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1.
Autops Case Rep ; 7(4): 26-29, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29264327

RESUMO

Pancreatic hamartomas are extremely rare tumors in adults and even more so in children. They are lesions characterized by acinar, islet and ductal components found in varying proportions and in a disorganized pattern. We report a case of a premature female with trisomy 18 diagnosed by amniocentesis. The newborn was delivered by cesarean section at thirty-three weeks of gestation and expired within one hour of birth. Postmortem examination exhibited numerous features associated with Trisomy 18 including lanugo on the torso and arms, micrognathia, microstomia, left low-set ear with small flat pinna, closed ear canal, clenched fists with overlapping fingers, rocker-bottom feet, narrow pelvis, large right diaphragmatic hernia and left pulmonary hypoplasia. Microscopic examination of the pancreas revealed an area, 1.2 cm in greatest dimension, with branching ducts and cysts lined by cuboidal epithelium intermingled within primitive mesenchymal proliferation and exocrine glands. The cysts measured up to 0.2 cm and were surrounded by a collarette of proliferating spindle cells as highlighted by Masson's trichrome stain. A diagnosis of pancreatic hamartoma was rendered. A total of thirty-four cases of pancreatic hamartomas have been reported in the literature including twenty-seven in adults, five in children and two in newborns. Our case may be the third pancreatic hamartoma reported in association with Trisomy 18. We recommend that careful examination of the pancreas be performed in individuals with Trisomy 18 to further characterize this lesion as one of the possible abnormal findings associated with this syndrome.

2.
Autops. Case Rep ; 7(4): 26-29, Oct.-Dec. 2017. ilus
Artigo em Inglês | LILACS | ID: biblio-905402

RESUMO

Pancreatic hamartomas are extremely rare tumors in adults and even more so in children. They are lesions characterized by acinar, islet and ductal components found in varying proportions and in a disorganized pattern. We report a case of a premature female with trisomy 18 diagnosed by amniocentesis. The newborn was delivered by cesarean section at thirty-three weeks of gestation and expired within one hour of birth. Postmortem examination exhibited numerous features associated with Trisomy 18 including lanugo on the torso and arms, micrognathia, microstomia, left low-set ear with small flat pinna, closed ear canal, clenched fists with overlapping fingers, rocker-bottom feet, narrow pelvis, large right diaphragmatic hernia and left pulmonary hypoplasia. Microscopic examination of the pancreas revealed an area, 1.2 cm in greatest dimension, with branching ducts and cysts lined by cuboidal epithelium intermingled within primitive mesenchymal proliferation and exocrine glands. The cysts measured up to 0.2 cm and were surrounded by a collarette of proliferating spindle cells as highlighted by Masson's trichrome stain. A diagnosis of pancreatic hamartoma was rendered. A total of thirty-four cases of pancreatic hamartomas have been reported in the literature including twenty-seven in adults, five in children and two in newborns. Our case may be the third pancreatic hamartoma reported in association with Trisomy 18. We recommend that careful examination of the pancreas be performed in individuals with Trisomy 18 to further characterize this lesion as one of the possible abnormal findings associated with this syndrome.


Assuntos
Humanos , Feminino , Recém-Nascido , Hamartoma/patologia , Síndrome da Trissomía do Cromossomo 18/patologia , Autopsia , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Doenças Raras , Síndrome da Trissomía do Cromossomo 18/diagnóstico
3.
Fetal Pediatr Pathol ; 34(3): 190-6, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25871299

RESUMO

Bilateral nephroblastomatosis (NB) is an uncommon renal anomaly characterized by multiple confluent nephrogenic rests scattered through both kidneys, with only a limited number of cases reported in the medical literature. Some of these children may have associated either Perlman or Beckwith-Wiedemann syndrome and others do not demonstrate syndromic features. We report a full-term boy with anteverted nose, bilateral bronchial stenosis due to lack of cartilage, bilateral obstructive renal dysplasia and NB with glomeruloid features. The infant had visceromegaly, but neither gigantism nor hemihypertrophy. Immunohistochemistry for PAX2 (Paired box gene-2) and WT-1 (Wilms Tumor 1) were strongly positive in the areas of NB. GLEPP-1 (Glomerular Epithelial Protein) did not stain the areas of NB with a glomeruloid appearance, but was positive in the renal glomeruli as expected. We found neither associated bronchial stenosis nor the histology of NB resembling giant glomeruli in any of the reported cases of NB.


