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1.
Medicine (Baltimore) ; 98(42): e17594, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626133

RESUMO

RATIONALE: Idiopathic pulmonary arterial hypertension (IPAH) is characterized by intense remodeling of small pulmonary arteries. Loss-of-function mutation of bone morphogenetic protein receptor II (BMPR2) gene and exaggerated activation of transforming growth factor (TGF)-ß signaling play a critical role in this process. PATIENT CONCERNS AND DIAGNOSIS: We report a novel frameshift mutation (c.117InsT, p.Y40fsX48) of the BMPR2 gene identified in a 19-year-old IPAH patient with syncope. Despite BMPR2 mutation, the phosphorylation of Smad2/3 and Samd1/5/8 was increased in the patient's peripheral blood mononuclear cells, and this event was accompanied by the upregulation of bone morphogenetic protein (BMP) signaling target genes, but not TGF-ß signaling target genes. Moreover, we observed an increased expression of other BMPRs, that is, anti-Mullerian hormone type-2 receptor and the activin receptor-like kinases (ALK) 1, ALK3, and ALK6. INTERVENTIONS AND OUTCOMES: The patient was prescribed a combination of macitentan, sildenafil, and nifedipine, which successfully controlled her symptom of syncope and normalized N-terminal pro-brain natriuretic peptide level after 3 months of medication. LESSONS: In light of these results, we propose a new pathogenetic mechanism for IPAH, based on enhanced BMP signaling via the functional replacement of mutated BMPR2 by other BMP receptors.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Proteínas Morfogenéticas Ósseas/genética , DNA/genética , Hipertensão Pulmonar Primária Familiar/genética , Mutação da Fase de Leitura , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Análise Mutacional de DNA , Hipertensão Pulmonar Primária Familiar/metabolismo , Feminino , Humanos , Transdução de Sinais , Adulto Jovem
2.
Braz Oral Res ; 33: e058, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31432925

RESUMO

Cementum is the mineralized tissue covering the tooth root that functions in tooth attachment and post-eruptive adjustment of tooth position. It has been reported to be highly similar to bone in several respects but remains poorly understood in terms of development and regeneration. Here, we investigate whether cementocytes, the residing cells in cellular cementum, have the potential to be protagonist in cementum homeostasis, responding to endocrine signals and directing local cementum metabolism. Cells from healthy erupted human teeth were isolated using sequential collagenase/EDTA digestions, and maintained in standard cell culture conditions. A cementocyte-like cell line was cloned (HCY-23, for human cementocyte clone 23), which presented a cementocyte compatible gene expression signature, including the expression of dentin matrix protein 1 ( DMP1 ), sclerostin ( SOST ), and E11/gp38/podoplanin ( E11 ). In contrast, these cells did not express the odontoblast/dentin marker dentin sialoprotein ( DSPP ). HCY-23 cells produced mineral-like nodules in vitro under differentiation conditions, and were highly responsive to inorganic phosphate (Pi). Within the limits of the present study, it can be concluded that cementocytes are phosphate-responsive cells, and have the potential do play a key role in periodontal homeostasis and regeneration.


Assuntos
Técnicas de Cultura de Células/métodos , Cemento Dentário/citologia , Adolescente , Adulto , Análise de Variância , Proteínas Morfogenéticas Ósseas/análise , Proteínas Morfogenéticas Ósseas/genética , Linhagem Celular , Cemento Dentário/metabolismo , Proteínas da Matriz Extracelular/análise , Proteínas da Matriz Extracelular/genética , Feminino , Imunofluorescência , Expressão Gênica , Marcadores Genéticos/genética , Humanos , Masculino , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/genética , Dente Molar/citologia , Fosfatos/farmacologia , Fosfoproteínas/análise , Fosfoproteínas/genética , Sialoglicoproteínas/análise , Sialoglicoproteínas/genética , Fatores de Tempo , Adulto Jovem
3.
Nat Commun ; 10(1): 3802, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444329

