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1.
Cell ; 155(1): 215-27, 2013 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-24074870

RESUMO

Hematopoietic stem cells (HSCs) develop from a specialized subpopulation of endothelial cells known as hemogenic endothelium (HE). Although the HE origin of HSCs is now well established in different species, the signaling pathways that control this transition remain poorly understood. Here, we show that activation of retinoic acid (RA) signaling in aorta-gonad-mesonephros-derived HE ex vivo dramatically enhanced its HSC potential, whereas conditional inactivation of the RA metabolizing enzyme retinal dehydrogenase 2 in VE-cadherin expressing endothelial cells in vivo abrogated HSC development. Wnt signaling completely blocked the HSC inductive effects of RA modulators, whereas inhibition of the pathway promoted the development of HSCs in the absence of RA signaling. Collectively, these findings position RA and Wnt signaling as key regulators of HSC development and in doing so provide molecular insights that will aid in developing strategies for their generation from pluripotent stem cells.


Assuntos
Células-Tronco Hematopoéticas/citologia , Tretinoína/metabolismo , Aldeído Oxirredutases/metabolismo , Animais , Aorta/citologia , Aorta/embriologia , Regulação para Baixo , Embrião de Mamíferos , Gônadas/citologia , Gônadas/embriologia , Células-Tronco Hematopoéticas/metabolismo , Mesonefro/citologia , Camundongos , Receptores do Ácido Retinoico/metabolismo , Via de Sinalização Wnt
2.
Development ; 149(2)2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34919128

RESUMO

Hematopoietic stem and progenitor cells (HSPCs) are multipotent cells that self-renew or differentiate to establish the entire blood hierarchy. HSPCs arise from the hemogenic endothelium of the dorsal aorta (DA) during development in a process called endothelial-to-hematopoietic transition. The factors and signals that control HSPC fate decisions from the hemogenic endothelium are not fully understood. We found that Vegfc has a role in HSPC emergence from the zebrafish DA. Using time-lapse live imaging, we show that some HSPCs in the DA of vegfc loss-of-function embryos display altered cellular behavior. Instead of typical budding from the DA, emergent HSPCs exhibit crawling behavior similar to myeloid cells. This was confirmed by increased myeloid cell marker expression in the ventral wall of the DA and the caudal hematopoietic tissue. This increase in myeloid cells corresponded with a decrease in HSPCs that persisted into larval stages. Together, our data suggest that Vegfc regulates HSPC emergence in the hemogenic endothelium, in part by suppressing a myeloid cell fate. Our study provides a potential signal for modulation of HSPC fate in stem cell differentiation protocols.


Assuntos
Aorta/citologia , Diferenciação Celular , Células-Tronco Hematopoéticas/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Aorta/embriologia , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/embriologia , Células-Tronco Hematopoéticas/citologia , Mutação com Perda de Função , Células Mieloides/citologia , Células Mieloides/metabolismo , Fator C de Crescimento do Endotélio Vascular/genética , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
3.
EMBO J ; 39(8): e104270, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32149421

RESUMO

Hematopoietic stem cells (HSCs) develop from the hemogenic endothelium in cluster structures that protrude into the embryonic aortic lumen. Although much is known about the molecular characteristics of the developing hematopoietic cells, we lack a complete understanding of their origin and the three-dimensional organization of the niche. Here, we use advanced live imaging techniques of organotypic slice cultures, clonal analysis, and mathematical modeling to show the two-step process of intra-aortic hematopoietic cluster (IACH) formation. First, a hemogenic progenitor buds up from the endothelium and undergoes division forming the monoclonal core of the IAHC. Next, surrounding hemogenic cells are recruited into the IAHC, increasing their size and heterogeneity. We identified the Notch ligand Dll4 as a negative regulator of the recruitment phase of IAHC. Blocking of Dll4 promotes the entrance of new hemogenic Gfi1+ cells into the IAHC and increases the number of cells that acquire HSC activity. Mathematical modeling based on our data provides estimation of the cluster lifetime and the average recruitment time of hemogenic cells to the cluster under physiologic and Dll4-inhibited conditions.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Aorta/embriologia , Proteínas de Ligação ao Cálcio/genética , Divisão Celular , Células Progenitoras Endoteliais/fisiologia , Feminino , Hemangioblastos/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Teóricos
4.
Dev Biol ; 476: 1-10, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33757801

