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1.
EMBO Rep ; 24(10): e55043, 2023 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-37551717

RESUMO

The cardiac endothelium influences ventricular chamber development by coordinating trabeculation and compaction. However, the endothelial-specific molecular mechanisms mediating this coordination are not fully understood. Here, we identify the Sox7 transcription factor as a critical cue instructing cardiac endothelium identity during ventricular chamber development. Endothelial-specific loss of Sox7 function in mice results in cardiac ventricular defects similar to non-compaction cardiomyopathy, with a change in the proportions of trabecular and compact cardiomyocytes in the mutant hearts. This phenotype is paralleled by abnormal coronary artery formation. Loss of Sox7 function disrupts the transcriptional regulation of the Notch pathway and connexins 37 and 40, which govern coronary arterial specification. Upon Sox7 endothelial-specific deletion, single-nuclei transcriptomics analysis identifies the depletion of a subset of Sox9/Gpc3-positive endocardial progenitor cells and an increase in erythro-myeloid cell lineages. Fate mapping analysis reveals that a subset of Sox7-null endothelial cells transdifferentiate into hematopoietic but not cardiomyocyte lineages. Our findings determine that Sox7 maintains cardiac endothelial cell identity, which is crucial to the cellular cross-talk that drives ventricular compaction and coronary artery development.


Assuntos
Vasos Coronários , Células Endoteliais , Animais , Camundongos , Vasos Coronários/metabolismo , Células Endoteliais/metabolismo , Miócitos Cardíacos/metabolismo , Regulação da Expressão Gênica , Endotélio/metabolismo , Fatores de Transcrição SOXF/genética , Fatores de Transcrição SOXF/metabolismo
2.
Nature ; 557(7705): 439-445, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29743679

RESUMO

In vertebrate hearts, the ventricular trabecular myocardium develops as a sponge-like network of cardiomyocytes that is critical for contraction and conduction, ventricular septation, papillary muscle formation and wall thickening through the process of compaction 1 . Defective trabeculation leads to embryonic lethality2-4 or non-compaction cardiomyopathy (NCC) 5 . There are divergent views on when and how trabeculation is initiated in different species. In zebrafish, trabecular cardiomyocytes extrude from compact myocardium 6 , whereas in chicks, chamber wall thickening occurs before overt trabeculation 7 . In mice, the onset of trabeculation has not been described, but is proposed to begin at embryonic day 9.0, when cardiomyocytes form radially oriented ribs 2 . Endocardium-myocardium communication is essential for trabeculation, and numerous signalling pathways have been identified, including Notch2,8 and Neuregulin (NRG) 4 . Late disruption of the Notch pathway causes NCC 5 . Whereas it has been shown that mutations in the extracellular matrix (ECM) genes Has2 and Vcan prevent the formation of trabeculae in mice9,10 and the matrix metalloprotease ADAMTS1 promotes trabecular termination 3 , the pathways involved in ECM dynamics and the molecular regulation of trabeculation during its early phases remain unexplored. Here we present a model of trabeculation in mice that integrates dynamic endocardial and myocardial cell behaviours and ECM remodelling, and reveal new epistatic relationships between the involved signalling pathways. NOTCH1 signalling promotes ECM degradation during the formation of endocardial projections that are critical for individualization of trabecular units, whereas NRG1 promotes myocardial ECM synthesis, which is necessary for trabecular rearrangement and growth. These systems interconnect through NRG1 control of Vegfa, but act antagonistically to establish trabecular architecture. These insights enabled the prediction of persistent ECM and cardiomyocyte growth in a mouse NCC model, providing new insights into the pathophysiology of congenital heart disease.


Assuntos
Coração/embriologia , Miocárdio/citologia , Miocárdio/metabolismo , Neuregulina-1/metabolismo , Organogênese , Receptor Notch1/metabolismo , Animais , Modelos Animais de Doenças , Endocárdio/citologia , Endocárdio/metabolismo , Matriz Extracelular/metabolismo , Cardiopatias/congênito , Cardiopatias/metabolismo , Camundongos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Neuregulina-1/genética , Receptor Notch1/genética , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
J Mol Cell Cardiol ; 163: 20-32, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34624332

RESUMO

Understanding the spatial gene expression and regulation in the heart is key to uncovering its developmental and physiological processes, during homeostasis and disease. Numerous techniques exist to gain gene expression and regulation information in organs such as the heart, but few utilize intuitive true-to-life three-dimensional representations to analyze and visualise results. Here we combined transcriptomics with 3D-modelling to interrogate spatial gene expression in the mammalian heart. For this, we microdissected and sequenced transcriptome-wide 18 anatomical sections of the adult mouse heart. Our study has unveiled known and novel genes that display complex spatial expression in the heart sub-compartments. We have also created 3D-cardiomics, an interface for spatial transcriptome analysis and visualization that allows the easy exploration of these data in a 3D model of the heart. 3D-cardiomics is accessible from http://3d-cardiomics.erc.monash.edu/.


