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1.
Nat Commun ; 11(1): 2082, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350257

RESUMO

Developmental progression depends on temporally defined changes in gene expression mediated by transient exposure of lineage intermediates to signals in the progenitor niche. To determine whether cell-intrinsic epigenetic mechanisms contribute to signal-induced transcriptional responses, here we manipulate the signalling environment and activity of the histone demethylase LSD1 during differentiation of hESC-gut tube intermediates into pancreatic endocrine cells. We identify a transient requirement for LSD1 in endocrine cell differentiation spanning a short time-window early in pancreas development, a phenotype we reproduced in mice. Examination of enhancer and transcriptome landscapes revealed that LSD1 silences transiently active retinoic acid (RA)-induced enhancers and their target genes. Furthermore, prolonged RA exposure phenocopies LSD1 inhibition, suggesting that LSD1 regulates endocrine cell differentiation by limiting the duration of RA signalling. Our findings identify LSD1-mediated enhancer silencing as a cell-intrinsic epigenetic feedback mechanism by which the duration of the transcriptional response to a developmental signal is limited.


Assuntos
Células Endócrinas/citologia , Células Endócrinas/metabolismo , Elementos Facilitadores Genéticos/genética , Inativação Gênica , Histona Desmetilases/metabolismo , Ilhotas Pancreáticas/citologia , Transdução de Sinais , Tretinoína/metabolismo , Adulto , Animais , Sequência de Bases , Diferenciação Celular/efeitos dos fármacos , Células Endócrinas/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Células-Tronco Embrionárias Humanas/citologia , Células-Tronco Embrionárias Humanas/efeitos dos fármacos , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Ilhotas Pancreáticas/embriologia , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Tretinoína/farmacologia , Adulto Jovem
2.
PLoS Comput Biol ; 16(4): e1007769, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32251433

RESUMO

Endocrine cells in the pituitary gland typically display either spiking or bursting electrical activity, which is related to the level of hormone secretion. Recent work, which combines mathematical modelling with dynamic clamp experiments, suggests the difference is due to the presence or absence of a few large-conductance potassium channels. Since endocrine cells only contain a handful of these channels, it is likely that stochastic effects play an important role in the pattern of electrical activity. Here, for the first time, we explicitly determine the effect of such noise by studying a mathematical model that includes the realistic noisy opening and closing of ion channels. This allows us to investigate how noise affects the electrical activity, examine the origin of spiking and bursting, and determine which channel types are responsible for the greatest noise. Further, for the first time, we address the role of cell size in endocrine cell electrical activity, finding that larger cells typically display more bursting, while the smallest cells almost always only exhibit spiking behaviour.


Assuntos
Potenciais de Ação/fisiologia , Células Endócrinas , Canais Iônicos/fisiologia , Modelos Neurológicos , Neurônios , Animais , Biologia Computacional , Células Endócrinas/citologia , Células Endócrinas/fisiologia , Neurônios/citologia , Neurônios/fisiologia , Técnicas de Patch-Clamp , Hipófise/citologia
3.
PLoS Biol ; 18(2): e3000609, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32097403

