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1.
Nat Immunol ; 25(9): 1546-1554, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39134750

RESUMO

Tumor angiogenesis and immunity show an inverse correlation in cancer progression and outcome1. Here, we report that ZBTB46, a repressive transcription factor and a widely accepted marker for classical dendritic cells (DCs)2,3, controls both tumor angiogenesis and immunity. Zbtb46 was downregulated in both DCs and endothelial cells by tumor-derived factors to facilitate robust tumor growth. Zbtb46 downregulation led to a hallmark pro-tumor microenvironment (TME), including dysfunctional vasculature and immunosuppressive conditions. Analysis of human cancer data revealed a similar association of low ZBTB46 expression with an immunosuppressive TME and a worse prognosis. In contrast, enforced Zbtb46 expression led to TME changes to restrict tumor growth. Mechanistically, Zbtb46-deficient endothelial cells were highly angiogenic, and Zbtb46-deficient bone marrow progenitors upregulated Cebpb and diverted the DC program to immunosuppressive myeloid lineage output, potentially explaining the myeloid lineage skewing phenomenon in cancer4. Conversely, enforced Zbtb46 expression normalized tumor vessels and, by suppressing Cebpb, skewed bone marrow precursors toward immunostimulatory myeloid lineage output, leading to an immune-hot TME. Remarkably, Zbtb46 mRNA treatment synergized with anti-PD1 immunotherapy to improve tumor management in preclinical models. These findings identify ZBTB46 as a critical factor for angiogenesis and for myeloid lineage skewing in cancer and suggest that maintaining its expression could have therapeutic benefits.


Assuntos
Células Dendríticas , Neovascularização Patológica , Microambiente Tumoral , Animais , Microambiente Tumoral/imunologia , Camundongos , Neovascularização Patológica/imunologia , Neovascularização Patológica/genética , Humanos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/genética , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/imunologia , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Feminino , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Camundongos Knockout , Angiogênese , Fatores de Transcrição
2.
PLoS Biol ; 21(5): e3001746, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37134077

RESUMO

Extramedullary hematopoiesis (EMH) expands hematopoietic capacity outside of the bone marrow in response to inflammatory conditions, including infections and cancer. Because of its inducible nature, EMH offers a unique opportunity to study the interaction between hematopoietic stem and progenitor cells (HSPCs) and their niche. In cancer patients, the spleen frequently serves as an EMH organ and provides myeloid cells that may worsen pathology. Here, we examined the relationship between HSPCs and their splenic niche in EMH in a mouse breast cancer model. We identify tumor produced IL-1α and leukemia inhibitory factor (LIF) acting on splenic HSPCs and splenic niche cells, respectively. IL-1α induced TNFα expression in splenic HSPCs, which then activated splenic niche activity, while LIF induced proliferation of splenic niche cells. IL-1α and LIF display cooperative effects in activating EMH and are both up-regulated in some human cancers. Together, these data expand avenues for developing niche-directed therapies and further exploring EMH accompanying inflammatory pathologies like cancer.


Assuntos
Doenças Hematológicas , Hematopoese Extramedular , Neoplasias , Humanos , Animais , Camundongos , Hematopoese Extramedular/fisiologia , Fator Inibidor de Leucemia/farmacologia , Interleucina-1alfa/farmacologia , Hematopoese
3.
Immunity ; 45(3): 468-470, 2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27653599

RESUMO

Macrophages residing in different organs have diverse gene-expression programs. Mass et al. (2016) propose that this diversity develops "at home"-within those organs-after the recruitment of a common precursor that had not made prior commitments to diversity.