Assuntos
Coração , Transcriptoma , Animais , Perfilação da Expressão Gênica/métodos , Mamíferos , Camundongos
4.
Development ; 146(4)2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787001

RESUMO

Congenital heart disease (CHD) is the most common type of birth defect. In recent years, research has focussed on identifying the genetic causes of CHD. However, only a minority of CHD cases can be attributed to single gene mutations. In addition, studies have identified different environmental stressors that promote CHD, but the additive effect of genetic susceptibility and environmental factors is poorly understood. In this context, we have investigated the effects of short-term gestational hypoxia on mouse embryos genetically predisposed to heart defects. Exposure of mouse embryos heterozygous for Tbx1 or Fgfr1/Fgfr2 to hypoxia in utero increased the incidence and severity of heart defects while Nkx2-5+/- embryos died within 2 days of hypoxic exposure. We identified the molecular consequences of the interaction between Nkx2-5 and short-term gestational hypoxia, which suggest that reduced Nkx2-5 expression and a prolonged hypoxia-inducible factor 1α response together precipitate embryo death. Our study provides insight into the causes of embryo loss and variable penetrance of monogenic CHD, and raises the possibility that cases of foetal death and CHD in humans could be caused by similar gene-environment interactions.


Assuntos
Interação Gene-Ambiente , Cardiopatias Congênitas/genética , Coração/embriologia , Proteína Homeobox Nkx-2.5/genética , Proteínas de Homeodomínio/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Animais , Apoptose , Proliferação de Células , Embrião de Mamíferos/metabolismo , Feminino , Predisposição Genética para Doença , Coração/diagnóstico por imagem , Heterozigoto , Proteína Homeobox Nkx-2.5/fisiologia , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oxigênio/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Proteínas com Domínio T/genética , Fatores de Tempo
5.
Circ Res ; 118(10): 1480-97, 2016 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-27056911

RESUMO

RATIONALE: The Notch signaling pathway is crucial for primitive cardiac valve formation by epithelial-mesenchymal transition, and NOTCH1 mutations cause bicuspid aortic valve; however, the temporal requirement for the various Notch ligands and receptors during valve ontogeny is poorly understood. OBJECTIVE: The aim of this study is to determine the functional specificity of Notch in valve development. METHODS AND RESULTS: Using cardiac-specific conditional targeted mutant mice, we find that endothelial/endocardial deletion of Mib1-Dll4-Notch1 signaling, possibly favored by Manic-Fringe, is specifically required for cardiac epithelial-mesenchymal transition. Mice lacking endocardial Jag1, Notch1, or RBPJ displayed enlarged valve cusps, bicuspid aortic valve, and septal defects, indicating that endocardial Jag1 to Notch1 signaling is required for post-epithelial-mesenchymal transition valvulogenesis. Valve dysmorphology was associated with increased mesenchyme proliferation, indicating that Jag1-Notch1 signaling restricts mesenchyme cell proliferation non-cell autonomously. Gene profiling revealed upregulated Bmp signaling in Jag1-mutant valves, providing a molecular basis for the hyperproliferative phenotype. Significantly, the negative regulator of mesenchyme proliferation, Hbegf, was markedly reduced in Jag1-mutant valves. Hbegf expression in embryonic endocardial cells could be readily activated through a RBPJ-binding site, identifying Hbegf as an endocardial Notch target. Accordingly, addition of soluble heparin-binding EGF-like growth factor to Jag1-mutant outflow tract explant cultures rescued the hyperproliferative phenotype. CONCLUSIONS: During cardiac valve formation, Dll4-Notch1 signaling leads to epithelial-mesenchymal transition and cushion formation. Jag1-Notch1 signaling subsequently restrains Bmp-mediated valve mesenchyme proliferation by sustaining Hbegf-EGF receptor signaling. Our studies identify a mechanism of signaling cross talk during valve morphogenesis involved in the origin of congenital heart defects associated with reduced NOTCH function.