RESUMO

Limb development starts with the formation of limb buds (LBs), which consist of tissues from two different germ layers; the lateral plate mesoderm-derived mesenchyme and ectoderm-derived surface epithelium. Here, we report means for induction of an LB-like mesenchymal/epithelial complex tissues from murine pluripotent stem cells (PSCs) in vitro. The LB-like tissues selectively differentiate into forelimb- or hindlimb-type mesenchymes, depending on a concentration of retinoic acid. Comparative transcriptome analysis reveals that the LB-like tissues show similar gene expression pattern to that seen in LBs. We also show that manipulating BMP signaling enables us to induce a thickened epithelial structure similar to the apical ectodermal ridge. Finally, we demonstrate that the induced tissues can contribute to endogenous digit tissue after transplantation. This PSC technology offers a first step for creating an artificial limb bud in culture and might open the door to inducing other mesenchymal/epithelial complex tissues from PSCs.


Assuntos
Técnicas de Cultura de Células/métodos , Botões de Extremidades/embriologia , Células-Tronco Embrionárias Murinas/fisiologia , Engenharia Tecidual/métodos , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Ectoderma/citologia , Ectoderma/metabolismo , Embrião de Mamíferos , Desenvolvimento Embrionário , Epitélio/metabolismo , Feminino , Membro Anterior/embriologia , Membro Anterior/transplante , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Membro Posterior/embriologia , Membro Posterior/transplante , Botões de Extremidades/transplante , Masculino , Camundongos , Células-Tronco Embrionárias Murinas/transplante , Transdução de Sinais/fisiologia
4.
Int J Mol Sci ; 20(14)2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31330871

RESUMO

In the brain, aging is accompanied by cellular and functional deficiencies that promote vulnerability to neurodegenerative disorders. In blood plasma from young and old animals, various factors such as growth differentiation factor 11 (GDF11), whose levels are elevated in young animals, have been identified. The blood concentrations of these factors appear to be inversely correlated with the age-related decline of neurogenesis. The identification of GDF11 as a "rejuvenating factor" opens up perspectives for the treatment of neurodegenerative diseases. As a pro-neurogenic and pro-angiogenic agent, GDF11 may constitute a basis for novel therapeutic strategies.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Encéfalo/fisiologia , Fatores de Diferenciação de Crescimento/genética , Fatores de Diferenciação de Crescimento/metabolismo , Neuroproteção/genética , Animais , Biomarcadores , Humanos , Neovascularização Fisiológica/genética , Neurogênese/genética , Rejuvenescimento
5.
Growth Factors ; 37(1-2): 12-28, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31272247

RESUMO

Breast cancer is the most prevalent type of cancer amongst women worldwide. The mortality rate for patients with early-stage breast cancer has been decreasing, however, the 5-year survival rate for patients with metastatic disease remains poor, currently at 27%. Here, we have reviewed the current understanding of the role of bone morphogenetic protein (BMP) signaling in breast cancer progression, and have highlighted the discordant results that are reported in different studies. We propose that some of these contradictory outcomes may result from signaling through either the canonical or non-canonical pathways in different cell lines and tumors, or from different tumor-stromal interactions that occur in vivo.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Neoplasias da Mama/genética , Transdução de Sinais , Animais , Proteínas Morfogenéticas Ósseas/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Proteínas Smad/genética , Proteínas Smad/metabolismo
6.
Int J Biol Macromol ; 138: 79-88, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31295489