Assuntos
Macrófagos/fisiologia , Animais , Expressão Gênica/fisiologia
4.
PLoS Biol ; 20(10): e3001811, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36215313

RESUMO

Nuclear envelope membrane proteins (NEMPs) are a conserved family of nuclear envelope (NE) proteins that reside within the inner nuclear membrane (INM). Even though Nemp1 knockout (KO) mice are overtly normal, they display a pronounced splenomegaly. This phenotype and recent reports describing a requirement for NE openings during erythroblasts terminal maturation led us to examine a potential role for Nemp1 in erythropoiesis. Here, we report that Nemp1 KO mice show peripheral blood defects, anemia in neonates, ineffective erythropoiesis, splenomegaly, and stress erythropoiesis. The erythroid lineage of Nemp1 KO mice is overrepresented until the pronounced apoptosis of polychromatophilic erythroblasts. We show that NEMP1 localizes to the NE of erythroblasts and their progenitors. Mechanistically, we discovered that NEMP1 accumulates into aggregates that localize near or at the edge of NE openings and Nemp1 deficiency leads to a marked decrease of both NE openings and ensuing enucleation. Together, our results for the first time demonstrate that NEMP1 is essential for NE openings and erythropoietic maturation in vivo and provide the first mouse model of defective erythropoiesis directly linked to the loss of an INM protein.


Assuntos
Membrana Nuclear , Esplenomegalia , Camundongos , Animais , Eritroblastos/metabolismo , Núcleo Celular/metabolismo , Eritropoese/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Knockout
5.
J Korean Med Sci ; 38(4): e38, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36718564

RESUMO

BACKGROUND: Although inequality in traumatic brain injury (TBI) by individual socioeconomic status (SES) exists, interventions to modify individual SES are difficult. However, as interventions for area-based SES can affect the individual SES, monitoring or public health intervention can be planned. We analyzed the effect of area-based SES on hospitalization for TBI and revealed yearly inequality trends to provide a basis for health intervention. METHODS: We included patients who were hospitalized due to intracranial injuries (ICIs) between 2008 and 2015 as a measure of severe TBI with data provided by the Korea National Hospital Discharge Survey. Area-based SES was synthesized using the 2010 census data. We assessed inequalities in ICI-related hospitalization rates using the relative index of inequality and the slope index of inequality for the periods 2008-2009, 2010-2011, 2012-2013, and 2014-2015. We analyzed the trends of these indices for the observation period by age and sex. RESULTS: The overall relative indices of inequality for each 2-year period were 1.82 (95% confidence interval, 1.5-2.3), 1.97 (1.6-2.5), 2.01 (1.6-2.5), and 2.01 (1.6-2.5), respectively. The overall slope indices of inequality in each period were 38.74 (23.5-54.0), 36.75 (21.7-51.8), 35.65 (20.7-50.6), and 43.11 (27.6-58.6), respectively. The relative indices of inequality showed a linear trend for men (P = 0.006), which was most evident in the ≥ 65-year age group. CONCLUSION: Inequality in hospitalization for ICIs by area-based SES tended to increase during the observation period. Practical preventive interventions and input in healthcare resources for populations with low area-based SES are likely needed.


Assuntos
Disparidades nos Níveis de Saúde , Classe Social , Masculino , Humanos , Estudos Retrospectivos , Hospitalização , República da Coreia/epidemiologia , Fatores Socioeconômicos
6.
Development ; 146(23)2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31740535

RESUMO

Hemangiogenic progenitors generating blood and endothelial cells are specified from FLK1-expressing (FLK1+) mesoderm by the transcription factor ETV2. FLK1+ mesoderm also contributes to smooth muscle and cardiomyocytes. However, the developmental process of FLK1+ mesoderm generation and its allocation to various cell fates remain obscure. Recent single cell RNA-sequencing studies of early embryos or in vitro-differentiated human embryonic stem (ES) cells have provided unprecedented information on the spatiotemporal resolution of cells in embryogenesis. These snapshots, however, lack information on continuous dynamic developmental processes. Here, we performed single cell RNA sequencing of in vitro-differentiated mouse ES cells to capture the continuous developmental process leading to hemangiogenesis. We found that hemangiogenic progenitors from ES cells develop through intermediate gastrulation stages, which are gradually specified by 'relay'-like highly overlapping transcription factor modules. Moreover, the transcriptional program of the Flk1+ mesoderm was maintained in the smooth muscle lineage, suggesting that smooth muscle is the default fate of Flk1+ mesoderm. We also identified the SRC kinase contributing to ETV2-mediated activation of the hemangiogenic program. This continuous transcriptome map will facilitate both basic and applied studies of mesoderm development.