RESUMO

Congenital heart defects (CHDs) affecting the cardiac outflow tract (OFT) constitute a significant cause of morbidity and mortality. The OFT develops from migratory cell populations which include the cardiac neural crest cells (cNCCs) and secondary heart field (SHF) derived myocardium and endocardium. The related transcription factors HAND1 and HAND2 have been implicated in human CHDs involving the OFT. Although Hand1 is expressed within the OFT, Hand1 NCC-specific conditional knockout mice (H1CKOs) are viable. Here we show that these H1CKOs present a low penetrance of OFT phenotypes, whereas SHF-specific Hand1 ablation does not reveal any cardiac phenotypes. Further, HAND1 and HAND2 appear functionally redundant within the cNCCs, as a reduction/ablation of Hand2 on an NCC-specific H1CKO background causes pronounced OFT defects. Double conditional Hand1 and Hand2 NCC knockouts exhibit persistent truncus arteriosus (PTA) with 100% penetrance. NCC lineage-tracing and Sema3c in situ mRNA expression reveal that Sema3c-expressing cells are mis-localized, resulting in a malformed septal bridge within the OFTs of H1CKO;H2CKO embryos. Interestingly, Hand1 and Hand2 also genetically interact within the SHF, as SHF H1CKOs on a heterozygous Hand2 background exhibit Ventricular Septal Defects (VSDs) with incomplete penetrance. Previously, we identified a BMP, HAND2, and GATA-dependent Hand1 OFT enhancer sufficient to drive reporter gene expression within the nascent OFT and aorta. Using these transcription inputs as a probe, we identify a novel Hand2 OFT enhancer, suggesting that a conserved BMP-GATA dependent mechanism transcriptionally regulates both HAND factors. These findings support the hypothesis that HAND factors interpret BMP signaling within the cNCCs to cooperatively coordinate OFT morphogenesis.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cardiopatias Congênitas/genética , Coração/embriologia , Animais , Aorta/embriologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Débito Cardíaco/fisiologia , Movimento Celular/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Cardiopatias Congênitas/metabolismo , Proteínas de Homeodomínio/metabolismo , Camundongos , Camundongos Knockout , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Crista Neural/metabolismo , Fenótipo , Transdução de Sinais/genética , Fatores de Transcrição/genética
5.
Blood ; 136(7): 831-844, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32457985

RESUMO

The defined location of a stem cell within a niche regulates its fate, behavior, and molecular identity via a complex extrinsic regulation that is far from being fully elucidated. To explore the molecular characteristics and key components of the aortic microenvironment, where the first hematopoietic stem cells are generated during development, we performed genome-wide RNA tomography sequencing on zebrafish, chicken, mouse, and human embryos. The resulting anterior-posterior and dorsal-ventral transcriptional maps provided a powerful resource for exploring genes and regulatory pathways active in the aortic microenvironment. By performing interspecies comparative RNA sequencing analyses and functional assays, we explored the complexity of the aortic microenvironment landscape and the fine-tuning of various factors interacting to control hematopoietic stem cell generation, both in time and space in vivo, including the ligand-receptor couple ADM-RAMP2 and SVEP1. Understanding the regulatory function of the local environment will pave the way for improved stem cell production in vitro and clinical cell therapy.


Assuntos
Aorta/embriologia , Células-Tronco Hematopoéticas/citologia , RNA/análise , Nicho de Células-Tronco/genética , Tomografia , Animais , Animais Geneticamente Modificados , Aorta/citologia , Rastreamento de Células/métodos , Embrião de Galinha , Embrião de Mamíferos , Embrião não Mamífero , Regulação da Expressão Gênica no Desenvolvimento , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , RNA/genética , Análise de Sequência de RNA/métodos , Análise de Célula Única , Especificidade da Espécie , Tomografia/métodos , Tomografia/veterinária , Peixe-Zebra/embriologia , Peixe-Zebra/genética
6.
J Vasc Res ; 59(1): 61-68, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34535602

RESUMO

Increasing evidence suggests that maternal cholesterol represents an important risk factor for atherosclerotic disease in offspring already during pregnancy, although the underlying mechanisms have not yet been elucidated. Eighteen human fetal aorta samples were collected from the spontaneously aborted fetuses of normal cholesterolemic and hypercholesterolemic mothers. Maternal total cholesterol levels were assessed during hospitalization. DNA methylation profiling of the whole SREBF2 gene CpG island was performed (p value <0.05). The Mann-Whitney U test was used for comparison between the 2 groups. For the first time, our study revealed that in fetal aortas obtained from hypercholesterolemic mothers, the SREBF2 gene shows 4 significant differentially hypermethylated sites in the 5'UTR-CpG island. This finding indicates that more effective long-term primary cardiovascular prevention programs need to be designed for the offspring of mothers with hypercholesterolemia. Further studies should be conducted to clarify the epigenetic mechanisms underlying the association between early atherogenesis and maternal hypercholesterolemia during pregnancy.