RESUMO

The final body size of any given individual underlies both genetic and environmental constraints. Both mammals and insects use target of rapamycin (TOR) and insulin signaling pathways to coordinate growth with nutrition. In holometabolous insects, the growth period is terminated through a cascade of peptide and steroid hormones that end larval feeding behavior and trigger metamorphosis, a nonfeeding stage during which the larval body plan is remodeled to produce an adult. This irreversible decision, termed the critical weight (CW) checkpoint, ensures that larvae have acquired sufficient nutrients to complete and survive development to adulthood. How insects assess body size via the CW checkpoint is still poorly understood on the molecular level. We show here that the Drosophila transcription factor Snail plays a key role in this process. Before and during the CW checkpoint, snail is highly expressed in the larval prothoracic gland (PG), an endocrine tissue undergoing endoreplication and primarily dedicated to the production of the steroid hormone ecdysone. We observed two Snail peaks in the PG, one before and one after the molt from the second to the third instar. Remarkably, these Snail peaks coincide with two peaks of PG cells entering S phase and a slowing of DNA synthesis between the peaks. Interestingly, the second Snail peak occurs at the exit of the CW checkpoint. Snail levels then decline continuously, and endoreplication becomes nonsynchronized in the PG after the CW checkpoint. This suggests that the synchronization of PG cells into S phase via Snail represents the mechanistic link used to terminate the CW checkpoint. Indeed, PG-specific loss of snail function prior to the CW checkpoint causes larval arrest due to a cessation of endoreplication in PG cells, whereas impairing snail after the CW checkpoint no longer affected endoreplication and further development. During the CW window, starvation or loss of TOR signaling disrupted the formation of Snail peaks and endocycle synchronization, whereas later starvation had no effect on snail expression. Taken together, our data demonstrate that insects use the TOR pathway to assess nutrient status during larval development to regulate Snail in ecdysone-producing cells as an effector protein to coordinate endoreplication and CW attainment.


Assuntos
Ciclo Celular/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Fatores de Transcrição da Família Snail/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Peso Corporal , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Ecdisona/metabolismo , Células Endócrinas/metabolismo , Endorreduplicação , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Larva/genética , Larva/crescimento & desenvolvimento , Larva/microbiologia , Metamorfose Biológica , Nutrientes/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/genética , Serina-Treonina Quinases TOR/genética
4.
FASEB J ; 34(1): 1901-1911, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914605

RESUMO

Human pancreatic islets engrafted into immunodeficient mice serve as an important model for in vivo human diabetes studies. Following engraftment, islet function can be monitored in vivo by measuring circulating glucose and human insulin; however, it will be important to recover viable cells for more complex graft analyses. Moreover, RNA analyses of dissected grafts have not distinguished which hormone-specific cell types contribute to gene expression. We developed a method for recovering live cells suitable for fluorescence-activated cell sorting from human islets engrafted in mice. Although yields of recovered islet cells were relatively low, the ratios of bulk-sorted ß, α, and δ cells and their respective hormone-specific RNA-Seq transcriptomes are comparable pretransplant and posttransplant, suggesting that the cellular characteristics of islet grafts posttransplant closely mirror the original donor islets. Single-cell RNA-Seq transcriptome analysis confirms the presence of appropriate ß, α, and δ cell subsets. In addition, ex vivo perifusion of recovered human islet grafts demonstrated glucose-stimulated insulin secretion. Viable cells suitable for patch-clamp analysis were recovered from transplanted human embryonic stem cell-derived ß cells. Together, our functional and hormone-specific transcriptome analyses document the broad applicability of this system for longitudinal examination of human islet cells undergoing developmental/metabolic/pharmacogenetic manipulation in vivo and may facilitate the discovery of treatments for diabetes.


Assuntos
Células Endócrinas/fisiologia , Ilhotas Pancreáticas/fisiologia , Transcriptoma/fisiologia , Adulto , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Células Endócrinas/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Sobrevivência de Enxerto/fisiologia , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/metabolismo , Transplante das Ilhotas Pancreáticas/métodos , Masculino , Camundongos , Transplante Heterólogo/métodos , Adulto Jovem
5.
Ann Anat ; 227: 151422, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31563568

RESUMO

The knowledge of bone biology has largely changed in the last few decades. Osteocytes are multifunctional bone cells that are surrounded by mineralized bone matrix and for decades it was considered that they might be relatively inactive cells. However, nowadays it is known that osteocytes are highly active cells which are indispensable for the normal function of the skeleton, playing main roles in several physiological processes, both within and beyond the bone microenvironment. This review highlights and updates the current state of knowledge of the osteocyte and focuses on its roles in bone remodeling and mineral homeostasis, and also reviews its recently discovered endocrine function. Osteocytes secrete sclerostin (a protein that works as a negative regulator of bone mass), and FGF-23, the most important osteocyte-secreted endocrine factor, since it is able to regulate the phosphate metabolism. Moreover, osteocytes can act as mechanosensory cells, transforming the mechanical strain into chemical signaling towards the effector cells (osteoblasts and osteoclasts). Therefore, the osteocyte plays an important role in bone biology, specifically in the remodeling process, since it regulates both the osteoblast and osteoclast activity. Finally, the paper discusses the clinical application of the bone biology, updating the new therapies against bone-loss disorders.