Assuntos
Células-Tronco Embrionárias Humanas/enzimologia , Mesoderma , Células-Tronco Embrionárias Murinas/enzimologia , Neovascularização Fisiológica/fisiologia , Análise de Célula Única , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Células-Tronco Embrionárias Humanas/citologia , Humanos , Mesoderma/irrigação sanguínea , Mesoderma/citologia , Mesoderma/embriologia , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Fatores de Transcrição/metabolismo , Transcrição Gênica , Proteínas de Peixe-Zebra/metabolismo , Quinases da Família src/metabolismo
7.
BMC Public Health ; 21(1): 1142, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34130679

RESUMO

BACKGROUND: To achieve the health equity, it is important to reduce socioeconomic inequalities when managing chronic diseases. In South Korea, a pilot program for chronic diseases was implemented at the national level. This study aimed to examine its effect on socioeconomic inequalities in chronic disease management at the individual and regional levels. METHODS: Korean National Health Insurance data from September 2016 to October 2017 were used. Study subjects in the national pilot program for chronic diseases included 31,765 participants and 5,741,922 non-participants. The dependent variable was continuity of prescription medication. Socioeconomic position indicators were health insurance contribution level and the area deprivation index. Covariates were gender, age, and the Charlson Comorbidity Index (CCI). A multilevel logistic regression model was used to address the effects at both the individual and regional levels. This is a cross-sectional study. RESULTS: Unlike the group of non-participants, the participants showed no inequality in prescription medication continuity according to individual-level socioeconomic position. However, continuity of prescription medication was higher among those in less deprived areas compared to those in more deprived areas in both the participation and non-participation groups. CONCLUSIONS: This study found that the pilot program for chronic diseases at the least did not contribute to the worsening of health inequalities at the individual level in South Korea. However, there was a trend showing health inequalities based on the socioeconomic level of the area. These findings suggest that additional policy measures are needed to attain equality in the management of chronic diseases regardless of the regional socioeconomic position.


Assuntos
Disparidades nos Níveis de Saúde , Doença Crônica , Estudos Transversais , Humanos , Projetos Piloto , República da Coreia/epidemiologia , Fatores Socioeconômicos
8.
Molecules ; 26(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072626

RESUMO

Background: Although nilotinib hepatotoxicity can cause severe clinical conditions and may alter treatment plans, risk factors affecting nilotinib-induced hepatotoxicity have not been investigated. This study aimed to elucidate the factors affecting nilotinib-induced hepatotoxicity. Methods: This retrospective cohort study was performed on patients using nilotinib from July of 2015 to June of 2020. We estimated the odds ratio and adjusted odds ratio from univariate and multivariate analyses, respectively. Several machine learning models were developed to predict risk factors of hepatotoxicity occurrence. The area under the curve (AUC) was analyzed to assess clinical performance. Results: Among 353 patients, the rate of patients with grade I or higher hepatotoxicity after nilotinib administration was 40.8%. Male patients and patients who received nilotinib at a dose of ≥300 mg had a 2.3-fold and a 3.5-fold increased risk for hepatotoxicity compared to female patients and compared with those who received <300 mg, respectively. H2 blocker use decreased hepatotoxicity by 11.6-fold. The area under the curve (AUC) values of machine learning methods ranged between 0.61-0.65 in this study. Conclusion: This study suggests that the use of H2 blockers was a reduced risk of nilotinib-induced hepatotoxicity, whereas male gender and a high dose were associated with increased hepatotoxicity.


