/patologia , Senescência Celular/fisiologia , Idoso , Envelhecimento/genética , Envelhecimento/imunologia , Doença de Alzheimer/etiologia , Animais , Aterosclerose/etiologia , Catarata/etiologia , Senescência Celular/genética , Senescência Celular/imunologia , Dano ao DNA , Diabetes Mellitus Tipo 2/etiologia , Instabilidade Genômica , Humanos , Vigilância Imunológica , Camundongos , Neoplasias/etiologia , Osteoporose/etiologia , Progéria/etiologia , Doença Pulmonar Obstrutiva Crônica/etiologia
18.
Nat Cell Biol ; 26(8): 1336-1345, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39103548

RESUMO

The accumulation of senescent cells promotes ageing and age-related diseases, but molecular mechanisms that senescent cells use to evade immune clearance and accumulate in tissues remain to be elucidated. Here we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in ageing and chronic inflammation. We show that p16-mediated inhibition of cell cycle kinases CDK4/6 induces PD-L1 stability in senescent cells via downregulation of its ubiquitin-dependent degradation. p16-expressing senescent alveolar macrophages elevate PD-L1 to promote an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with activating anti-PD-L1 antibodies engaging Fcγ receptors on effector cells leads to the elimination of PD-L1 and p16-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of targeting PD-L1 to improve immunosurveillance of senescent cells and ameliorate senescence-associated inflammation.


Assuntos
Antígeno B7-H1 , Senescência Celular , Inibidor p16 de Quinase Dependente de Ciclina , Estabilidade Proteica , Senescência Celular/imunologia , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Animais , Humanos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/genética , Vigilância Imunológica , Camundongos Endogâmicos C57BL , Quinase 6 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/genética , Camundongos , Proteólise , Receptores de IgG/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Inflamação/genética
19.
Nat Neurosci ; 27(6): 1116-1124, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38637622

RESUMO

Alzheimer's disease (AD) and dementia in general are age-related diseases with multiple contributing factors, including brain inflammation. Microglia, and specifically those expressing the AD risk gene TREM2, are considered important players in AD, but their exact contribution to pathology remains unclear. In this study, using high-throughput mass cytometry in the 5×FAD mouse model of amyloidosis, we identified senescent microglia that express high levels of TREM2 but also exhibit a distinct signature from TREM2-dependent disease-associated microglia (DAM). This senescent microglial protein signature was found in various mouse models that show cognitive decline, including aging, amyloidosis and tauopathy. TREM2-null mice had fewer microglia with a senescent signature. Treating 5×FAD mice with the senolytic BCL2 family inhibitor ABT-737 reduced senescent microglia, but not the DAM population, and this was accompanied by improved cognition and reduced brain inflammation. Our results suggest a dual and opposite involvement of TREM2 in microglial states, which must be considered when contemplating TREM2 as a therapeutic target in AD.


Assuntos
Envelhecimento , Doença de Alzheimer , Encéfalo , Modelos Animais de Doenças , Glicoproteínas de Membrana , Microglia , Receptores Imunológicos , Animais , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Microglia/metabolismo , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Camundongos , Envelhecimento/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Camundongos Transgênicos , Senescência Celular/fisiologia , Senescência Celular/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout
20.
Nat Cardiovasc Res ; 3(8): 915-932, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39196027

RESUMO

Senescence plays a key role in various physiological and pathological processes. We reported that injury-induced transient senescence correlates with heart regeneration, yet the multi-omics profile and molecular underpinnings of regenerative senescence remain obscure. Using proteomics and single-cell RNA sequencing, here we report the regenerative senescence multi-omic signature in the adult mouse heart and establish its role in neonatal heart regeneration and agrin-mediated cardiac repair in adult mice. We identified early growth response protein 1 (Egr1) as a regulator of regenerative senescence in both models. In the neonatal heart, Egr1 facilitates angiogenesis and cardiomyocyte proliferation. In adult hearts, agrin-induced senescence and repair require Egr1, activated by the integrin-FAK-ERK-Akt1 axis in cardiac fibroblasts. We also identified cathepsins as injury-induced senescence-associated secretory phenotype components that promote extracellular matrix degradation and potentially assist in reducing fibrosis. Altogether, we uncovered the molecular signature and functional benefits of regenerative senescence during heart regeneration, with Egr1 orchestrating the process.


Assuntos
Proliferação de Células , Senescência Celular , Proteína 1 de Resposta de Crescimento Precoce , Miócitos Cardíacos , Regeneração , Animais , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/genética , Regeneração/fisiologia , Senescência Celular/fisiologia , Miócitos Cardíacos/metabolismo , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/fisiologia , Transdução de Sinais , Fibroblastos/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Cultivadas , Animais Recém-Nascidos , Modelos Animais de Doenças , Fenótipo Secretor Associado à Senescência , Proteômica , Análise de Célula Única , Masculino , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Camundongos Knockout , Quinase 1 de Adesão Focal
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