Assuntos
Valva Mitral/metabolismo , Morfogênese , Receptor Notch1/genética , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas de Ligação ao Cálcio , Transição Epitelial-Mesenquimal , Receptores ErbB/metabolismo , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Valva Mitral/anormalidades , Valva Mitral/embriologia , Receptor Notch1/metabolismo , Regulação para Cima
6.
Nat Commun ; 15(1): 6480, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39090108

RESUMO

Regulatory T cells (Tregs) are key immune regulators that have shown promise in enhancing cardiac repair post-MI, although the mechanisms remain elusive. Here, we show that rapidly increasing Treg number in the circulation post-MI via systemic administration of exogenous Tregs improves cardiac function in male mice, by limiting cardiomyocyte death and reducing fibrosis. Mechanistically, exogenous Tregs quickly home to the infarcted heart and adopt an injury-specific transcriptome that mediates repair by modulating monocytes/macrophages. Specially, Tregs lead to a reduction in pro-inflammatory Ly6CHi CCR2+ monocytes/macrophages accompanied by a rapid shift of macrophages towards a pro-repair phenotype. Additionally, exogenous Treg-derived factors, including nidogen-1 and IL-10, along with a decrease in cardiac CD8+ T cell number, mediate the reduction of the pro-inflammatory monocyte/macrophage subset in the heart. Supporting the pivotal role of IL-10, exogenous Tregs knocked out for IL-10 lose their pro-repair capabilities. Together, this study highlights the beneficial use of a Treg-based therapeutic approach for cardiac repair with important mechanistic insights that could facilitate the development of novel immunotherapies for MI.


Assuntos
Interleucina-10 , Macrófagos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio , Linfócitos T Reguladores , Animais , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Linfócitos T Reguladores/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Interleucina-10/metabolismo , Interleucina-10/genética , Fenótipo , Miocárdio/patologia , Miocárdio/imunologia , Miocárdio/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/imunologia , Fibrose , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Camundongos Knockout
7.
Elife ; 122023 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-37272612

RESUMO

Unlike single-gene mutations leading to Mendelian conditions, common human diseases are likely to be emergent phenomena arising from multilayer, multiscale, and highly interconnected interactions. Atrial and ventricular septal defects are the most common forms of cardiac congenital anomalies in humans. Atrial septal defects (ASD) show an open communication between the left and right atria postnatally, potentially resulting in serious hemodynamic consequences if untreated. A milder form of atrial septal defect, patent foramen ovale (PFO), exists in about one-quarter of the human population, strongly associated with ischaemic stroke and migraine. The anatomic liabilities and genetic and molecular basis of atrial septal defects remain unclear. Here, we advance our previous analysis of atrial septal variation through quantitative trait locus (QTL) mapping of an advanced intercross line (AIL) established between the inbred QSi5 and 129T2/SvEms mouse strains, that show extremes of septal phenotypes. Analysis resolved 37 unique septal QTL with high overlap between QTL for distinct septal traits and PFO as a binary trait. Whole genome sequencing of parental strains and filtering identified predicted functional variants, including in known human congenital heart disease genes. Transcriptome analysis of developing septa revealed downregulation of networks involving ribosome, nucleosome, mitochondrial, and extracellular matrix biosynthesis in the 129T2/SvEms strain, potentially reflecting an essential role for growth and cellular maturation in septal development. Analysis of variant architecture across different gene features, including enhancers and promoters, provided evidence for the involvement of non-coding as well as protein-coding variants. Our study provides the first high-resolution picture of genetic complexity and network liability underlying common congenital heart disease, with relevance to human ASD and PFO.


Assuntos
Isquemia Encefálica , Forame Oval Patente , Cardiopatias Congênitas , Acidente Vascular Cerebral , Humanos , Camundongos , Animais , Forame Oval Patente/genética , Fenótipo , Perfilação da Expressão Gênica
9.
J Am Coll Cardiol ; 75(17): 2169-2188, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32354384

RESUMO

The extracellular matrix (ECM) is the noncellular component of tissues in the cardiovascular system and other organs throughout the body. It is formed of filamentous proteins, proteoglycans, and glycosaminoglycans, which extensively interact and whose structure and dynamics are modified by cross-linking, bridging proteins, and cleavage by matrix degrading enzymes. The ECM serves important structural and regulatory roles in establishing tissue architecture and cellular function. The ECM of the developing heart has unique properties created by its emerging contractile nature; similarly, ECM lining blood vessels is highly elastic in order to sustain the basal and pulsatile forces imposed on their walls throughout life. In this part 1 of a 4-part JACC Focus Seminar, we focus on the role, function, and basic biology of the ECM in both heart development and in the adult.