Assuntos
Fígado/efeitos dos fármacos , Aprendizado de Máquina , Pirimidinas/efeitos adversos , Medição de Risco/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Área Sob a Curva , Doença Hepática Induzida por Substâncias e Drogas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Estudos Retrospectivos , Risco , Fatores de Risco , Adulto Jovem
9.
Dev Biol ; 440(1): 40-52, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29753018

RESUMO

The molecular mechanisms initiating the formation of the lymphatic system, lymphangiogenesis, are still poorly understood. Here we have identified a novel role in lymphangiogenesis for an ETS transcription factor, Etv2/Etsrp, a known regulator of embryonic vascular development. Through the use of fully validated photoactivatable morpholinos we show that inducible Etv2 inhibition in zebrafish embryos at 1 day post-fertilization (dpf) results in significant inhibition of lymphangiogenesis, while development of blood vessels is unaffected. In Etv2-inhibited embryos and larvae, the number of lymphatic progenitors is greatly reduced, the major lymphatic vessel, the thoracic duct, is absent or severely fragmented, and lymphangiogenesis-associated marker expression, including lyve1b, prox1a, and vegfr3/flt4, is strongly downregulated. We also demonstrate that lymphatic progenitors in Etv2 deficient embryos fail to respond to Vegfc signaling. Chromatin immunoprecipitation and sequencing (ChIP-Seq) studies using differentiated mouse embryonic stem (ES) cells as well as luciferase reporter studies in the ES cells and in zebrafish embryos argue that Etv2 directly binds the promoter/enhancer regions of Vegfc receptor Vegfr3/Flt4 and lymphatic marker Lyve1, and promotes their expression. Together these data support a model where Etv2 initiates lymphangiogenesis by directly promoting the expression of flt4 within the posterior cardinal vein.


Assuntos
Linfangiogênese/fisiologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/fisiologia , Animais , Diferenciação Celular , Embrião não Mamífero , Células-Tronco Embrionárias , Células Endoteliais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Células HEK293 , Humanos , Linfangiogênese/genética , Vasos Linfáticos/embriologia , Vasos Linfáticos/metabolismo , Camundongos , Morfolinos/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia , Fator C de Crescimento do Endotélio Vascular/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Peixe-Zebra
10.
J Opt Soc Am A Opt Image Sci Vis ; 36(12): D23-D30, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31873363

RESUMO

For this research, we have developed key technologies for a 1.5 µm pixel pitch spatial light modulator (SLM) using Ge2Sb2Te5 (GST) phase change material. To uniformly modulate each pixel, we designed a lateral pixel structure in which a heating current flows through a bottom indium tin oxide layer. To check hologram reconstruction both after multilevel fabrication processes and before implementing full source and driver circuits, we fabricated an 8K×2K hologram on the topology by changing the GST film's phase using laser irradiation. To overcome the limitation of SLM size, we tested a physical tiling structure and found that flatness of tiled SLMs was the most important factor in the realization of holographic displays.

11.
Fish Physiol Biochem ; 45(3): 873-883, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30387033

RESUMO

n-Butyl acrylate (nBA) is one of acrylate esters which has been applied to diverse industrial fields. For unveiling of xeno-estrogenic effects and oxidative stress induction by nBA under two-generational exposure regimen (17 weeks), the biomarkers relevant to an estrogenic effect and oxidative stress were analyzed. Acute toxicity value of nBA in Oryzias latipes was 7.2 mg/L (96 h-LC50). Over exposure time, the significant transcriptional change of cytochrome P450 19A (CYP19A) and vitellogenin 1/2 (VTG1/2) was not observed (one-way ANOVA, P < 0.05), meaning no estrogenic effect of nBA. Significant reduction of glutathione (GSH) content was observed in F0 male and female fish, while in F1 male, the content was increased (P < 0.05). Catalase (CAT) activity of male fish showed the significant decrease in both F0 and F1 fish, showing multi-generational suppressing effect of nBA on CAT activity. But in case of reactive oxygen species (ROS), expression level and glutathione S-transferase (GST) activity were not modulated in response to nBA. These findings suggest that nBA could affect an antioxidant system alteration through GSH depletion and inhibition of CAT activity which could be transferred to the next generation, whereas xeno-estrogenic effect would be questionable.