Assuntos
Anormalidades Múltiplas/patologia , Brônquios/anormalidades , Nefropatias/patologia , Rim/anormalidades , Constrição Patológica , Humanos , Recém-Nascido , Masculino
4.
J Am Soc Nephrol ; 26(1): 133-47, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24925721

RESUMO

Diabetic kidney disease (DKD) is the most common cause of ESRD in the United States. Podocyte injury is an important feature of DKD that is likely to be caused by circulating factors other than glucose. Soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor found to be elevated in the serum of patients with FSGS and causes podocyte αVß3 integrin-dependent migration in vitro. Furthermore, αVß3 integrin activation occurs in association with decreased podocyte-specific expression of acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3b) in kidney biopsy specimens from patients with FSGS. However, whether suPAR-dependent αVß3 integrin activation occurs in diseases other than FSGS and whether there is a direct link between circulating suPAR levels and SMPDL3b expression in podocytes remain to be established. Our data indicate that serum suPAR levels are also elevated in patients with DKD. However, unlike in FSGS, SMPDL3b expression was increased in glomeruli from patients with DKD and DKD sera-treated human podocytes, where it prevented αVß3 integrin activation by its interaction with suPAR and led to increased RhoA activity, rendering podocytes more susceptible to apoptosis. In vivo, inhibition of acid sphingomyelinase reduced proteinuria in experimental DKD but not FSGS, indicating that SMPDL3b expression levels determined the podocyte injury phenotype. These observations suggest that SMPDL3b may be an important modulator of podocyte function by shifting suPAR-mediated podocyte injury from a migratory phenotype to an apoptotic phenotype and that it represents a novel therapeutic glomerular disease target.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Regulação Enzimológica da Expressão Gênica , Nefropatias/metabolismo , Glomérulos Renais/patologia , Podócitos/patologia , Esfingomielina Fosfodiesterase/metabolismo , Animais , Apoptose , Movimento Celular , Feminino , Células HEK293 , Humanos , Integrina alfaVbeta3/metabolismo , Integrinas/metabolismo , Glomérulos Renais/lesões , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Neuropeptídeos/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Podócitos/citologia , Receptores de Ativador de Plasminogênio Tipo Uroquinase/sangue , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo
5.
J Clin Invest ; 123(4): 1492-500, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23524969

RESUMO

Type II deiodinase (D2) activates thyroid hormone by converting thyroxine (T4) to 3,5,3'-triiodothyronine (T3). This allows plasma T4 to signal a negative feedback loop that inhibits production of thyrotropin-releasing hormone (TRH) in the mediobasal hypothalamus (MBH) and thyroid-stimulating hormone (TSH) in the pituitary. To determine the relative contributions of these D2 pathways in the feedback loop, we developed 2 mouse strains with pituitary- and astrocyte-specific D2 knockdown (pit-D2 KO and astro-D2 KO mice, respectively). The pit-D2 KO mice had normal serum T3 and were systemically euthyroid, but exhibited an approximately 3-fold elevation in serum TSH levels and a 40% reduction in biological activity. This was the result of elevated serum T4 that increased D2-mediated T3 production in the MBH, thus decreasing Trh mRNA. That tanycytes, not astrocytes, are the cells within the MBH that mediate T4-to-T3 conversion was defined by studies using the astro-D2 KO mice. Despite near-complete loss of brain D2, tanycyte D2 was preserved in astro-D2 KO mice at levels that were sufficient to maintain both the T4-dependent negative feedback loop and thyroid economy. Taken together, these data demonstrated that the hypothalamic-thyroid axis is wired to maintain normal plasma T3 levels, which is achieved through coordination of T4-to-T3 conversion between thyrotrophs and tanycytes.