RESUMO

This study investigates if the application of bone marrow-derived mesenchymal stem cells (BM-MSCs) loaded 3D-printed scaffolds could improve rotator cuff repair. The polylactic-co-glycolic acid (PLGA) scaffolds were fabricated by 3D print technology. Rabbit BM-MSCs were transfected with a recombinant adenovirus encoding bone morphogenic protein 12 (BMP-12). The effect of BM-MSCs loaded PLGA scaffolds on tendon-bone healing was assessed by biomechanical testing and histological analysis in a rabbit rotator cuff repair model. We found that the PLGA scaffolds had good biocompatible and biodegradable property. Overexpression of BMP-12 increased the mRNA and protein expression of tenogenic genes in BM-MSCs cultured with DMEM medium and seeded in PLGA scaffolds. When BMP-12-overexpressing BM-MSCs-loaded PLGA scaffolds were implanted into the injured rabbit supraspinatus tendon-bone junctions, the tendon-bone healing was improved. Our results suggest that application of BMP-12 overexpressing BM-MSCs loaded 3D-printed PLGA scaffolds promote the healing of tendon-bone interface, improve collagen organization and increase fibrocartilage in the rabbit rotor cuff repair. Rotator cuff regeneration achieved by BMP-12-overexpressing BM-MSCs-loaded PLGA scaffolds may represent a novel approach for the management of rotator cuff defect.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Células-Tronco Mesenquimais/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Impressão Tridimensional , Manguito Rotador/fisiologia , Tecidos Suporte/química , Animais , Biomarcadores/metabolismo , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Expressão Gênica , Células-Tronco Mesenquimais/química , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Coelhos , Regeneração , Tendões/fisiologia
8.
Cells ; 8(6)2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174355

RESUMO

Bone morphogenetic protein (BMP) and Notch signaling are critical for endothelial cell (EC) differentiation in vascular development. Recent studies have shown that excess BMP activity induces Notch signaling in cerebral ECs resulting in arteriovenous malformation (AVMs). However, it is unclear how the crosstalk between BMP and Notch signaling affects cerebral EC differentiation at the gene regulatory level. Here, we report that BMP6 activates the activin receptor-like kinase (ALK) 3, a BMP type 1 receptor, to induce Notch1 receptor and Jagged1 and Jagged2 ligands. We show that increased expression of the Notch components alters the transcriptional regulatory complex in the SRY-Box 2 (Sox2) promoter region so as to induce its expression in cerebral ECs. Together, our results identify Sox2 as a direct target of BMP and Notch signaling and provide information on how altered BMP and Notch signaling affects the endothelial transcriptional landscape.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Receptor Notch1/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Receptores de Ativinas Tipo I/antagonistas & inibidores , Receptores de Ativinas Tipo I/genética , Receptores de Ativinas Tipo I/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Encéfalo/citologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Expressão Gênica , Humanos , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Proteína Jagged-2/genética , Proteína Jagged-2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regiões Promotoras Genéticas , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptor Notch1/genética , Fatores de Transcrição SOXB1/genética
9.
Mol Med Rep ; 20(2): 985-994, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173222

RESUMO

As a common degenerative disease, osteoporosis (OS) is characterized by reduced bone mass and microarchitectural deterioration of bone tissue. Both genetic and environmental factors are involved in OS development. To date, ~300 genes have been confirmed to be involved in the pathogenesis of OS, a large majority of which have been independently investigated. As OS is a polygenetic disease, a comprehensive analysis focusing on the biological functions and interactions of OS­related genes would provide valuable information. In this study, OS related research deposited in PubMed was retrieved and genes related to OS were catalogued. Pathways with an enriched biological function for these genes were extracted, and the crosstalk between the enriched pathways was analyzed. A comprehensive network was constructed, and a minimal network was extracted using the Steiner minimal network algorithm. In this study, a total of 294 genes in were retrieved from PubMed. Biological processes found to be enriched included those related to bone metabolism and the immune system. In total, 58 pathways were enriched. Furthermore, the comprehensive network consisting of 3,943 nodes and 7,976 edges was constructed, among which 631 nodes and 2,581 edges contributed to the OS­specific molecular network. In this network, in excess of 300 potential genes associated with OS and two modules were identified. Thus, this study provides a mechanistic insight into OS and suggests more than 300 potential OS­related genes for future research.