Assuntos
Acrilatos/toxicidade , Antioxidantes/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Oryzias/genética , Acrilatos/metabolismo , Adaptação Fisiológica/fisiologia , Animais , Feminino , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Fígado/metabolismo , Masculino , Oryzias/metabolismo , Testes de Toxicidade Aguda
12.
Curr Opin Hematol ; 25(4): 253-258, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29697486

RESUMO

PURPOSE OF REVIEW: Recent studies have established that haematopoietic stem cells (HSCs) remain quiescent in homeostatic conditions, and minimally contribute to haematopoietic homeostasis. However, they undergo extensive cell cycle and expansion upon bone marrow transplantation or haematopoietic injury to reestablish the haematopoietic system. Molecular basis for the HSC activation and expansion is not completely understood. Here, we review the recent study elucidating the role of the developmentally critical Ets transcription factor Etv2 in reestablishing haematopoietic system upon injury through promoting HSC regeneration. RECENT FINDINGS: We recently demonstrated that the ETS transcription factor Etv2, a critical factor for haematopoietic and vascular development, is also required for haematopoietic regeneration. Etv2, which is silent in homeostatic HSCs, was transiently activated in regenerating HSPCs and was required for the HSC expansion and regeneration following bone marrow transplantation or haematopoietic injury. As such, while Etv2 is dispensable for maintaining HSCs in steady states, it is required for emergency haematopoiesis. SUMMARY: Etv2 has been identified as a novel regulator of haematopoietic regeneration. Comprehensive understanding of the upstream regulators and downstream effectors of Etv2 in haematopoietic regeneration would be critical for fundamental understanding of haematopoietic stem cell biology, and the findings will be broadly applicable to clinical practice involving haematopoietic regenerative medicine; bone marrow transplantation, gene therapy and in-vitro HSC expansion.


Assuntos
Transplante de Medula Óssea , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Neovascularização Fisiológica , Regeneração , Fatores de Transcrição/metabolismo , Animais , Células-Tronco Hematopoéticas/patologia , Humanos
13.
Immunity ; 30(3): 408-20, 2009 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-19303389

RESUMO

The lymphotoxin LTalpha(1)beta(2) supports the development and maintenance of several aspects of spleen structure, but its significance for marginal sinus (MS) vascular organization is unclear. We showed here that, in early postnatal lymphotoxin-deficient mice, the developing Flk-1+ white pulp vessels failed to organize or upregulate MAdCAM-1, leading to altered spatial rearrangement of both the white pulp endothelial cells and the smooth muscle actin-expressing cells. In vitro, MAdCAM-1 directed the reorganization of LTbeta receptor+ endothelial cells grown on Matrigel. LTalpha(1)beta(2) also regulated the maintenance of both MAdCAM-1 expression and mature MS structure in adult mice, contributing importantly to normal trafficking of CD11b+ cells in response to bacterial antigens. Together, our studies demonstrate that LTalpha(1)beta(2) and LTbeta receptor signals control proper development and maintenance of the mature MS structure and implicate MAdCAM-1 in the structuring of the MS endothelial cells that is important for the movement of immune cells within the spleen.


Assuntos
Heterotrímero de Linfotoxina alfa1 e beta2/imunologia , Baço/imunologia , Animais , Antígenos de Bactérias/imunologia , Antígenos CD/metabolismo , Caderinas/metabolismo , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Células Cultivadas , Células Endoteliais/metabolismo , Ensaio de Imunoadsorção Enzimática , Heterotrímero de Linfotoxina alfa1 e beta2/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucoproteínas , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Baço/citologia
14.
Int J Mol Sci ; 19(2)2018 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-29425184

RESUMO

Adipose-derived stem cells (ADSCs) have the potential to treat ischemic diseases. In general, ADSCs facilitate angiogenesis by secreting various pro-angiogenic growth factors. However, transplanted ADSCs have a low therapeutic efficacy in ischemic tissues due to their poor engraftment and low viability. Stromal cell-derived factor-1α (SDF-1α) improves the survival rate of stem cells transplanted into ischemic regions. In this study, we developed acid-degradable poly(ethylene glycol)-poly(amino ketal) (PEG-PAK)-based micelles for efficient intracellular delivery of SDF-1α plasmid DNA. The SDF-1α gene was successfully delivered into human ADSCs (hADSCs) using PEG-PAK micelles. Transfection of SDF-1α increased SDF-1α, vascular endothelial growth factor, and basic fibroblast growth factor gene expression and decreased apoptotic activity in hADSCs cultured under hypoxic conditions in comparison with conventional gene transfection using polyethylenimine. SDF-1α-transfected hADSCs also showed significantly increased SDF-1α and VEGF expression together with reduced apoptotic activity at 4 weeks after transplantation into mouse ischemic hindlimbs. Consequently, these cells improved angiogenesis in ischemic hindlimb regions. These PEG-PAK micelles may lead to the development of a novel therapeutic modality for ischemic diseases based on an acid-degradable polymer specialized for gene delivery.