Assuntos
Aorta/metabolismo , Metilação de DNA , Epigênese Genética , Hipercolesterolemia/genética , Complicações na Gravidez/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Aorta/embriologia , Biomarcadores/sangue , Estudos de Casos e Controles , Colesterol/sangue , Epigenoma , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Idade Gestacional , Humanos , Hipercolesterolemia/sangue , Gravidez , Complicações na Gravidez/sangue , Mapas de Interação de Proteínas
7.
Development ; 145(2)2018 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-29358215

RESUMO

Hematopoietic stem cells (HSCs) develop in discrete anatomical niches, migrating during embryogenesis from the aorta-gonad-mesonephros (AGM) region to the fetal liver, and finally to the bone marrow, where most HSCs reside throughout adult life. These niches provide supportive microenvironments that specify, expand and maintain HSCs. Understanding the constituents and molecular regulation of HSC niches is of considerable importance as it could shed new light on the mechanistic principles of HSC emergence and maintenance, and provide novel strategies for regenerative medicine. However, controversy exists concerning the cellular complexity of the bone marrow niche, and our understanding of the different HSC niches during development remains limited. In this Review, we summarize and discuss what is known about the heterogeneity of the HSC niches at distinct stages of their ontogeny, from the embryo to the adult bone marrow, drawing predominantly on data from mouse studies.


Assuntos
Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Nicho de Células-Tronco/fisiologia , Envelhecimento/patologia , Envelhecimento/fisiologia , Animais , Aorta/embriologia , Linhagem da Célula , Feminino , Gônadas/embriologia , Neoplasias Hematológicas/patologia , Sistema Hematopoético/embriologia , Humanos , Masculino , Mesonefro/embriologia , Camundongos , Placenta/citologia , Placenta/fisiologia , Gravidez , Células Estromais/citologia , Células Estromais/fisiologia , Sistema Nervoso Simpático/embriologia , Sistema Nervoso Simpático/fisiologia
8.
Ultrasound Obstet Gynecol ; 58(6): 846-852, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33998082

RESUMO

OBJECTIVE: To investigate prenatal changes in cardiac biometric and flow parameters in fetuses with bicuspid aortic valve (BAV) diagnosed neonatally compared with controls with normal cardiac anatomy. METHODS: This analysis was conducted as part of the Copenhagen Baby Heart Study, a multicenter cohort study of 25 556 neonates that underwent second-trimester anomaly scan at 18 + 0 to 22 + 6 weeks' gestation and neonatal echocardiography within 4 weeks after birth, in Copenhagen University Hospital Herlev, Hvidovre Hospital and Rigshospitalet in greater Copenhagen, between April 2016 and October 2018. From February 2017 (Rigshospitalet) and September 2017 (Herlev and Hvidovre hospitals), the protocol for second-trimester screening of the heart was extended to include evaluation of the four-chamber view, with assessment of flow across the atrioventricular valves, sagittal view of the aortic arch and midumbilical artery and ductus venosus pulsatility indices. All images were evaluated by two investigators, and cardiac biometric and flow parameters were measured and compared between cases with BAV and controls. All cases with neonatal BAV were assessed by a specialist. Maternal characteristics and first- and second-trimester biomarkers were also compared between the two groups. RESULTS: Fifty-five infants with BAV and 8316 controls with normal cardiac anatomy were identified during the study period and assessed using the extended prenatal cardiac imaging protocol. There were three times as many mothers who smoked before pregnancy in the group with BAV as in the control group (9.1% vs 2.7%; P = 0.003). All other baseline characteristics were similar between the two groups. Fetuses with BAV, compared with controls, had a significantly larger diameter of the aorta at the level of the aortic valve (3.1 mm vs 3.0 mm (mean difference, 0.12 mm (95% CI, 0.03-0.21 mm))) and the pulmonary artery at the level of the pulmonary valve (4.1 mm vs 3.9 mm (mean difference, 0.15 mm (95% CI, 0.03-0.28 mm))). Following conversion of the diameter measurements of the aorta and pulmonary artery to Z-scores and Bonferroni correction, the differences between the two groups were no longer statistically significant. Pregnancy-associated plasma protein-A (PAPP-A) multiples of the median (MoM) was significantly lower in the BAV group than in the control group (0.85 vs 1.03; P = 0.04). CONCLUSIONS: Our findings suggest that fetuses with BAV may have a larger aortic diameter at the level of the aortic valve, measured in the left-ventricular-outflow-tract view, and a larger pulmonary artery diameter at the level of the pulmonary valve, measured in the three-vessel view, at 20 weeks' gestation. Moreover, we found an association of maternal smoking and low PAPP-A MoM with BAV. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.