Assuntos
Regulação da Expressão Gênica , Hipotálamo/enzimologia , Iodeto Peroxidase/metabolismo , Hipófise/enzimologia , Tireotropina/genética , Tri-Iodotironina/sangue , Animais , Astrócitos/enzimologia , Composição Corporal , Córtex Cerebral/metabolismo , Ativação Enzimática , Retroalimentação Fisiológica , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Hipotálamo/citologia , Hipotálamo/metabolismo , Iodeto Peroxidase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Especificidade de Órgãos , Hipófise/citologia , Glândula Tireoide/metabolismo , Glândula Tireoide/fisiologia , Tireotrofos/enzimologia , Tireotropina/sangue , Hormônio Liberador de Tireotropina , Tiroxina/sangue , Tiroxina/fisiologia , Tri-Iodotironina/fisiologia
6.
Diabetes ; 60(4): 1082-9, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21335378

RESUMO

OBJECTIVE: Thyroid hormone accelerates energy expenditure; thus, hypothyroidism is intuitively associated with obesity. However, studies failed to establish such a connection. In brown adipose tissue (BAT), thyroid hormone activation via type 2 deiodinase (D2) is necessary for adaptive thermogenesis, such that mice lacking D2 (D2KO) exhibit an impaired thermogenic response to cold. Here we investigate whether the impaired thermogenesis of D2KO mice increases their susceptibility to obesity when placed on a high-fat diet. RESEARCH DESIGN AND METHODS: To test this, D2KO mice were admitted to a comprehensive monitoring system acclimatized to room temperature (22°C) or thermoneutrality (30°C) and kept either on chow or high-fat diet for 60 days. RESULTS: At 22°C, D2KO mice preferentially oxidize fat, have a similar sensitivity to diet-induced obesity, and are supertolerant to glucose. However, when thermal stress is eliminated at thermoneutrality (30°C), an opposite phenotype is encountered, one that includes obesity, glucose intolerance, and exacerbated hepatic steatosis. We suggest that a compensatory increase in BAT sympathetic activation of the D2KO mice masks metabolic repercussions that they would otherwise exhibit. CONCLUSIONS: Thus, upon minimization of thermal stress, high-fat feeding reveals the defective capacity of D2KO mice for diet-induced thermogenesis, provoking a paradigm shift in the understanding of the role of the thyroid hormone in metabolism.


Assuntos
Intolerância à Glucose/etiologia , Intolerância à Glucose/genética , Iodeto Peroxidase/fisiologia , Obesidade/genética , Hormônios Tireóideos/metabolismo , Animais , Composição Corporal/genética , Calorimetria Indireta , Gorduras na Dieta/efeitos adversos , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/genética , Teste de Tolerância a Glucose , Iodeto Peroxidase/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Obesidade/induzido quimicamente , RNA Mensageiro , Temperatura Ambiente , Hormônios Tireóideos/genética , Triglicerídeos/metabolismo , Ganho de Peso/genética , Ganho de Peso/fisiologia
7.
Endocrinology ; 152(4): 1616-26, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21285314

RESUMO

The goal of this study was to investigate how the Arg386Pro mutation prolongs KiSS-1 receptor (KISS1R) responsiveness to kisspeptin, contributing to human central precocious puberty. Confocal imaging showed colocalization of wild-type (WT) KISS1R with a membrane marker, which persisted for up to 5 h of stimulation. Conversely, no colocalization with a lysosome marker was detected. Also, overnight treatment with a lysosome inhibitor did not affect WT KISS1R protein, whereas overnight treatment with a proteasome inhibitor increased protein levels by 24-fold. WT and Arg386Pro KISS1R showed time-dependent internalization upon stimulation. However, both receptors were recycled back to the membrane. The Arg386Pro mutation did not affect the relative distribution of KISS1R in membrane and internalized fractions when compared to WT KISS1R for up to 120 min of stimulation, demonstrating that this mutation does not affect KISS1R trafficking rate. Nonetheless, total Arg386Pro KISS1R was substantially increased compared with WT after 120 min of kisspeptin stimulation. This net increase was eliminated by blockade of detection of recycled receptors, demonstrating that recycled receptors account for the increased responsiveness of this mutant to kisspeptin. We therefore conclude the following: 1) WT KISS1R is degraded by proteasomes rather than lysosomes; 2) WT and Arg386Pro KISS1R are internalized upon stimulation, but most of the internalized receptors are recycled back to the membrane rather than degraded; 3) the Arg386Pro mutation does not affect the rate of KISS1R trafficking--instead, it prolongs responsiveness to kisspeptin by decreasing KISS1R degradation, resulting in the net increase on mutant receptor recycled back to the plasma membrane.