Assuntos
Quimiocina CXCL12/genética , Técnicas de Transferência de Genes , Terapia Genética/métodos , Isquemia/terapia , Micelas , Neovascularização Fisiológica , Animais , Apoptose , Plásticos Biodegradáveis/química , Células Cultivadas , Quimiocina CXCL12/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Membro Posterior/irrigação sanguínea , Humanos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Polietilenoglicóis/química , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
15.
Dev Dyn ; 246(4): 318-327, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28026128

RESUMO

The major goal in regenerative medicine is to repair and restore injured, diseased or aged tissue function, thereby promoting general health. As such, the field of regenerative medicine has great translational potential in undertaking many of the health concerns and needs that we currently face. In particular, hematopoietic and vascular systems supply oxygen and nutrients and thus play critical roles in tissue development and tissue regeneration. Additionally, tissue vasculature serves as a tissue stem cell niche and thus contributes to tissue homeostasis. Notably, hematopoietic and vascular systems are sensitive to injury and subject to regeneration. As such, successful hematopoietic and vascular regeneration is prerequisite for efficient tissue repair and organismal survival and health. Recent studies have established that the interplay among the ETS transcription factor ETV2, vascular endothelial growth factor, and its receptor VEGFR2/FLK1 is essential for hematopoietic and vascular development. Emerging studies also support the role of these three factors and possible interplay in hematopoietic and vascular regeneration. Comprehensive understanding of the molecular mechanisms involved in the regulation and function of these three factors may lead to more effective approaches in promoting tissue repair and regeneration. Developmental Dynamics 246:318-327, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Vasos Sanguíneos/crescimento & desenvolvimento , Sistema Hematopoético/crescimento & desenvolvimento , Proteínas Proto-Oncogênicas c-ets/fisiologia , Regeneração , Animais , Vasos Sanguíneos/fisiologia , Sistema Hematopoético/fisiologia , Humanos , Fatores de Transcrição/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/fisiologia
16.
EMBO Rep ; 16(5): 654-69, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25802403

RESUMO

The ETS factor ETV2 (aka ER71) is essential for the generation of the blood and vascular system, as ETV2 deficiency leads to a complete block in blood and endothelial cell formation and embryonic lethality in the mouse. However, the ETV2-mediated gene regulatory network and signaling governing hematopoietic and endothelial cell development are poorly understood. Here, we map ETV2 global binding sites and carry out in vitro differentiation of embryonic stem cells, and germ line and conditional knockout mouse studies to uncover mechanisms involved in the hemangiogenic fate commitment from mesoderm. We show that ETV2 binds to enhancers that specify hematopoietic and endothelial cell lineages. We find that the hemangiogenic progenitor population in the developing embryo can be identified as FLK1(high)PDGFRα(-). Notably, these hemangiogenic progenitors are exclusively sensitive to ETV2-dependent FLK1 signaling. Importantly, ETV2 turns on other Ets genes, thereby establishing an ETS hierarchy. Consequently, the hematopoietic and endothelial cell program initiated by ETV2 is maintained partly by other ETS factors through an ETS switching mechanism. These findings highlight the critical role that transient ETV2 expression plays in the regulation of hematopoietic and endothelial cell lineage specification and stability.