Assuntos
Osso e Ossos/citologia , Osteócitos/fisiologia , Apoptose/fisiologia , Remodelação Óssea/fisiologia , Reabsorção Óssea/fisiopatologia , Cálcio/sangue , Células Endócrinas/fisiologia , Humanos , Mecanorreceptores/fisiologia , Mecanotransdução Celular/fisiologia , Osteócitos/citologia , Osteogênese/fisiologia
6.
J Morphol ; 281(1): 55-67, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31782555

RESUMO

Goblet cells (GCs) and endocrine cells (ECs) play an important role in intestine physiology, and few studies currently exist for Amazonian fishes. This study aimed to quantify the distribution of GCs and ECs producing cholecystokinin-8 and neuropeptide Y, assessed by mucin histochemistry and peptides immunohistochemistry, in the intestine of two Amazonian species with different feeding habits Tambaqui (Colossosoma macropomum) and hybrid catfish (Pseudoplatystoma reticulatum × Leiarius marmoratus), an omnivore and carnivore, respectively. A systematic literature review correlating feeding habit and GC and EC distribution was also included to contribute to the comparative study. The results of this study provided novel information about the gut cells of Tambaqui and hybrid catfish. Both, GCs and ECs can be found sweeping the entire intestine of Tambaqui and hybrid catfish although the cells can be more concentrated in certain segments. The GCs and ECs in Tambaqui were more uniformly distributed in the midgut segments (T1, T2, and T3). Unlike, in hybrid catfish GCs were more concentrated in the hindgut (C4) and ECs mainly in the two midgut segments (C1 and C2) of hybrid catfish. Based on the comparison between Tambaqui, hybrid catfish, and other fishes in the literature review, we suggest that cell distribution can be partially explained by feeding habits, carnivorous vs. omnivorous.


Assuntos
Peixes-Gato/genética , Células Endócrinas/citologia , Água Doce , Hibridização Genética , Intestinos/citologia , Animais , Contagem de Células , Colecistocinina/metabolismo , Mucinas/metabolismo , Neuropeptídeo Y/metabolismo , Fragmentos de Peptídeos/metabolismo , Revisões Sistemáticas como Assunto
7.
Adv Immunol ; 143: 1-9, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31607366

RESUMO

Diverse infectious, inflammatory, and environmental stimuli induce type 2 inflammation in the body. Group 2 innate lymphoid cells (ILC2s) are potent producers of type 2 cytokines and play important roles in promoting type 2 inflammation. In addition to alarmins and other cytokines which are known to regulate ILC2 responses, emerging studies identified the regulation of ILC2s by the nervous system through neurotransmitter and neuropeptides. In this review, we highlight recent advances in the regulation of ILC2s and type 2 inflammation by the nervous system.


Assuntos
Citocinas/metabolismo , Imunidade Inata , Inflamação/imunologia , Linfócitos/imunologia , Neuroimunomodulação , Neurônios/imunologia , Neuropeptídeos/metabolismo , Animais , Células Endócrinas/imunologia , Células Endócrinas/metabolismo , Retroalimentação Fisiológica/fisiologia , Humanos , Linfócitos/metabolismo , Linfócitos/fisiologia , Neurônios/metabolismo , Neurotransmissores/imunologia , Neurotransmissores/metabolismo , Neurotransmissores/farmacologia , Células Estromais/metabolismo , Células Estromais/fisiologia
8.
Anticancer Res ; 39(10): 5581-5588, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570453