Assuntos
Doença da Válvula Aórtica Bicúspide/diagnóstico , Biometria , Ecocardiografia , Coração Fetal/fisiopatologia , Ultrassonografia Pré-Natal , Adulto , Aorta/diagnóstico por imagem , Aorta/embriologia , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/embriologia , Doença da Válvula Aórtica Bicúspide/embriologia , Circulação Sanguínea , Estudos de Casos e Controles , Feminino , Coração Fetal/diagnóstico por imagem , Coração Fetal/embriologia , Feto/irrigação sanguínea , Feto/diagnóstico por imagem , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Gravidez , Segundo Trimestre da Gravidez , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/embriologia , Valva Pulmonar/diagnóstico por imagem , Valva Pulmonar/embriologia
9.
J Mol Cell Cardiol ; 147: 62-73, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32777295

RESUMO

BACKGROUND: During the formation of the coronary artery stem, endothelial strands from the endothelial progenitor pool surrounding the conotruncus penetrate into the aortic wall. Vascular endothelial growth factors (VEGFs) as well as CXCL12/CXCR4 signaling are thought to play a role in the formation of the coronary stem. However, the mechanisms regulating how endothelial strands exclusively invade into the aorta remain unknown. METHODS AND RESULTS: Immunohistochemistry showed that before the formation of endothelial strands, Sema3a was highly expressed in endothelial progenitors surrounding the great arteries. At the onset of/during invasion of endothelial strands into the aorta, Sema3a was downregulated and CXCR4 was upregulated in the endothelial strands. In situ hybridization showed that Cxcl12 was highly expressed in the aortic wall compared with in the pulmonary artery. Using avian embryonic hearts, we established two types of endothelial penetration assay, in which coronary endothelial strands preferentially invaded into the aorta in culture. Sema3a blocking peptide induced an excess number of endothelial strands penetrating into the pulmonary artery, whereas recombinant Sema3a inhibited the formation of endothelial strands. In cultured coronary endothelial progenitors, recombinant VEGF protein induced CXCR4-positive endothelial strands, which were capable of being attracted by CXCL12-impregnated beads. Monoazo rhodamine detected that hypoxia was predominant in aortic/subaortic region in ovo and hypoxic condition downregulated the expression of Sema3a in culture. CONCLUSION: Results suggested that hypoxia in the aortic region downregulates the expression of Sema3a, thereby enhancing VEGF activity to induce the formation of CXCR4-positive endothelial strands, which are subsequently attracted into the Cxcl12-positive aortic wall to connect the aortic lumen.


Assuntos
Quimiocina CXCL12/metabolismo , Vasos Coronários/metabolismo , Regulação para Baixo/genética , Hipóxia/genética , Receptores CXCR4/metabolismo , Animais , Aorta/embriologia , Aorta/metabolismo , Células Cultivadas , Galinhas , Vasos Coronários/embriologia , Células Endoteliais/metabolismo , Codorniz/embriologia , Semaforina-3A/metabolismo , Regulação para Cima
10.
Dev Biol ; 456(1): 8-16, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400307