Assuntos
Células Sanguíneas/citologia , Células Sanguíneas/metabolismo , Diferenciação Celular , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Fatores de Transcrição/metabolismo , Animais , Sítios de Ligação , Diferenciação Celular/genética , Linhagem da Célula/genética , Imunoprecipitação da Cromatina , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Imunofenotipagem , Masculino , Camundongos , Camundongos Knockout , Motivos de Nucleotídeos , Especificidade de Órgãos/genética , Matrizes de Pontuação de Posição Específica , Ligação Proteica , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo
17.
Arterioscler Thromb Vasc Biol ; 36(1): 86-96, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26586661

RESUMO

OBJECTIVE: Comprehensive understanding of the mechanisms regulating angiogenesis might provide new strategies for angiogenic therapies for treating diverse physiological and pathological ischemic conditions. The E-twenty six (ETS) factor Ets variant 2 (ETV2; aka Ets-related protein 71) is essential for the formation of hematopoietic and vascular systems. Despite its indispensable function in vessel development, ETV2 role in adult angiogenesis has not yet been addressed. We have therefore investigated the role of ETV2 in vascular regeneration. APPROACH AND RESULTS: We used endothelial Etv2 conditional knockout mice and ischemic injury models to assess the role of ETV2 in vascular regeneration. Although Etv2 expression was not detectable under steady-state conditions, its expression was readily observed in endothelial cells after injury. Mice lacking endothelial Etv2 displayed impaired neovascularization in response to eye injury, wounding, or hindlimb ischemic injury. Lentiviral Etv2 expression in ischemic hindlimbs led to improved recovery of blood perfusion with enhanced vessel formation. After injury, fetal liver kinase 1 (Flk1), aka VEGFR2, expression and neovascularization were significantly upregulated by Etv2, whereas Flk1 expression and vascular endothelial growth factor response were significantly blunted in Etv2-deficient endothelial cells. Conversely, enforced Etv2 expression enhanced vascular endothelial growth factor-mediated endothelial sprouting from embryoid bodies. Lentiviral Flk1 expression rescued angiogenesis defects in endothelial Etv2 conditional knockout mice after hindlimb ischemic injury. Furthermore, Etv2(+/-); Flk1(+/-) double heterozygous mice displayed a more severe hindlimb ischemic injury response compared with Etv2(+/-) or Flk1(+/-) heterozygous mice, revealing an epistatic interaction between ETV2 and FLK1 in vascular regeneration. CONCLUSIONS: Our study demonstrates a novel obligatory role for the ETV2 in postnatal vascular repair and regeneration.


Assuntos
Proteínas Angiogênicas/metabolismo , Células Endoteliais/metabolismo , Isquemia/metabolismo , Músculo Esquelético/irrigação sanguínea , Neovascularização Fisiológica , Regeneração , Fatores de Transcrição/metabolismo , Proteínas Angiogênicas/deficiência , Proteínas Angiogênicas/genética , Animais , Células Cultivadas , Neovascularização de Coroide/genética , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/fisiopatologia , Modelos Animais de Doenças , Células Endoteliais/patologia , Regulação da Expressão Gênica , Técnicas de Transferência de Genes , Vetores Genéticos , Heterozigoto , Membro Posterior , Isquemia/genética , Isquemia/patologia , Isquemia/fisiopatologia , Isquemia/terapia , Lentivirus/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Fenótipo , Recuperação de Função Fisiológica , Transdução de Sinais , Pele/irrigação sanguínea , Fatores de Tempo , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Cicatrização
18.
Environ Sci Technol ; 51(13): 7624-7638, 2017 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-28441862

RESUMO

We evaluated the spatial-temporal dispersion of airborne nanomaterials during the use of spray consumer products and estimated the level of consumer inhalation exposure. A total of eight spray products including five propellant and three pump types were selected to evaluate the dispersion of airborne nanoparticles across time and space in a cleanroom which could control the background particles. Four products were advertised to contain silver and one contained titanium nanoparticles, while three products were specified no ENM but as being manufactured through the use of nanotechnology. We used direct-reading instruments with a thermodesorber unit to measure the particles (number, mass, surface area), as well as filter sampling to examine physicochemical characteristics. Sampling was conducted simultaneously at each location (1 m, near-field; 2, 3 m, far-field) by distance from the source. We estimated the inhaled doses at the breathing zone, and the doses deposited in each part of the respiratory tract using the experimental data and mathematical models. Nanoparticles released from the propellant sprays persisted in the air and dispersed over a large distance due to their small size (1466-5565 particles/cm3). Conversely, the pump sprays produced larger droplets that settled out of the air relatively close to the source, so the concentration was similar to background level (<200 particles/cm3). The estimates of inhalation exposure also suggested that exposure to nanoparticles was greater with propellant sprays (1.2 × 108 ± 4.0 × 107 particles/kgbw/day) than pump sprays (2.7 × 107 ± 6.5 × 106 particles/kgbw/day). We concluded that the propellant sprays create a higher risk of exposure than the pump sprays.