RESUMO

BACKGROUND/AIM: The utility of peripheral blood neutrophil-to-lymphocyte ratios (NLRs) and platelet-to-lymphocyte ratios (PLRs) as prognostic predictors of surgery and chemotherapy in breast cancer has been reported. In this study, NLRs and PLRs were calculated before treatment and during cancer progression in primary hormone receptor-positive breast cancer (HRBC) patients who chose endocrine therapy (ET) as the primary treatment, and prognostic prediction and factor analysis were performed. PATIENTS AND METHODS: A total of 55 patients diagnosed with stage IIIB, IIIC, or IV HRBC who received ET as the primary treatment were included. RESULTS: Increased NLRs were found to significantly contribute to a shorter overall survival from cancer progression (OS-CP) (p=0.040, log-rank). Increased PLRs were similarly associated with a shorter OS-CP (p=0.036, log-rank). In multivariate analysis, an increased NLR was an independent prognostic factor (p=0.035, hazard ratio(HR)=5.221). CONCLUSION: Changes in NLRs and PLRs become prognostic indicators when the therapeutic effect of ET is limited.


Assuntos
Plaquetas/patologia , Neoplasias da Mama/patologia , Células Endócrinas/patologia , Linfócitos/patologia , Neutrófilos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Contagem de Leucócitos/métodos , Contagem de Linfócitos/métodos , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Prognóstico , Estudos Retrospectivos
9.
Open Vet J ; 9(2): 114-119, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31360649

RESUMO

The peptide hormones of the adenohypophysis are produced by proteolytic processing of their prohormone precursors. Cathepsin L is known to function as a major proteolytic enzyme involved in the production of the peptide hormones. The structure of the propeptide region of cathepsin L is identical to cytotoxic T-lymphocyte antigen-2 alpha (CTLA-2α) which is also shown to exhibit selective inhibitory activities against cathepsin L. However, the specific cell types synthesizing CTLA-2α in mouse adenohypophysis and its functional implications as relevant in vivo have not been demonstrated. In this study, CTLA-2α expression in the adenohypophysis was evaluated by immunohistochemistry. In both male and female mice, strong immunoreactivity was specifically detected in folliculostellate (FS) cells surrounding endocrine cells which were delineated by CTLA-2α. These findings suggest that the CTLA-2α may be involved in the proteolytic processing and secretion of the hormones in the adenohypophysis through regulation of cathepsin L.


Assuntos
Antígenos de Diferenciação/metabolismo , Células Endócrinas/metabolismo , Adeno-Hipófise/metabolismo , Animais , Catepsina L/metabolismo , Feminino , Imuno-Histoquímica , Masculino , Camundongos
10.
PLoS One ; 14(5): e0216254, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31075154

RESUMO

BACKGROUND: Pancreatic islet xenotransplantation is a potential treatment for diabetes mellitus, and porcine pancreas may provide a readily available source of islets. Islets in juvenile pigs are smaller than those in young adult pigs, but the insulin content is very similar. In addition, as juvenile pigs are more easily reared in uncontaminated conditions, many researchers have conducted studies using pancreatic islets from juvenile pigs. We aimed to analyze the distributions of endocrine cell clusters by comprehensively evaluating juvenile porcine pancreatic development and to propose an appropriate age at which islets could be isolated from the juvenile porcine pancreas. METHODS: Splenic (SL) and duodenal lobe (DL) samples were collected from the pancreases of pigs aged 0-180 days (n = 3/day after birth). The chronological changes in endocrine cell clustering were analyzed in relation to morphological changes, cell characterization, numbers, islet areas, and gene expression. RESULTS: In juvenile pigs aged 0-21 days, the pancreas contained numerous endocrine cells, and compact islets appeared from 21 days of age. Well-defined small islets were seen at 28 days of age, and the clusters were denser in the SL than in the DL. At 35 days of age, the islets were morphologically similar to those observed at 180 days of age, and the greater number of islets was similar to that seen at 90 days of age. The differences in the islets' cytoarchitecture between the lobes were negligible. The expression of ß-cell-related genes was higher in the juvenile pancreas than in the adult pancreas, and the expression of neurogenin-3 decreased dramatically over time. CONCLUSIONS: These findings may have implications for attempts to refine the most appropriate age for islet isolation from porcine donors. Focusing on porcine pancreatic islets isolated at around 35 days after birth may offer benefits regarding their xenotransplantation potential.