RESUMO

We describe a method by which early developing vasculature can be gene-manipulated independently of the heart in a spatio-temporally controlled manner. Lipofectamine 2000 or 3000, an easy-to-use lipid reagent, has been found to yield a high efficiency of transfection when co-injected with GFP DNA within a critical range of lipid concentration. By exploiting developmentally changing patterns of vasculature and blood flow, we have succeed in controlling the site of transfection: injection with a lipid-DNA cocktail into the heart before or after the blood circulation starts results in a limited and widely spread patterns of transfection, respectively. Furthermore, a cocktail injection into the right dorsal aorta leads to transgenesis of the right half of embryonic vasculature. In addition, this method combined with the siRNA technique has allowed, for the first time, to knockdown the endogenous expression of VE-cadherin (also called Cdh5), which has been implicated in assembly of nasant blood vessels: when Cah5 siRNA is injected into the right dorsal aorta, pronounced defects in the right half of vasculature are observed without heart defects. Whereas infusion-mediated gene transfection method has previously been reported using lipid reagents that were elaborately prepared on their own, Lipofectamine is an easy-use reagent with no requirement of special expertise. The methods reported here would overcome shortcomings of conventional vascular-transgenic animals, such as mice and zebrafish, in which pan-endothelial enhancer-driven transgenesis often leads to the heart malformation, which, in turn, indirectly affects peripheral vasculature due to flow defects. Since a variety of subtypes in vasculature have increasingly been appreciated, the spatio-temporally controllable gene manipulation described in this study offers a powerful tool to understand how the vasculature is established at the molecular level.


Assuntos
Sistema Cardiovascular/embriologia , Neovascularização Fisiológica/genética , Transfecção/métodos , Animais , Aorta/embriologia , Aorta/metabolismo , Sistema Cardiovascular/metabolismo , Embrião de Galinha , Galinhas/genética , Técnicas de Transferência de Genes , Terapia Genética , Coração/embriologia , Lipídeos/farmacologia , RNA de Cadeia Dupla , RNA Interferente Pequeno
11.
Development ; 144(13): 2352-2363, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28526756

RESUMO

Hematopoietic stem cells (HSCs), which are responsible for blood cell production, are generated during embryonic development. Human and chicken embryos share features that position the chicken as a reliable and accessible alternative model to study developmental hematopoiesis. However, the existence of HSCs has never been formally proven in chicken embryos. Here, we have established a complete cartography and quantification of hematopoietic cells in the aorta during development. We demonstrate the existence of bona fide HSCs, originating from the chicken embryo aorta (and not the yolk sac, allantois or head), through an in vivo transplantation assay. Embryos transplanted in ovo with GFP embryonic tissues on the chorio-allantoic membrane provided multilineage reconstitution in adulthood. Historically, most breakthrough discoveries in the field of developmental hematopoiesis were first made in birds and later extended to mammals. Our study sheds new light on the avian model as a valuable system to study HSC production and regulation in vivo.


Assuntos
Linhagem da Célula , Galinhas/metabolismo , Células-Tronco Hematopoéticas/citologia , Animais , Aorta/citologia , Aorta/embriologia , Linfócitos B/citologia , Proliferação de Células , Sobrevivência Celular , Embrião de Galinha , Membrana Corioalantoide/transplante , Desenvolvimento Embrionário , Proteínas de Fluorescência Verde/metabolismo , Hematopoese , Saco Vitelino/embriologia
12.
Development ; 144(1): 115-127, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27913637

RESUMO

Mural cells (vascular smooth muscle cells and pericytes) play an essential role in the development of the vasculature, promoting vascular quiescence and long-term vessel stabilization through their interactions with endothelial cells. However, the mechanistic details of how mural cells stabilize vessels are not fully understood. We have examined the emergence and functional role of mural cells investing the dorsal aorta during early development using the zebrafish. Consistent with previous literature, our data suggest that cells ensheathing the dorsal aorta emerge from a sub-population of cells in the adjacent sclerotome. Inhibition of mural cell recruitment to the dorsal aorta through disruption of pdgfr signaling leads to a reduced vascular basement membrane, which in turn results in enhanced dorsal aorta vessel elasticity and failure to restrict aortic diameter. Our results provide direct in vivo evidence for a functional role for mural cells in patterning and stabilization of the early vasculature through production and maintenance of the vascular basement membrane to prevent abnormal aortic expansion and elasticity.