Assuntos
Receptores Acoplados a Proteínas-G/metabolismo , Animais , Western Blotting , Células CHO , Células COS , Membrana Celular/metabolismo , Cricetinae , Cricetulus , Imunofluorescência , Humanos , Imunoprecipitação , Lisossomos/metabolismo , Mutação , Transporte Proteico/genética , Transporte Proteico/fisiologia , Receptores Acoplados a Proteínas-G/genética , Receptores de Kisspeptina-1
8.
PLoS One ; 5(12): e14250, 2010 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-21170377

RESUMO

In carcinomas stromal cells participate in cancer progression by producing proteases such as MMPs. The expression MMP1 is a prognostic factor in human chondrosarcoma, however the role in tumor progression is unknown. Laser capture microdissection and In Situ hybridization were used to determine cellular origin of MMP1 in human sarcomas. A xenogenic model of tumor progression was then used and mice were divided in two groups: each harboring either the control or a stably MMP1 silenced cell line. Animals were sacrificed; the neovascularization, primary tumor volumes, and metastatic burden were assessed. LCM and RNA-ISH analysis revealed MMP1 expression was predominantly localized to the tumor cells in all samples of sarcoma (p = 0.05). The percentage lung metastatic volume at 5 weeks (p = 0.08) and number of spontaneous deaths secondary to systemic tumor burden were lower in MMP1 silenced cell bearing mice. Interestingly, this group also demonstrated a larger primary tumor size (p<0.04) and increased angiogenesis (p<0.01). These findings were found to be consistent when experiment was repeated using a second independent MMP1 silencing sequence. Prior clinical trials employing MMP1 inhibitors failed because of a poor understanding of the role of MMPs in tumor progression. The current findings indicating tumor cell production of MMP1 by sarcoma cells is novel and highlights the fundamental differences in MMP biology between carcinomas and sarcomas. The results also emphasize the complex roles of MMP in tumor progression of sarcomas. Not only does metastasis seem to be affected by MMP1 silencing, but also local tumor growth and angiogenesis are affected inversely.


Assuntos
Regulação Enzimológica da Expressão Gênica , Metaloproteinase 1 da Matriz/metabolismo , Sarcoma/enzimologia , Animais , Proliferação de Células , Progressão da Doença , Inativação Gênica , Humanos , Hibridização in Situ Fluorescente , Camundongos , Camundongos SCID , Modelos Biológicos , Invasividade Neoplásica , Transplante de Neoplasias , Neovascularização Patológica
9.
BMC Genomics ; 11: 509, 2010 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-20860821

RESUMO

BACKGROUND: MicroRNAs are non-coding RNAs that regulate gene expression including differentiation and development by either inhibiting translation or inducing target degradation. The aim of this study is to determine the microRNA expression signature during human pancreatic development and to identify potential microRNA gene targets calculating correlations between the signature microRNAs and their corresponding mRNA targets, predicted by bioinformatics, in genome-wide RNA microarray study. RESULTS: The microRNA signature of human fetal pancreatic samples 10-22 weeks of gestational age (wga), was obtained by PCR-based high throughput screening with Taqman Low Density Arrays. This method led to identification of 212 microRNAs. The microRNAs were classified in 3 groups: Group number I contains 4 microRNAs with the increasing profile; II, 35 microRNAs with decreasing profile and III with 173 microRNAs, which remain unchanged. We calculated Pearson correlations between the expression profile of microRNAs and target mRNAs, predicted by TargetScan 5.1 and miRBase algorithms, using genome-wide mRNA expression data. Group I correlated with the decreasing expression of 142 target mRNAs and Group II with the increasing expression of 876 target mRNAs. Most microRNAs correlate with multiple targets, just as mRNAs are targeted by multiple microRNAs. Among the identified targets are the genes and transcription factors known to play an essential role in pancreatic development. CONCLUSIONS: We have determined specific groups of microRNAs in human fetal pancreas that change the degree of their expression throughout the development. A negative correlative analysis suggests an intertwined network of microRNAs and mRNAs collaborating with each other. This study provides information leading to potential two-way level of combinatorial control regulating gene expression through microRNAs targeting multiple mRNAs and, conversely, target mRNAs regulated in parallel by other microRNAs as well. This study may further the understanding of gene expression regulation in the human developing pancreas.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , MicroRNAs/genética , Pâncreas/embriologia , Pâncreas/metabolismo , Algoritmos , Feminino , Humanos , MicroRNAs/classificação , MicroRNAs/metabolismo , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
10.
Endocrinology ; 151(9): 4573-82, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20660060