Assuntos
Fatores Etários , Células Endócrinas/citologia , Transplante das Ilhotas Pancreáticas/métodos , Ilhotas Pancreáticas/crescimento & desenvolvimento , Transplante Heterólogo/métodos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Análise por Conglomerados , Diabetes Mellitus/terapia , Humanos , Ilhotas Pancreáticas/citologia , Proteínas do Tecido Nervoso/metabolismo , Suínos
11.
Diabetes ; 68(6): 1230-1239, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30936150

RESUMO

Pancreatic ß-cells play a pivotal role in maintaining normoglycemia. Recent studies have revealed that the ß-cell is not a homogeneous cell population but, rather, is heterogeneous in a number of properties such as electrical activity, gene expression, and cell surface markers. Identification of specific ß-cell subpopulations altered in diabetic conditions would open a new avenue to develop targeted therapeutic interventions. As intense studies of ß-cell heterogeneity are anticipated in the next decade, it is important that heterogeneity of the islet be recognized. Many studies in the past were undertaken with a small sample of islets, which might overlook important individual variance. In this study, by systematic analyses of the human islet in two and three dimensions, we demonstrate islet heterogeneity in size, number, architecture, cellular composition, and capillary density. There is no stereotypic human islet, and thus, a sufficient number of islets should be examined to ensure study reproducibility.


Assuntos
Células Secretoras de Glucagon/citologia , Células Secretoras de Insulina/citologia , Ilhotas Pancreáticas/citologia , Células Secretoras de Somatostatina/citologia , Adolescente , Adulto , Idoso , Animais , Células Endócrinas/citologia , Células Endócrinas/metabolismo , Feminino , Células Secretoras de Glucagon/metabolismo , Humanos , Imageamento Tridimensional , Imuno-Histoquímica , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/irrigação sanguínea , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Microscopia Confocal , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Células Secretoras de Somatostatina/metabolismo , Adulto Jovem
12.
PLoS One ; 14(3): e0211134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30917119

RESUMO

Neurotensin is a peptide hormone released from enteroendocrine cells in the small intestine in response to fat ingestion. Although the mechanisms regulating neurotensin secretion are still incompletely understood, our recent findings implicate a role for extracellular signal-regulated kinase 1 and 2 as positive regulators of free fatty acid-stimulated neurotensin secretion. Previous studies have shown that kinase suppressor of Ras 1 acts as a molecular scaffold of the Raf/MEK/extracellular signal-regulated kinase 1 and 2 kinase cascade and regulates intensity and duration of extracellular signal-regulated kinase 1 and 2 signaling. Here, we demonstrate that inhibition of kinase suppressor of Ras 1 attenuates neurotensin secretion and extracellular signal-regulated kinase 1 and 2 signaling in human endocrine cells. Conversely, we show that overexpression of kinase suppressor of Ras 1 enhances neurotensin secretion and extracellular signal-regulated kinase 1 and 2 signaling. We also show that inhibition of extracellular signal-regulated kinase 2 and exocyst complex component 70, a substrate of extracellular signal-regulated kinase 2 and mediator of secretory vesicle exocytosis, potently inhibits basal and docosahexaenoic acid-stimulated neurotensin secretion, whereas overexpression of exocyst complex component 70 enhances basal and docosahexaenoic acid-stimulated neurotensin secretion. Together, our findings demonstrate a role for kinase suppressor of Ras 1 as a positive regulator of neurotensin secretion from human endocrine cells and indicate that this effect is mediated by the extracellular signal-regulated kinase 1 and 2 signaling pathway. Moreover, we reveal a novel role for exocyst complex component 70 in regulation of neurotensin vesicle exocytosis through its interaction with the extracellular signal-regulated kinase 1 and 2 signaling pathway.