Assuntos
Aorta/embriologia , Comunicação Celular/fisiologia , Células Endoteliais/fisiologia , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/fisiologia , Pericitos/fisiologia , Peixe-Zebra/embriologia , Animais , Animais Geneticamente Modificados , Membrana Basal/citologia , Embrião não Mamífero , Neovascularização Fisiológica/genética , Pericitos/citologia , Receptores do Fator de Crescimento Derivado de Plaquetas/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/fisiologia , Transdução de Sinais/genética , Peixe-Zebra/genética
13.
Nature ; 512(7514): 314-8, 2014 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-25119043

RESUMO

Haematopoietic stem cells (HSCs) are self-renewing stem cells capable of replenishing all blood lineages. In all vertebrate embryos that have been studied, definitive HSCs are generated initially within the dorsal aorta (DA) of the embryonic vasculature by a series of poorly understood inductive events. Previous studies have identified that signalling relayed from adjacent somites coordinates HSC induction, but the nature of this signal has remained elusive. Here we reveal that somite specification of HSCs occurs via the deployment of a specific endothelial precursor population, which arises within a sub-compartment of the zebrafish somite that we have defined as the endotome. Endothelial cells of the endotome are specified within the nascent somite by the activity of the homeobox gene meox1. Specified endotomal cells consequently migrate and colonize the DA, where they induce HSC formation through the deployment of chemokine signalling activated in these cells during endotome formation. Loss of meox1 activity expands the endotome at the expense of a second somitic cell type, the muscle precursors of the dermomyotomal equivalent in zebrafish, the external cell layer. The resulting increase in endotome-derived cells that migrate to colonize the DA generates a dramatic increase in chemokine-dependent HSC induction. This study reveals the molecular basis for a novel somite lineage restriction mechanism and defines a new paradigm in induction of definitive HSCs.


Assuntos
Células Endoteliais/citologia , Células-Tronco Hematopoéticas/citologia , Proteínas de Homeodomínio/metabolismo , Somitos/citologia , Fatores de Transcrição/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Aorta/citologia , Aorta/embriologia , Biomarcadores/análise , Movimento Celular , Quimiocina CXCL12/análise , Quimiocina CXCL12/metabolismo , Embrião de Galinha , Células Endoteliais/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Proteínas de Homeodomínio/análise , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Músculos/citologia , Músculos/metabolismo , Mutação/genética , Somitos/metabolismo , Fatores de Transcrição/análise , Fatores de Transcrição/genética , Proteínas Wnt/análise , Proteínas Wnt/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/análise , Proteínas de Peixe-Zebra/genética
14.
J Clin Ultrasound ; 48(7): 423-427, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32324908

RESUMO

In utero diagnosis of anomalous origin of one pulmonary artery from the ascending aorta (AOPA) has been rarely reported, although this malformation has a high mortality rate due to the rapid development of pulmonary hypertension. We report two cases of AOPA, in which either the left or the right pulmonary artery originated from the distal part of the ascending aorta. Scanning around the three-vessel view to search for the origin of the left and right pulmonary arteries is essential for the diagnosis. In addition, recognition of an abnormal vessel at the three-vessel tracheal view is also useful. Three-dimensional echocardiography with high-definition flow imaging and spatiotemporal image correlation technique facilitates the identification of the anomalous origin of the pulmonary artery and should be considered a complementary modality in fetal cardiac examinations.


Assuntos
Aorta/diagnóstico por imagem , Ecocardiografia Tridimensional/métodos , Coração Fetal/diagnóstico por imagem , Artéria Pulmonar/diagnóstico por imagem , Malformações Vasculares/diagnóstico , Adulto , Aorta/embriologia , Feminino , Humanos , Gravidez , Diagnóstico Pré-Natal , Artéria Pulmonar/anormalidades , Artéria Pulmonar/embriologia , Malformações Vasculares/embriologia
15.
Dev Dyn ; 248(9): 771-783, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31175693

RESUMO

BACKGROUND: Second heart field cells and neural crest cells have been reported to participate in the morphogenesis of the pharyngeal arch arteries (PAAs); however, how the PAAs grow out and are separated from the aortic sac into left and right sections is unknown. RESULTS: An Isl-1 positive pharyngeal mesenchyme protrusion in the aortic sac ventrally extends and fuses with the aortic sac wall to form a midsagittal septum that divides the aortic sac. The aortic sac division separates the left and right PAAs to form independent arteries. The midsagittal septum dividing the aortic sac has a different expression pattern from the aortic-pulmonary (AP) septum in which Isl-1 positive cells are absent. At 11 days post-conception (dpc) in a mouse embryo, the Isl-1 positive mesenchyme protrusion appears as a heart-shaped structure, in which subpopulations with Isl-1+ Tbx3+ and Isl-1+ Nkx2.5+ cells are included. CONCLUSIONS: The aortic sac is a dynamic structure that is continuously divided during the migration from the pharyngeal mesenchyme to the pericardial cavity. The separation of the aortic sac is not complete until the AP septum divides the aortic sac into the ascending aorta and pulmonary trunk. Moreover, the midsagittal septum and the AP septum are distinct structures.