Assuntos
Algoritmos , Proteínas Morfogenéticas Ósseas/genética , Osso e Ossos/metabolismo , Proteínas da Matriz Extracelular/genética , Redes Reguladoras de Genes , Osteoporose/genética , Densidade Óssea , Proteínas Morfogenéticas Ósseas/classificação , Proteínas Morfogenéticas Ósseas/imunologia , Osso e Ossos/patologia , Biologia Computacional/métodos , Proteínas da Matriz Extracelular/classificação , Proteínas da Matriz Extracelular/imunologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Imunidade Inata , Anotação de Sequência Molecular , Osteoporose/metabolismo , Osteoporose/patologia , Receptores Acoplados a Proteínas-G/classificação , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/imunologia , Transdução de Sinais
10.
Int J Mol Sci ; 20(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31197079

RESUMO

Wnt signaling plays a pivotal role in maintaining bone mass. Secreted pathway modulators such as sclerostin (SOST) and Dickkopfs (DKKs) may influence bone mass inhibiting the canonical Wnt pathway. We evaluated whether bone protein content of secreted Wnt antagonists is related to age, bone mass, and strength in postmenopausal osteoporosis. We measured cortical and trabecular bone contents of SOST and Dickkopf-1 (DKK1) in combined extracts obtained after ethylenediaminetetraacetic acid and guanidine hydrochloride extraction in 56 postmenopausal women aged 47-74 (mean, 63) yr with a previous distal forearm fracture and a hip or spine Z-score less than 0. Our findings were (i) SOST and DKK1 protein levels were higher in trabecular bone, (ii) cortical and trabecular DKK1 and trabecular SOST correlated positively with bone matrix levels of osteocalcin (r between 0.28 and 0.45, p < 0.05), (iii) cortical DKK1 correlated with lumbar spine bone mineral density (BMD) (r = 0.32, p < 0.05) and femoral neck BMD (r = 0.41, p < 0.01), and (iv) cortical DKK1 and SOST correlated with apparent bone volumetric density and compressive strength (r between 0.34 and 0.51, p < 0.01). In conclusion, cortical bone matrix levels of DKK1 and SOST were positively correlated with bone mass and bone strength in postmenopausal osteoporotic women.


Assuntos
Matriz Óssea/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Osteoporose Pós-Menopausa/metabolismo , Idoso , Densidade Óssea , Proteínas Morfogenéticas Ósseas/genética , Feminino , Marcadores Genéticos/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Pessoa de Meia-Idade , Osteocalcina/genética , Osteocalcina/metabolismo , Osteoporose Pós-Menopausa/diagnóstico por imagem , Osteoporose Pós-Menopausa/patologia
11.
Cell Mol Life Sci ; 76(20): 3939-3952, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31201464

RESUMO

Articular cartilage is formed at the end of epiphyses in the synovial joint cavity and permanently contributes to the smooth movement of synovial joints. Most skeletal elements develop from transient cartilage by a biological process known as endochondral ossification. Accumulating evidence indicates that articular and growth plate cartilage are derived from different cell sources and that different molecules and signaling pathways regulate these two kinds of cartilage. As the first sign of joint development, the interzone emerges at the presumptive joint site within a pre-cartilage tissue. After that, joint cavitation occurs in the center of the interzone, and the cells in the interzone and its surroundings gradually form articular cartilage and the synovial joint. During joint development, the interzone cells continuously migrate out to the epiphyseal cartilage and the surrounding cells influx into the joint region. These complicated phenomena are regulated by various molecules and signaling pathways, including GDF5, Wnt, IHH, PTHrP, BMP, TGF-ß, and FGF. Here, we summarize current literature and discuss the molecular mechanisms underlying joint formation and articular development.