RESUMO

Type 2 deiodinase (D2), which is highly expressed in brown adipose tissue (BAT), is an enzyme that amplifies thyroid hormone signaling in individual cells. Mice with inactivation of the D2 pathway (D2KO) exhibit dramatically impaired thermogenesis in BAT, leading to hypothermia during cold exposure and a greater susceptibility to diet-induced obesity. This was interpreted as a result of defective acute activation of BAT D2. Here we report that the adult D2KO BAT has a permanent thermogenic defect that stems from impaired embryonic BAT development. D2KO embryos have normal serum T3 but due to lack of D2-generated T3 in BAT, this tissue exhibits decreased expression of genes defining BAT identity [i.e. UCP1, PGC-1alpha and Dio2 (nonfunctional)], which results in impaired differentiation and oxidative capacity. Coinciding with a reduction of these T3-responsive genes, there is oxidative stress that in a cell model of brown adipogenesis can be linked to decreased insulin signaling and decreased adipogenesis. This discovery highlights the importance of deiodinase-controlled thyroid hormone signaling in BAT development, where it has important metabolic repercussions for energy homeostasis in adulthood.


Assuntos
Tecido Adiposo Marrom/metabolismo , Iodeto Peroxidase/metabolismo , Termogênese/fisiologia , Hormônios Tireóideos/metabolismo , Aclimatação/genética , Aclimatação/fisiologia , Adipócitos/citologia , Adipócitos/metabolismo , Adipogenia/genética , Adipogenia/fisiologia , Tecido Adiposo Marrom/embriologia , Tecido Adiposo Marrom/crescimento & desenvolvimento , Animais , Western Blotting , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Iodeto Peroxidase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Consumo de Oxigênio/genética , Consumo de Oxigênio/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Temperatura Ambiente , Termogênese/genética , Hormônios Tireóideos/sangue , Fatores de Tempo
11.
Proc Natl Acad Sci U S A ; 107(14): 6465-70, 2010 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-20308565

RESUMO

Extracellular ATP has been proposed as a paracrine signal in rodent islets, but it is unclear what role ATP plays in human islets. We now show the presence of an ATP signaling pathway that enhances the human beta cell's sensitivity and responsiveness to glucose fluctuations. By using in situ hybridization, RT-PCR, immunohistochemistry, and Western blotting as well as recordings of cytoplasmic-free Ca(2+) concentration, [Ca(2+)](i), and hormone release in vitro, we show that human beta cells express ionotropic ATP receptors of the P2X(3) type and that activation of these receptors by ATP coreleased with insulin amplifies glucose-induced insulin secretion. Released ATP activates P2X(3) receptors in the beta-cell plasma membrane, resulting in increased [Ca(2+)](i) and enhanced insulin secretion. Therefore, in human islets, released ATP forms a positive autocrine feedback loop that sensitizes the beta cell's secretory machinery. This may explain how the human pancreatic beta cell can respond so effectively to relatively modest changes in glucose concentration under physiological conditions in vivo.


Assuntos
Trifosfato de Adenosina/metabolismo , Comunicação Autócrina , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Receptores Purinérgicos P2/metabolismo , Cálcio/metabolismo , Humanos , Secreção de Insulina , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2X3 , Transdução de Sinais
12.
J Histochem Cytochem ; 57(9): 811-24, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19365093

RESUMO

The development of efficient, reproducible protocols for directed in vitro differentiation of human embryonic stem (hES) cells into insulin-producing beta cells will benefit greatly from increased knowledge regarding the spatiotemporal expression profile of key instructive factors involved in human endocrine cell generation. Human fetal pancreases 7 to 21 weeks of gestational age, were collected following consent immediately after pregnancy termination and processed for immunostaining, in situ hybridization, and real-time RT-PCR expression analyses. Islet-like structures appear from approximately week 12 and, unlike the mixed architecture observed in adult islets, fetal islets are initially formed predominantly by aggregated insulin- or glucagon-expressing cells. The period studied (7-22 weeks) coincides with a decrease in the proliferation and an increase in the differentiation of the progenitor cells, the initiation of NGN3 expression, and the appearance of differentiated endocrine cells. The present study provides a detailed characterization of islet formation and expression profiles of key intrinsic and extrinsic factors during human pancreas development. This information is beneficial for the development of efficient protocols that will allow guided in vitro differentiation of hES cells into insulin-producing cells.