Assuntos
Sistema de Sinalização das MAP Quinases , Neurotensina/metabolismo , Proteínas Quinases/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Células Endócrinas/metabolismo , Células Enteroendócrinas/metabolismo , Exocitose , Ácidos Graxos/metabolismo , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Ligação Proteica , Vesículas Secretórias/metabolismo , Transdução de Sinais
13.
PLoS Genet ; 15(3): e1008002, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30893315

RESUMO

Mammary epithelial progenitors are the normal cell-of-origin of breast cancer. We previously defined a population of p27+ quiescent hormone-responsive progenitor cells in the normal human breast whose frequency associates with breast cancer risk. Here, we describe that deletion of the Cdkn1b gene encoding the p27 cyclin-dependent kinase inhibitor in the estrogen-induced mammary tumor-susceptible ACI rat strain leads to a decrease in the relative frequencies of Cd49b+ mammary luminal epithelial progenitors and pregnancy-related differentiation. We show by comprehensive gene expression profiling of purified progenitor and differentiated mammary epithelial cell populations that p27 deletion has the most pronounced effects on luminal progenitors. Cdkn1b-/- females have decreased fertility, but rats that are able to get pregnant had normal litter size and were able to nurse their pups implying that loss of p27 in ACI rats does not completely abrogate ovarian function and lactation. Reciprocal mammary gland transplantation experiments indicate that the p27-loss-induced changes in mammary epithelial cells are not only caused by alterations in their intrinsic properties, but are likely due to altered hormonal signaling triggered by the perturbed systemic endocrine environment observed in Cdkn1b-/- females. We also observed a decrease in the frequency of mammary epithelial cells positive for progesterone receptor (Pr) and FoxA1, known direct transcriptional targets of the estrogen receptor (Erα), and an increase in phospho-Stat5 positive cells commonly induced by prolactin (Prl). Characterization of genome-wide Pr chromatin binding revealed distinct binding patterns in mammary epithelial cells of Cdkn1b+/+ and Cdkn1b-/- females and enrichment in genes with known roles in Notch, ErbB, leptin, and Erα signaling and regulation of G1-S transition. Our data support a role for p27 in regulating the pool size of hormone-responsive luminal progenitors that could impact breast cancer risk.


Assuntos
Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/fisiologia , Animais , Animais Geneticamente Modificados/genética , Neoplasias da Mama/genética , Diferenciação Celular , Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Células Endócrinas/fisiologia , Células Epiteliais , Receptor alfa de Estrogênio , Estrogênios , Feminino , Predisposição Genética para Doença/genética , Humanos , Integrina alfa1 , Glândulas Mamárias Animais , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Gravidez , Progesterona , Ratos , Ratos Endogâmicos ACI , Ratos Sprague-Dawley , Receptores Estrogênicos , Receptores de Progesterona , Fatores de Risco , Transdução de Sinais , Células-Tronco
14.
J Inherit Metab Dis ; 42(1): 147-158, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30740741