Assuntos
Exposição por Inalação , Nanopartículas , Aerossóis , Cosméticos , Produtos Domésticos , Humanos , Nanotecnologia , Tamanho da Partícula , Prata
19.
Int J Equity Health ; 16(1): 56, 2017 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-28359262

RESUMO

BACKGROUND: A steadily increasing pattern of breast cancer mortality has been reported in South Korea since the late 1980s. This paper explored the trends of educational inequalities of female breast cancer mortality between 1983 and 2012 in Korea, and conducted age-period-cohort (APC) analysis by educational level. METHODS: Age-standardized mortality rates of breast cancer per 100,000 person-years were calculated. Relative index of inequality (RII) for breast cancer mortality was used as an inequality measure. APC analyses were conducted using the Web tool for APC analysis provided by the Division of Cancer Epidemiology and Genetics at the U.S. National Cancer Institute. RESULTS: An increasing trend in breast cancer mortality among Korean women between 1983 and 2012 was due to the increased mortality of the lower education groups (i.e., no formal education or primary education and secondary education groups), not the highest education group. The breast cancer mortality was higher in women with a tertiary education than in women with no education or a primary education during 1983-1992, and the reverse was true in 1993-2012. Consequently, RII was changed from positive to negative associations in the early 2000s. The lower education groups had the increased breast cancer mortality and significant cohort and period effects between 1983 and 2012, whereas the highest group did not. CONCLUSIONS: APC analysis by socioeconomic position used in this study could provide an important clue for the causes on breast cancer mortality. The long-term monitoring of socioeconomic patterning in breast cancer risk factors is urgently needed.


Assuntos
Neoplasias da Mama/mortalidade , Escolaridade , Adulto , Efeito de Coortes , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Fatores de Risco , Classe Social , Fatores Socioeconômicos
20.
Mol Cell ; 36(4): 667-81, 2009 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-19941826

RESUMO

GATA factors interact with simple DNA motifs (WGATAR) to regulate critical processes, including hematopoiesis, but very few WGATAR motifs are occupied in genomes. Given the rudimentary knowledge of mechanisms underlying this restriction and how GATA factors establish genetic networks, we used ChIP-seq to define GATA-1 and GATA-2 occupancy genome-wide in erythroid cells. Coupled with genetic complementation analysis and transcriptional profiling, these studies revealed a rich collection of targets containing a characteristic binding motif of greater complexity than WGATAR. GATA factors occupied loci encoding multiple components of the Scl/TAL1 complex, a master regulator of hematopoiesis and leukemogenic target. Mechanistic analyses provided evidence for crossregulatory and autoregulatory interactions among components of this complex, including GATA-2 induction of the hematopoietic corepressor ETO-2 and an ETO-2-negative autoregulatory loop. These results establish fundamental principles underlying GATA factor mechanisms in chromatin and illustrate a complex network of considerable importance for the control of hematopoiesis.


Assuntos
Cromatina/metabolismo , Fator de Transcrição GATA1/metabolismo , Fator de Transcrição GATA2/metabolismo , Genoma Humano/genética , Sistema Hematopoético/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Imunoprecipitação da Cromatina , Biologia Computacional , Perfilação da Expressão Gênica , Loci Gênicos , Homeostase , Humanos , Células K562 , Leucemia/metabolismo , Leucemia/patologia , Camundongos , Complexos Multiproteicos/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Análise de Sequência de DNA , Proteína 1 de Leucemia Linfocítica Aguda de Células T
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