Assuntos
Aorta/crescimento & desenvolvimento , Região Branquial/irrigação sanguínea , Coração/embriologia , Proteínas com Homeodomínio LIM/análise , Mesoderma/embriologia , Fatores de Transcrição/análise , Animais , Aorta/embriologia , Artérias/embriologia , Artérias/crescimento & desenvolvimento , Região Branquial/embriologia , Embrião de Mamíferos , Mesoderma/citologia , Camundongos , Morfogênese
16.
Dev Biol ; 434(2): 292-303, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29253505

RESUMO

The embryonic aorta produces hematopoietic stem and progenitor cells from a hemogenic endothelium localized in the aortic floor through an endothelial to hematopoietic transition. It has been long proposed that the Bone Morphogenetic Protein (BMP)/Transforming Growth Factor ß (TGFß) signaling pathway was implicated in aortic hematopoiesis but the very nature of the signal was unknown. Here, using thorough expression analysis of the BMP/TGFß signaling pathway members in the endothelial and hematopoietic compartments of the aorta at pre-hematopoietic and hematopoietic stages, we show that the TGFß pathway is preferentially balanced with a prominent role of Alk1/TgfßR2/Smad1 and 5 on both chicken and mouse species. Functional analysis using embryonic stem cells mutated for Acvrl1 revealed an enhanced propensity to produce hematopoietic cells. Collectively, we reveal that TGFß through the Alk1/TgfßR2 receptor axis is acting on endothelial cells to produce hematopoiesis.


Assuntos
Aorta/embriologia , Proteínas Aviárias/metabolismo , Endotélio Vascular/embriologia , Hematopoese Extramedular/fisiologia , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Aorta/citologia , Embrião de Galinha , Galinhas , Endotélio Vascular/citologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteína Smad1/metabolismo , Proteína Smad5/metabolismo
17.
J Biol Chem ; 293(15): 5668-5678, 2018 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-29467228

RESUMO

The cardiovascular system develops during the early stages of embryogenesis, and differentiation of smooth muscle cells (SMCs) is essential for that process. SMC differentiation is critically regulated by transforming growth factor (TGF)-ß/SMAD family member 3 (SMAD3) signaling, but other regulators may also play a role. For example, long noncoding RNAs (lncRNAs) regulate various cellular activities and events, such as proliferation, differentiation, and apoptosis. However, whether long noncoding RNAs also regulate SMC differentiation remains largely unknown. Here, using the murine cell line C3H10T1/2, we found that brain cytoplasmic RNA 1 (BC1) is an important regulator of SMC differentiation. BC1 overexpression suppressed, whereas BC1 knockdown promoted, TGF-ß-induced SMC differentiation, as indicated by altered cell morphology and expression of multiple SMC markers, including smooth muscle α-actin (αSMA), calponin, and smooth muscle 22α (SM22α). BC1 appeared to block SMAD3 activity and inhibit SMC marker gene transcription. Mechanistically, BC1 bound to SMAD3 via RNA SMAD-binding elements (rSBEs) and thus impeded TGF-ß-induced SMAD3 translocation to the nucleus. This prevented SMAD3 from binding to SBEs in SMC marker gene promoters, an essential event in SMC marker transcription. In vivo, BC1 overexpression in mouse embryos impaired vascular SMC differentiation, leading to structural defects in the artery wall, such as random breaks in the elastic lamina, abnormal collagen deposition on SM fibers, and disorganized extracellular matrix proteins in the media of the neonatal aorta. Our results suggest that BC1 is a suppressor of SMC differentiation during vascular development.


Assuntos
Aorta/embriologia , Diferenciação Celular/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Músculo Liso Vascular/embriologia , Miócitos de Músculo Liso/metabolismo , RNA Longo não Codificante/biossíntese , Animais , Antígenos de Diferenciação/biossíntese , Antígenos de Diferenciação/genética , Aorta/citologia , Linhagem Celular , Humanos , Camundongos , Proteínas Musculares/biossíntese , Proteínas Musculares/genética , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , RNA Longo não Codificante/genética
18.
Adv Anat Embryol Cell Biol ; 230: 1-70, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30543033

RESUMO

The observation of two precursor groups of the early stem cells (Groups I and II) leads to the realization that a first amount of fetal stem cells (Group I) migrate from the AMG (Aortal-Mesonephric-Gonadal)-region into the aorta and its branching vessels. A second group (Group II) gains quite a new significance during human development. This group presents a specific developmental step which is found only in the human. This continuation of the early development along a different way indicates a general alteration of the stem cell biology. This changed process in the stem cell scene dominates the further development of the human stem cells. It remains unclear where this phylogenetic step first appears. By far not all advanced mammals show this second group of stem cells and their axonal migration. Essentially only primates seem to be involved in this special development.