Assuntos
Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Condrogênese/genética , Regulação da Expressão Gênica , Cápsula Articular/metabolismo , Via de Sinalização Wnt , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Cartilagem Articular/citologia , Cartilagem Articular/crescimento & desenvolvimento , Diferenciação Celular , Linhagem da Célula/genética , Movimento Celular , Condrócitos/citologia , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fator 5 de Diferenciação de Crescimento/genética , Fator 5 de Diferenciação de Crescimento/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Cápsula Articular/citologia , Cápsula Articular/crescimento & desenvolvimento , Osteogênese/genética , Proteína Relacionada ao Hormônio Paratireóideo/genética , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
12.
Dev Cell ; 50(2): 155-166.e4, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31204171

RESUMO

Amphibians form fingers without webbing by differential growth between digital and interdigital regions. Amniotes, however, employ interdigital cell death (ICD), an additional mechanism that contributes to a greater variation of limb shapes. Here, we investigate the role of environmental oxygen in the evolution of ICD in tetrapods. While cell death is restricted to the limb margin in amphibians with aquatic tadpoles, Eleutherodactylus coqui, a frog with terrestrial-direct-developing eggs, has cell death in the interdigital region. Chicken requires sufficient oxygen and reactive oxygen species to induce cell death, with the oxygen tension profile itself being distinct between the limbs of chicken and Xenopus laevis frogs. Notably, increasing blood vessel density in X. laevis limbs, as well as incubating tadpoles under high oxygen levels, induces ICD. We propose that the oxygen available to terrestrial eggs was an ecological feature crucial for the evolution of ICD, made possible by conserved autopod-patterning mechanisms.


Assuntos
Padronização Corporal , Morte Celular , Extremidades/irrigação sanguínea , Extremidades/patologia , Larva/crescimento & desenvolvimento , Morfogênese , Oxigênio/farmacologia , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Morte Celular/efeitos dos fármacos , Embrião de Galinha , Larva/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Xenopus laevis
13.
Zoology (Jena) ; 133: 17-26, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30979387

RESUMO

Bone morphogenetic proteins play a pivotal role in the epimorphic regeneration in vertebrates. Blastema formation is central to the epimorphic regeneration and crucially determines its fate. Despite an elaborate understanding of importance of Bone morphogenetic protein signaling in regeneration, its specific role during the blastema formation remains to be addressed. Regulatory role of BMP signaling during blastema formation was investigated using LDN193189, a potent inhibitor of BMP receptors. The study involved morphological observation, in vivo proliferation assay by incorporation of BrdU, comet assay, qRT-PCR and western blot. Blastemal outgrowth was seen reduced due to LDN193189 treatment, typified by dimensional differences, reduced number of proliferating cells and decreased levels of PCNA. Additionally, proapoptotic markers were found to be upregulated signifying a skewed cellular turnover. Further, the cell migration was seen obstructed and ECM remodeling was disturbed as well. These findings were marked by differential transcript as well as protein expressions of the key signaling and regulatory components, their altered enzymatic activities and other microscopic as well as molecular characterizations. Our results signify, for the first time, that BMP signaling manifests its effect on blastema formation by controlling the pivotal cellular processes possibly via PI3K/AKT. Our results indicate the pleiotropic role of BMPs specifically during blastema formation in regulating cell migration, cell proliferation and apoptosis, and lead to the generation of a molecular regulatory map of determinative molecules.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Poecilia/fisiologia , Nadadeiras de Animais/efeitos dos fármacos , Animais , Proteínas Morfogenéticas Ósseas/genética , Ciclo Celular , Fragmentação do DNA , Matriz Extracelular , Feminino , Masculino , Pirazóis/farmacologia , Pirimidinas/farmacologia , Regeneração
14.
Gene Expr Patterns ; 32: 67-71, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30980961