RESUMO

BACKGROUND: Transaldolase deficiency (TALDO-D) is a rare autosomal recessive inborn error of the pentose phosphate pathway. Since its first description in 2001, several case reports have been published, but there has been no comprehensive overview of phenotype, genotype, and phenotype-genotype correlation. METHODS: We performed a retrospective questionnaire and literature study of clinical, biochemical, and molecular data of 34 patients from 25 families with proven TALDO-D. In some patients, endocrine abnormalities have been found. To further evaluate these abnormalities, we performed biochemical investigations on blood of 14 patients. RESULTS AND CONCLUSIONS: Most patients (n = 22) had an early-onset presentation (prenatally or before 1 month of age); 12 patients had a late-onset presentation (3 months to 9 years). Main presenting symptoms were intrauterine growth restriction, dysmorphic facial features, congenital heart disease, anemia, thrombocytopenia, and hepato(spleno)megaly. An older sib of two affected patients was asymptomatic until the age of 9 years, and only after molecular diagnosis was hepatomegaly noted. In some patients, there was gonadal dysfunction with low levels of testosterone and secondary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) abnormalities later in life. This overview provides information that can be helpful for managing patients and counseling families regarding prognosis. Diagnostic guidelines, possible genotype-phenotype correlations, treatment options, and pathophysiological disease mechanisms are proposed.


Assuntos
Erros Inatos do Metabolismo dos Carboidratos/genética , Erros Inatos do Metabolismo dos Carboidratos/metabolismo , Células Endócrinas/metabolismo , Hormônios/metabolismo , Transaldolase/deficiência , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Estudos Retrospectivos , Inquéritos e Questionários , Transaldolase/genética , Transaldolase/metabolismo
15.
Cell Metab ; 29(3): 769-783.e4, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30713110

RESUMO

The interaction between the immune system and endocrine cells in the pancreas is crucial for the initiation and progression of type 1 diabetes (T1D). Imaging mass cytometry (IMC) enables multiplexed assessment of the abundance and localization of more than 30 proteins on the same tissue section at 1-µm resolution. Herein, we have developed a panel of 33 antibodies that allows for the quantification of key cell types including pancreatic exocrine cells, islet cells, immune cells, and stromal components. We employed this panel to analyze 12 pancreata obtained from donors with clinically diagnosed T1D and 6 pancreata from non-diabetic controls. In the pancreata from donors with T1D, we simultaneously visualized significant alterations in islet architecture, endocrine cell composition, and immune cell presentation. Indeed, we demonstrate the utility of IMC to investigate complex events on the cellular level that will provide new insights on the pathophysiology of T1D.


Assuntos
Diabetes Mellitus Tipo 1 , Citometria por Imagem/métodos , Ilhotas Pancreáticas , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Células Endócrinas/imunologia , Células Endócrinas/metabolismo , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/ultraestrutura
17.
Nat Cell Biol ; 21(2): 263-274, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30710150

RESUMO

Despite advances in the differentiation of insulin-producing cells from human embryonic stem cells, the generation of mature functional ß cells in vitro has remained elusive. To accomplish this goal, we have developed cell culture conditions to closely mimic events occurring during pancreatic islet organogenesis and ß cell maturation. In particular, we have focused on recapitulating endocrine cell clustering by isolating and reaggregating immature ß-like cells to form islet-sized enriched ß-clusters (eBCs). eBCs display physiological properties analogous to primary human ß cells, including robust dynamic insulin secretion, increased calcium signalling in response to secretagogues, and improved mitochondrial energization. Notably, endocrine cell clustering induces metabolic maturation by driving mitochondrial oxidative respiration, a process central to stimulus-secretion coupling in mature ß cells. eBCs display glucose-stimulated insulin secretion as early as three days after transplantation in mice. In summary, replicating aspects of endocrine cell clustering permits the generation of stem-cell-derived ß cells that resemble their endogenous counterparts.


Assuntos
Diferenciação Celular , Células-Tronco Embrionárias/citologia , Células Endócrinas/citologia , Fibroblastos/citologia , Células-Tronco Embrionárias Humanas/citologia , Células Secretoras de Insulina/citologia , Animais , Células Cultivadas , Células-Tronco Embrionárias/fisiologia , Células Endócrinas/fisiologia , Fibroblastos/fisiologia , Glucose/farmacologia , Células-Tronco Embrionárias Humanas/fisiologia , Humanos , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/citologia , Camundongos , Mitocôndrias/metabolismo
18.
Dev Cell ; 48(1): 49-63.e7, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30620902