Assuntos
Cardiologia/educação , Sistema Cardiovascular/citologia , Sistema Cardiovascular/crescimento & desenvolvimento , Matriz Extracelular/fisiologia , Animais , Sistema Cardiovascular/metabolismo , Homeostase/fisiologia , Humanos , Proteoglicanas/metabolismo
10.
Cardiovasc Res ; 115(12): 1716-1731, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504268

RESUMO

Endothelial-to-mesenchymal transition (EndMT) is the process wherein endothelial cells lose their typical endothelial cell markers and functions and adopt a mesenchymal-like phenotype. EndMT is required for development of the cardiac valves, the pulmonary and dorsal aorta, and arterial maturation, but activation of the EndMT programme during adulthood is believed to contribute to several pathologies including organ fibrosis, cardiovascular disease, and cancer. Non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, modulate EndMT during development and disease. Here, we review the mechanisms by which non-coding RNAs facilitate or inhibit EndMT during development and disease and provide a perspective on the therapeutic application of non-coding RNAs to treat fibroproliferative cardiovascular disease.


Assuntos
Doenças Cardiovasculares/metabolismo , Células Endoteliais/metabolismo , Transição Epitelial-Mesenquimal , RNA não Traduzido/metabolismo , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/terapia , Células Endoteliais/patologia , Transição Epitelial-Mesenquimal/genética , Regulação da Expressão Gênica , Humanos , Fenótipo , RNA não Traduzido/genética , RNA não Traduzido/uso terapêutico , Transdução de Sinais
11.
Cell Rep ; 23(11): 3312-3326, 2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29898401

RESUMO

Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced resistance is observed for three clinically relevant inhibitors. To address this clinical problem, we have mapped tumor hypoxia by both immunofluorescence and phosphorescence lifetime imaging of oxygen-sensitive nanoparticles and demonstrate that these hypoxic regions move transiently around the tumor. To overlay this microenvironmental information with drug response, we applied a FRET biosensor for Akt activity, which is a key effector of the PI3K pathway. Performing dual intravital imaging of drug response in different tumor compartments, we demonstrate an improved drug response to a combination therapy using the dual mTORC1/2 inhibitor AZD2014 with the hypoxia-activated pro-drug TH-302.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Animais , Benzamidas , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Transferência Ressonante de Energia de Fluorescência , Humanos , Hipóxia , Microscopia Intravital/métodos , Camundongos , Camundongos Endogâmicos BALB C , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Nanopartículas/química , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Mostardas de Fosforamida/farmacologia , Mostardas de Fosforamida/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas , Transdução de Sinais/efeitos dos fármacos , Transplante Heterólogo , Microambiente Tumoral
12.
Nat Commun ; 8(1): 578, 2017 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-28924218

RESUMO

Coronary artery anomalies may cause life-threatening cardiac complications; however, developmental mechanisms underpinning coronary artery formation remain ill-defined. Here we identify an angiogenic cell population for coronary artery formation in mice. Regulated by a DLL4/NOTCH1/VEGFA/VEGFR2 signaling axis, these angiogenic cells generate mature coronary arteries. The NOTCH modulator POFUT1 critically regulates this signaling axis. POFUT1 inactivation disrupts signaling events and results in excessive angiogenic cell proliferation and plexus formation, leading to anomalous coronary arteries, myocardial infarction and heart failure. Simultaneous VEGFR2 inactivation fully rescues these defects. These findings show that dysregulated angiogenic precursors link coronary anomalies to ischemic heart disease.Though coronary arteries are crucial for heart function, the mechanisms guiding their formation are largely unknown. Here, Wang et al. identify a unique, endocardially-derived angiogenic precursor cell population for coronary artery formation in mice and show that a DLL4/NOTCH1/VEGFA/VEGFR2 signaling axis is key for coronary artery development.