RESUMO

Tooth cusp is a crucial structure, since the shape of the molar tooth is determined by number, shape, and size of the cusp. Bone morphogenetic protein (Bmp) signaling is known to play a critical role in tooth development, including in initiation. However, it remains unclear whether Bmp signaling is also involved in cusp formation. To address this question, we examined cusp in two different transgenic mouse lines: mice with overexpression of Bmp4 (K14-Bmp4), and those with Bmp inhibitor, Noggin, (K14-Noggin) under keratin14 (K14) promoter. K14-Noggin mice demonstrated extra cusps, whereas reduced number of cusps was observed in K14-Bmp4 mice. To further understand how Bmps are expressed during cusp formation, we performed whole-mount in situ hybridisation analysis of three major Bmps (Bmp2, Bmp4, and Bmp7) in murine maxillary and mandibular molars from E14.5 to P3. The linear expressions of Bmp2 and Bmp4 were observed in both maxillary and mandibular molars at E14.5. The expression patterns of Bmp2 and Bmp4 became significantly different between the maxillary and mandibular molars at E16.5. At P3, all Bmps were expressed in all the cusp regions of the maxillary molar; however, the patterns differed. All Bmps thus exhibited dynamic temporo-spatial expression during the cusp formation. It could therefore be inferred that Bmp signaling is involved in regulating cusp formation.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Dente Molar/embriologia , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Proteínas de Transporte/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hibridização In Situ , Camundongos , Camundongos Transgênicos , Dente Molar/metabolismo , Odontogênese , Transdução de Sinais/genética , Dente/metabolismo
15.
Mol Cell Endocrinol ; 490: 37-46, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30953749

RESUMO

Development of mammalian ovarian follicles is promoted by the combined action of endocrine cues and paracrine factors. Follicle stimulating hormone (FSH), through the action of cAMP drives follicular growth and development. The oocyte secretes powerful growth factors such as bone morphogenetic protein 15 (BMP15) to regulate granulosa cell proliferation, metabolism, steroidogenesis and differentiation through the activation of SMAD1/5/8. This study investigated the role of the cAMP signalling pathway on SMAD1/5/8 action in human granulosa cells. Cyclic AMP enhanced BMP15-induction of a SMAD1/5/8-specific BRE reporter. Moreover, in the absence of BMP ligand, cAMP also activated SMAD1/5/8-induced BRE activity. Cyclic AMP increased canonical downstream targets of BMP signalling such as inhibitor of differentiation (ID) mRNA expression. The observed effects were not mediated by secretion of BMPs as cAMP did not promote BMP ligand mRNA expression and a BMP extracellular antagonist, the BMP type II receptor ectodomain, did not affect cAMP-induced ID mRNA expression. Finally, the ERK1/2 pathway was shown to be required for the maintenance of cAMP-induced SMAD1/5/8 activity. Together our results suggest a novel and non-canonical pathway for cAMP signalling in human granulosa cells. Cyclic AMP appears to promote SMAD1/5/8 pathway activity intracellularly and has the ability to activate canonical SMAD1/5/8 downstream targets. Our results add another layer of complexity to the interactions between endocrine signalling and oocyte-secreted BMP ligands during folliculogenesis. Given the importance of both cAMP and SMAD1/5/8 pathways in follicular development, these interactions are likely required for the fine-tuning of oocyte paracrine signalling by endocrine stimuli.


Assuntos
AMP Cíclico/metabolismo , Células da Granulosa/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismo , 1-Metil-3-Isobutilxantina/farmacologia , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Células Cultivadas , Colforsina/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células da Granulosa/efeitos dos fármacos , Humanos , Proteínas Inibidoras de Diferenciação/genética , Proteínas Inibidoras de Diferenciação/metabolismo , Ligantes , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/genética
16.
Genesis ; 57(7-8): e23296, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31021058