Assuntos
Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/ultraestrutura , Gônadas/citologia , Gônadas/embriologia , Células APUD/citologia , Córtex Suprarrenal/citologia , Córtex Suprarrenal/embriologia , Córtex Suprarrenal/fisiologia , Córtex Suprarrenal/ultraestrutura , Medula Suprarrenal/citologia , Medula Suprarrenal/embriologia , Medula Suprarrenal/fisiologia , Aorta/citologia , Aorta/embriologia , Aorta/ultraestrutura , Sistema Nervoso Autônomo/citologia , Sistema Nervoso Autônomo/embriologia , Sistema Nervoso Autônomo/fisiologia , Orientação de Axônios/fisiologia , Movimento Celular/fisiologia , Células-Tronco Embrionárias/fisiologia , Gônadas/fisiologia , Gônadas/ultraestrutura , Desenvolvimento Humano/fisiologia , Humanos , Microscopia Eletrônica , Crista Neural/citologia , Crista Neural/embriologia , Crista Neural/fisiologia , Pâncreas/citologia , Pâncreas/crescimento & desenvolvimento , Pâncreas/ultraestrutura , Paragânglios Cromafins/citologia , Paragânglios Cromafins/fisiologia , Paragânglios Cromafins/ultraestrutura , Teratoma/embriologia , Teratoma/fisiopatologia
19.
J Ultrasound Med ; 38(12): 3335-3347, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31206762

RESUMO

In 2018, the American Institute of Ultrasound in Medicine revised its obstetric Practice Parameter for the second-trimester fetal anatomic survey. The 2018 Practice Parameter recommends incorporation of the 3-vessel view and 3-vessel and trachea view "if technically feasible." Sonographers and other medical providers may require additional training and education to develop greater proficiency in obtaining and interpreting these views. This pictorial essay, including ultrasound images alongside their respective schematic diagrams, provides an up-to-date, practical, and clinically oriented review of the 3-vessel view and 3-vessel and trachea view and their most common presentations in the context of congenital heart disease.


Assuntos
Aorta/diagnóstico por imagem , Aorta/embriologia , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/embriologia , Traqueia/diagnóstico por imagem , Traqueia/embriologia , Ultrassonografia Pré-Natal , Veia Cava Superior/diagnóstico por imagem , Veia Cava Superior/embriologia , Feminino , Humanos , Gravidez
20.
Dev Biol ; 421(2): 108-117, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-27955943

RESUMO

Oxygenated blood from the heart is directed into the systemic circulation through the aortic arch arteries (AAAs). The AAAs arise by remodeling of three symmetrical pairs of pharyngeal arch arteries (PAAs), which connect the heart with the paired dorsal aortae at mid-gestation. Aberrant PAA formation results in defects frequently observed in patients with lethal congenital heart disease. How the PAAs form in mammals is not understood. The work presented in this manuscript shows that the second heart field (SHF) is the major source of progenitors giving rise to the endothelium of the pharyngeal arches 3 - 6, while the endothelium in the pharyngeal arches 1 and 2 is derived from a different source. During the formation of the PAAs 3 - 6, endothelial progenitors in the SHF extend cellular processes toward the pharyngeal endoderm, migrate from the SHF and assemble into a uniform vascular plexus. This plexus then undergoes remodeling, whereby plexus endothelial cells coalesce into a large PAA in each pharyngeal arch. Taken together, our studies establish a platform for investigating cellular and molecular mechanisms regulating PAA formation and alterations that lead to disease.


Assuntos
Região Branquial/embriologia , Endotélio/embriologia , Coração/embriologia , Animais , Aorta/embriologia , Região Branquial/citologia , Sobrevivência Celular , Embrião de Mamíferos/metabolismo , Células Endoteliais/metabolismo , Endotélio/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Camundongos Transgênicos , Células-Tronco/citologia , Fatores de Tempo
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