Assuntos
Doença da Artéria Coronariana/genética , Fucosiltransferases/genética , Neovascularização Fisiológica/genética , Transdução de Sinais/genética , Animais , Proliferação de Células/genética , Doença da Artéria Coronariana/fisiopatologia , Ecocardiografia , Fucosiltransferases/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/deficiência , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/deficiência , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética
13.
Cell Rep ; 21(1): 274-288, 2017 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-28978480

RESUMO

The small GTPase RhoA is involved in a variety of fundamental processes in normal tissue. Spatiotemporal control of RhoA is thought to govern mechanosensing, growth, and motility of cells, while its deregulation is associated with disease development. Here, we describe the generation of a RhoA-fluorescence resonance energy transfer (FRET) biosensor mouse and its utility for monitoring real-time activity of RhoA in a variety of native tissues in vivo. We assess changes in RhoA activity during mechanosensing of osteocytes within the bone and during neutrophil migration. We also demonstrate spatiotemporal order of RhoA activity within crypt cells of the small intestine and during different stages of mammary gestation. Subsequently, we reveal co-option of RhoA activity in both invasive breast and pancreatic cancers, and we assess drug targeting in these disease settings, illustrating the potential for utilizing this mouse to study RhoA activity in vivo in real time.


Assuntos
Técnicas Biossensoriais , Transferência Ressonante de Energia de Fluorescência/métodos , Microscopia Intravital/métodos , Imagem com Lapso de Tempo/métodos , Proteínas rho de Ligação ao GTP/genética , Animais , Antineoplásicos/farmacologia , Osso e Ossos/citologia , Osso e Ossos/metabolismo , Movimento Celular/efeitos dos fármacos , Dasatinibe/farmacologia , Cloridrato de Erlotinib/farmacologia , Feminino , Transferência Ressonante de Energia de Fluorescência/instrumentação , Regulação da Expressão Gênica , Intestino Delgado/metabolismo , Intestino Delgado/ultraestrutura , Microscopia Intravital/instrumentação , Glândulas Mamárias Animais/irrigação sanguínea , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/ultraestrutura , Neoplasias Mamárias Experimentais/irrigação sanguínea , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/ultraestrutura , Mecanotransdução Celular , Camundongos , Camundongos Transgênicos , Neutrófilos/metabolismo , Neutrófilos/ultraestrutura , Osteócitos/metabolismo , Osteócitos/ultraestrutura , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/ultraestrutura , Imagem com Lapso de Tempo/instrumentação , Proteínas rho de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP
14.
Sci Transl Med ; 9(384)2017 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-28381539

RESUMO

The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer.


Assuntos
Progressão da Doença , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Paclitaxel Ligado a Albumina/farmacologia , Paclitaxel Ligado a Albumina/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Técnicas Biossensoriais , Proteína Quinase CDC2/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Matriz Extracelular/metabolismo , Humanos , Fígado/patologia , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Quinases Associadas a rho/metabolismo , Quinases da Família src/metabolismo , Gencitabina
16.
Nat Cell Biol ; 18(1): 7-20, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26641715

RESUMO

Ventricular chambers are essential for the rhythmic contraction and relaxation occurring in every heartbeat throughout life. Congenital abnormalities in ventricular chamber formation cause severe human heart defects. How the early trabecular meshwork of myocardial fibres forms and subsequently develops into mature chambers is poorly understood. We show that Notch signalling first connects chamber endocardium and myocardium to sustain trabeculation, and later coordinates ventricular patterning and compaction with coronary vessel development to generate the mature chamber, through a temporal sequence of ligand signalling determined by the glycosyltransferase manic fringe (MFng). Early endocardial expression of MFng promotes Dll4-Notch1 signalling, which induces trabeculation in the developing ventricle. Ventricular maturation and compaction require MFng and Dll4 downregulation in the endocardium, which allows myocardial Jag1 and Jag2 signalling to Notch1 in this tissue. Perturbation of this signalling equilibrium severely disrupts heart chamber formation. Our results open a new research avenue into the pathogenesis of cardiomyopathies.


Assuntos
Ventrículos do Coração/metabolismo , Organogênese/fisiologia , Receptores Notch/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Ligação ao Cálcio/metabolismo , Células Cultivadas , Glucosiltransferases , Ventrículos do Coração/embriologia , Hexosiltransferases/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ligantes , Proteínas de Membrana/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais/fisiologia
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