RESUMO

This article is concerned with the roles of retinoids and other known anterior-posterior morphogens in setting up the embryonic vertebrate anterior-posterior axis. The discussion is restricted to the very earliest events in setting up the anterior-posterior axis (from blastula to tailbud stages in Xenopus embryos). In these earliest developmental stages, morphogen concentration gradients are not relevant for setting up this axis. It emerges that at these stages, the core patterning mechanism is timing: BMP-anti BMP mediated time space translation that regulates Hox temporal and spatial collinearities and Hox-Hox auto- and cross- regulation. The known anterior-posterior morphogens and signaling pathways--retinoids, FGF's, Cdx, Wnts, Gdf11 and others--interact with this core mechanism at and after space-time defined "decision points," leading to the separation of distinct axial domains. There are also other roles for signaling pathways. Besides the Hox regulated hindbrain/trunk part of the axis, there is a rostral part (including the anterior part of the head and the extreme anterior domain [EAD]) that appears to be regulated by additional mechanisms. Key aspects of anterior-posterior axial patterning, including: the nature of different phases in early patterning and in the whole process; the specificities of Hox action and of intercellular signaling; and the mechanisms of Hox temporal and spatial collinearities, are discussed in relation to the facts and hypotheses proposed above.


Assuntos
Padronização Corporal , Proteínas de Homeodomínio/genética , Retinoides/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/metabolismo , Humanos , Transdução de Sinais
17.
Int J Cancer ; 145(7): 1913-1920, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30889293

RESUMO

Colorectal cancer (CRC) is one of the most malignant tumors worldwide. Stromal cells residing in the tumor microenvironment strongly contribute to cancer progression through their crosstalk with cancer cells and extracellular matrix. Here we provide the first evidence that CRC-associated lymphatic endothelium displays a distinct matrisome-associated transcriptomic signature, which distinguishes them from healthy intestinal lymphatics. We also demonstrate that CRC-associated human intestinal lymphatic endothelial cells regulate tumor cell growth via growth differentiation factor 11, a soluble matrisome component which in CRC patients was found to be associated with tumor progression. Our data provide new insights into lymphatic contribution to CRC growth, aside from their conventional role as conduits of metastasis.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Neoplasias Colorretais/genética , Endotélio Linfático/citologia , Matriz Extracelular/genética , Fatores de Diferenciação de Crescimento/genética , Animais , Células CACO-2 , Técnicas de Cultura de Células/métodos , Proliferação de Células , Células Cultivadas , Progressão da Doença , Células Endoteliais/química , Células Endoteliais/citologia , Endotélio Linfático/química , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Transplante de Neoplasias , Microambiente Tumoral
18.
Nat Commun ; 10(1): 1089, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842446

RESUMO

The essential roles played by Nodal and Bmp signalling during early mouse development have been extensively documented. Here we use conditional deletion strategies to investigate functional contributions made by Nodal, Bmp and Smad downstream effectors during primordial germ cell (PGC) development. We demonstrate that Nodal and its target gene Eomes provide early instructions during formation of the PGC lineage. We discover that Smad2 inactivation in the visceral endoderm results in increased numbers of PGCs due to an expansion of the PGC niche. Smad1 is required for specification, whereas in contrast Smad4 controls the maintenance and migration of PGCs. Additionally we find that beside Blimp1, down-regulated phospho-Smad159 levels also distinguishes PGCs from their somatic neighbours so that emerging PGCs become refractory to Bmp signalling that otherwise promotes mesodermal development in the posterior epiblast. Thus balanced Nodal/Bmp signalling cues regulate germ cell versus somatic cell fate decisions in the early posterior epiblast.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Células Germinativas/fisiologia , Proteína Nodal/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Linhagem Celular , Movimento Celular/fisiologia , Embrião de Mamíferos , Endoderma/citologia , Endoderma/fisiologia , Feminino , Técnicas de Inativação de Genes , Masculino , Camundongos , Camundongos Knockout , Células-Tronco Embrionárias Murinas , Proteína Nodal/genética , Transdução de Sinais/genética , Proteínas Smad/genética , Proteínas Smad/metabolismo
19.
J Immunol ; 202(8): 2296-2306, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30814306