RESUMO

In the developing pancreas, transient Neurog3-expressing progenitors give rise to four major islet cell types: α, ß, δ, and γ; when and how the Neurog3+ cells choose cell fate is unknown. Using single-cell RNA-seq, trajectory analysis, and combinatorial lineage tracing, we showed here that the Neurog3+ cells co-expressing Myt1 (i.e., Myt1+Neurog3+) were biased toward ß cell fate, while those not simultaneously expressing Myt1 (Myt1-Neurog3+) favored α fate. Myt1 manipulation only marginally affected α versus ß cell specification, suggesting Myt1 as a marker but not determinant for islet-cell-type specification. The Myt1+Neurog3+ cells displayed higher Dnmt1 expression and enhancer methylation at Arx, an α-fate-promoting gene. Inhibiting Dnmts in pancreatic progenitors promoted α cell specification, while Dnmt1 overexpression or Arx enhancer hypermethylation favored ß cell production. Moreover, the pancreatic progenitors contained distinct Arx enhancer methylation states without transcriptionally definable sub-populations, a phenotype independent of Neurog3 activity. These data suggest that Neurog3-independent methylation on fate-determining gene enhancers specifies distinct endocrine-cell programs.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/fisiologia , Ilhotas Pancreáticas/citologia , Proteínas do Tecido Nervoso/metabolismo , Organogênese/fisiologia , Pâncreas/metabolismo , Animais , Diferenciação Celular/genética , Linhagem da Célula/fisiologia , Células Endócrinas/metabolismo , Proteínas de Homeodomínio/metabolismo , Células Secretoras de Insulina/metabolismo , Camundongos , Fatores de Transcrição/metabolismo
19.
Nihon Shokakibyo Gakkai Zasshi ; 116(1): 71-79, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30626856

RESUMO

We report a case of endocrine cell carcinoma (ECC) of the esophagus with long term survival after chemoradiotherapy. The patient had a complete response and remains without any recurrence. A 69-year-old woman visited our hospital because of progressive dysphagia. The patient was diagnosed by computed tomography and histology examination of biopsy specimens with small cell ECC of the esophagus, cT2N1M0, cStage II based on the Classification of Esophageal Carcinoma. She was treated with chemoradiotherapy comprising 45Gy of irradiation and four courses of cisplatin and etoposide chemotherapy. After completion of the treatment, she was found to have a complete response. She remains alive to date without evidence of any recurrence after 7 years. This case suggests that chemoradiotherapy is an effective treatment for ECC of the esophagus.


Assuntos
Quimiorradioterapia , Células Endócrinas , Neoplasias Esofágicas/terapia , Recidiva Local de Neoplasia/terapia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Feminino , Fluoruracila , Humanos
20.
Carcinogenesis ; 40(2): 203-215, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-30596981

RESUMO

Resistant breast and prostate cancers remain a major clinical problem, new therapeutic approaches and better predictors of therapeutic response are clearly needed. Because of the involvement of the unfolded protein response (UPR) in cell proliferation and apoptosis evasion, an increasing number of publications support the hypothesis that impairments in this network trigger and/or exacerbate cancer. Moreover, UPR activation could contribute to the development of drug resistance phenotypes in both breast and prostate cancers. Therefore, targeting this pathway has recently emerged as a promising strategy in anticancer therapy. This review addresses the contribution of UPR to breast and prostate tissues homeostasis and its significance to cancer endocrine response with focus on the current progress on UPR research related to cancer biology, detection, prognosis and treatment.


Assuntos
Neoplasias da Mama/patologia , Mama/patologia , Células Endócrinas/patologia , Homeostase/fisiologia , Próstata/patologia , Neoplasias da Próstata/patologia , Resposta a Proteínas não Dobradas/fisiologia , Animais , Apoptose/fisiologia , Proliferação de Células/fisiologia , Feminino , Humanos , Masculino
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