Assuntos
Células Endócrinas/citologia , Ilhotas Pancreáticas/citologia , Pâncreas/citologia , Diferenciação Celular , Células Endócrinas/metabolismo , Feminino , Feto , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização In Situ , Ilhotas Pancreáticas/embriologia , Ilhotas Pancreáticas/metabolismo , Pessoa de Meia-Idade , Pâncreas/embriologia , Pâncreas/metabolismo , Gravidez , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
Gene Expr Patterns ; 9(4): 193-9, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19135553

RESUMO

MicroRNAs (miRNA) are small non-coding RNAs that inhibit gene expression through binding to complementary messenger RNA sequences. miRNAs have been predicted to target genes important for pancreas development, proper endocrine cell function and metabolism. We previously described that miRNA-7 (miR-7) was the most abundant and differentially expressed islet miRNA, with 200-fold higher expression in mature human islets than in acinar tissue. Here we have analyzed the temporal and spatial expression of miR-7 in human fetal pancreas from 8 to 22 weeks of gestational age (wga). Human fetal (8-22wga) and adult pancreases were processed for immunohistochemistry, in situ hybridization, and quantitative RT-PCR of miRNA and mRNA. miR-7 was expressed in the human developing pancreas from around 9wga and reached its maximum expression levels between 14 and 18wga, coinciding with the exponential increase of the pancreatic endocrine hormones. Throughout development miR-7 expression was preferentially localized to endocrine cells and its expression persisted in the adult pancreas. The present study provides a detailed analysis of the spatiotemporal expression of miR-7 in developing human pancreas. The specific localization of miR-7 expression to fetal and adult endocrine cells indicates a potential role for miR-7 in endocrine cell differentiation and/or function. Future functional studies of a potential role for miR-7 function in islet cell differentiation and physiology are likely to identify novel targets for the treatment of diabetes and will lead to the development of improved protocols for generating insulin-producing cells for cell replacement therapy.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , MicroRNAs/genética , Pâncreas/metabolismo , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Feminino , Feto/citologia , Feto/metabolismo , Imunofluorescência , Idade Gestacional , Glucagon/genética , Glucagon/metabolismo , Humanos , Hibridização In Situ , Insulina/genética , Insulina/metabolismo , MicroRNAs/metabolismo , Microscopia Confocal , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Pâncreas/citologia , Pâncreas/embriologia , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Somatostatina/genética , Somatostatina/metabolismo
14.
PLoS One ; 3(7): e2841, 2008 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-18665267

RESUMO

The identification of secreted factors that can selectively stimulate the generation of insulin producing beta-cells from stem and/or progenitor cells represent a significant step in the development of stem cell-based beta-cell replacement therapy. By elucidating the molecular mechanisms that regulate the generation of beta-cells during normal pancreatic development such putative factors may be identified. In the mouse, beta-cells increase markedly in numbers from embryonic day (e) 14.5 and onwards, but the extra-cellular signal(s) that promotes the selective generation of beta-cells at these stages remains to be identified. Here we show that the retinoic acid (RA) synthesizing enzyme Raldh1 is expressed in developing mouse and human pancreas at stages when beta-cells are generated. We also provide evidence that RA induces the generation of Ngn3(+) endocrine progenitor cells and stimulates their further differentiation into beta-cells by activating a program of cell differentiation that recapitulates the normal temporal program of beta-cell differentiation.


Assuntos
Sistema Endócrino/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células Secretoras de Insulina/citologia , Pâncreas/metabolismo , Células-Tronco/citologia , Tretinoína/metabolismo , Aldeído Desidrogenase/metabolismo , Animais , Diferenciação Celular , Humanos , Hibridização In Situ , Camundongos , Camundongos Transgênicos , Pâncreas/embriologia , Retinal Desidrogenase , Transdução de Sinais , Fatores de Tempo
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