RESUMO

NK cells are innate-like lymphocytes that eliminate virally infected and cancerous cells, but the mechanisms that control NK cell development and cytotoxicity are incompletely understood. We identified roles for sclerostin domain-containing-1 (Sostdc1) in NK cell development and function. Sostdc1-knockout (Sostdc1 -/-) mice display a progressive accumulation of transitional NK cells (tNKs) (CD27+CD11b+) with age, indicating a partial developmental block. The NK cell Ly49 repertoire in Sostdc1 -/- mice is also changed. Lower frequencies of Sostdc1 -/- splenic tNKs express inhibitory Ly49G2 receptors, but higher frequencies express activating Ly49H and Ly49D receptors. However, the frequencies of Ly49I+, G2+, H+, and D+ populations were universally decreased at the most mature (CD27-CD11b+) stage. We hypothesized that the Ly49 repertoire in Sostdc1 -/- mice would correlate with NK killing ability and observed that Sostdc1-/- NK cells are hyporesponsive against MHC class I-deficient cell targets in vitro and in vivo, despite higher CD107a surface levels and similar IFN-γ expression to controls. Consistent with Sostdc1's known role in Wnt signaling regulation, Tcf7 and Lef1 levels were higher in Sostdc1 -/- NK cells. Expression of the NK development gene Id2 was decreased in Sostdc1-/- immature NK and tNK cells, but Eomes and Tbx21 expression was unaffected. Reciprocal bone marrow transplant experiments showed that Sostdc1 regulates NK cell maturation and expression of Ly49 receptors in a cell-extrinsic fashion from both nonhematopoietic and hematopoietic sources. Taken together, these data support a role for Sostdc1 in the regulation of NK cell maturation and cytotoxicity, and identify potential NK cell niches.


Assuntos
Proteínas Morfogenéticas Ósseas/imunologia , Imunidade Celular , Células Matadoras Naturais/imunologia , Via de Sinalização Wnt/imunologia , Animais , Proteínas Morfogenéticas Ósseas/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/imunologia , Proteína 2 Inibidora de Diferenciação/genética , Proteína 2 Inibidora de Diferenciação/imunologia , Células Matadoras Naturais/citologia , Fator 1 de Ligação ao Facilitador Linfoide/genética , Fator 1 de Ligação ao Facilitador Linfoide/imunologia , Camundongos , Camundongos Knockout , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Via de Sinalização Wnt/genética
20.
J Mol Histol ; 50(3): 217-227, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30895425

RESUMO

Sjögren's syndrome or radiotherapy for head and neck cancer leads to the irreversible hypofunction of salivary gland (SG). The stem/progenitor cell-based regenerative strategy has been proven to be the most promising approach to repair the function of SG. The molecular mechanisms that regulate SG morphogenesis, especially during lumen formation, provide valuable hints for establishment of such regenerative strategies. It has been demonstrated that numerous growth factors particularly belonging to SHH, BMP, and FGF signaling pathway are involved in the regulation of lumen formation and have shown protective effects on the SG from irradiation in mouse models. However, it remains elusive whether the expression pattern and function of these signaling molecules are conserved in humans. In this study, we examined the expression patterns of the molecules critical for SHH, BMP, and FGF signaling cascades from the canalicular stage to the terminal bud stage, the key stages for lumen formation, in human SG and compared them with the expression data observed in mice. Our results manifested that genes involved in SHH signaling pathway showed identical expression patterns, while genes involved in BMP as well as FGF pathway exhibited similar but distinct expression patterns in humans to those in the mouse. We concluded that the expression patterns of genes involved in SHH, BMP, and FGF pathways in the development of human SG exhibit high similarity to that in the development of mouse SG during lumen formation, suggesting that the molecular mechanism regulating the morphogenesis of SG during lumen formation may be conserved in mice and humans. Our results will have an implication in the future establishment of stem-cell based approaches for the repair of SG function.


Assuntos
Fatores de Crescimento de Fibroblastos/genética , Proteínas Hedgehog/genética , Morfogênese/genética , Glândulas Salivares/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Hibridização In Situ , Camundongos , Glândulas Salivares/crescimento & desenvolvimento , Transdução de Sinais/genética , Células-Tronco/metabolismo
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