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1.
Int J Mol Sci ; 24(21)2023 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-37958648

RESUMO

The enteric nervous system (ENS) is principally derived from vagal neural crest cells that migrate caudally along the entire length of the gastrointestinal tract, giving rise to neurons and glial cells in two ganglionated plexuses. Incomplete migration of enteric neural crest-derived cells (ENCDC) leads to Hirschsprung disease, a congenital disorder characterized by the absence of enteric ganglia along variable lengths of the colorectum. Our previous work strongly supported the essential role of the avian ceca, present at the junction of the midgut and hindgut, in hindgut ENS development, since ablation of the cecal buds led to incomplete ENCDC colonization of the hindgut. In situ hybridization shows bone morphogenetic protein-4 (BMP4) is highly expressed in the cecal mesenchyme, leading us to hypothesize that cecal BMP4 is required for hindgut ENS development. To test this, we modulated BMP4 activity using embryonic intestinal organ culture techniques and retroviral infection. We show that overexpression or inhibition of BMP4 in the ceca disrupts hindgut ENS development, with GDNF playing an important regulatory role. Our results suggest that these two important signaling pathways are required for normal ENCDC migration and enteric ganglion formation in the developing hindgut ENS.


Assuntos
Neoplasias Colorretais , Sistema Nervoso Entérico , Humanos , Transdução de Sinais/fisiologia , Diferenciação Celular/fisiologia , Sistema Nervoso Entérico/metabolismo , Movimento Celular/fisiologia , Neoplasias Colorretais/metabolismo , Crista Neural/metabolismo , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/metabolismo
2.
Nutrients ; 15(20)2023 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-37892386

RESUMO

Bariatric surgery induces bone loss, but the exact mechanisms by which this process occurs are not fully known. The aims of this 2-year longitudinal study were to (i) investigate the changes in areal bone mineral density (aBMD) and bone turnover markers following sleeve gastrectomy (SG) and (ii) determine the parameters associated with the aBMD variations. Bone turnover markers, sclerostin, periostin and semaphorin 4D were assessed before and 1, 12 and 24 months after SG, and aBMD was determined by DXA at baseline and after 12 and 24 months in 83 patients with obesity. Bone turnover increased from 1 month, peaked at 12 months and remained elevated at 24 months. Periostin and sclerostin presented only modest increases at 1 month, whereas semaphorin 4D showed increases only at 12 and 24 months. A significant aBMD decrease was observed only at total hip regions at 12 and 24 months. This demineralisation was mainly related to body weight loss. In summary, reduced aBMD was observed after SG in the hip region (mechanical-loading bone sites) due to an increase in bone turnover in favour of bone resorption. Periostin, sclerostin and semaphorin 4D levels varied after SG, showing different time lags, but contrary to weight loss, these biological parameters did not seem to be directly implicated in the skeletal deterioration.


Assuntos
Densidade Óssea , Osso e Ossos , Humanos , Estudos Longitudinais , Gastrectomia/efeitos adversos
3.
Dig Dis Sci ; 68(10): 3857-3871, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37650948

RESUMO

Visceral myopathy is a rare, life-threatening disease linked to identified genetic mutations in 60% of cases. Mostly due to the dearth of knowledge regarding its pathogenesis, effective treatments are lacking. The disease is most commonly diagnosed in children with recurrent or persistent disabling episodes of functional intestinal obstruction, which can be life threatening, often requiring long-term parenteral or specialized enteral nutritional support. Although these interventions are undisputedly life-saving as they allow affected individuals to avoid malnutrition and related complications, they also seriously compromise their quality of life and can carry the risk of sepsis and thrombosis. Animal models for visceral myopathy, which could be crucial for advancing the scientific knowledge of this condition, are scarce. Clearly, a collaborative network is needed to develop research plans to clarify genotype-phenotype correlations and unravel molecular mechanisms to provide targeted therapeutic strategies. This paper represents a summary report of the first 'European Forum on Visceral Myopathy'. This forum was attended by an international interdisciplinary working group that met to better understand visceral myopathy and foster interaction among scientists actively involved in the field and clinicians who specialize in care of people with visceral myopathy.


Assuntos
Pseudo-Obstrução Intestinal , Desnutrição , Animais , Criança , Humanos , Qualidade de Vida , Modelos Animais , Mutação , Doenças Raras
4.
Calcif Tissue Int ; 113(3): 304-316, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37353625

RESUMO

Spinal cord injury (SCI) induces severe losses of trabecular and cortical volumetric bone mineral density (vBMD), which cannot be discriminated with conventional dual-energy X-ray absorptiometry (DXA) analysis. The objectives were to: (i) determine the effects of SCI on areal BMD (aBMD) and vBMD determined by advanced 3D-DXA-based methods at various femoral regions and (ii) model the profiles of 3D-DXA-derived parameters with the time since injury. Eighty adult males with SCI and 25 age-matched able-bodied (AB) controls were enrolled in this study. Trabecular and cortical vBMD, cortical thickness and derived strength parameters were assessed by 3D-SHAPER® software at various femoral subregions. Individuals with SCI had significantly lower integral vBMD, trabecular vBMD, cortical vBMD, cortical thickness and derived bone strength parameters (p < 0.001 for all) in total proximal femur compared with AB controls. These alterations were approximately to the same degree for all three femoral subregions, and the difference between the two groups tended to be greater for cortical vBMD than trabecular vBMD. There were minor differences according to the lesion level (paraplegics vs tetraplegics) for all 3D-DXA-derived parameters. For total proximal femur, the decreasing bone parameters tended to reach a new steady state after 5.1 years for integral vBMD, 7.4 years for trabecular vBMD and 9.2 years for cortical vBMD following SCI. At proximal femur, lower vBMD (integral, cortical and trabecular) and cortical thickness resulted in low estimated bone strength in individuals with SCI. It remains to be demonstrated whether these new parameters are more closely associated with fragility fracture than aBMD.


Assuntos
Densidade Óssea , Traumatismos da Medula Espinal , Adulto , Masculino , Humanos , Absorciometria de Fóton/métodos , Fêmur/patologia , Osso e Ossos , Traumatismos da Medula Espinal/complicações
5.
Int J Mol Sci ; 24(8)2023 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-37108337

RESUMO

Gastrointestinal stromal tumor (GIST), the most common sarcoma, is mainly caused by an oncogenic mutation in the KIT receptor tyrosine kinase. Targeting KIT using tyrosine kinase inhibitors, such as imatinib and sunitinib, provides substantial benefit; however, in most patients, the disease will eventually progress due to KIT secondary mutations leading to treatment failure. Understanding how GIST cells initially adapt to KIT inhibition should guide the selection of appropriate therapies to overcome the emergence of resistance. Several mechanisms have been broadly implicated in the resistance to imatinib anti-tumoral effects, including the reactivation of MAPK signaling upon KIT/PDGFRA targeted inhibition. This study provides evidence that LImb eXpression 1 (LIX1), a protein we identified as a regulator of the Hippo transducers YAP1 and TAZ, is upregulated upon imatinib or sunitinib treatment. LIX1 silencing in GIST-T1 cells impaired imatinib-induced MAPK signaling reactivation and enhanced imatinib anti-tumor effect. Our findings identified LIX1 as a key regulator of the early adaptative response of GIST cells to targeted therapies.


Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas Relacionadas à Autofagia/genética , Resistencia a Medicamentos Antineoplásicos/genética , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico , Sistema de Sinalização das MAP Quinases
6.
Nutrients ; 15(5)2023 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-36904198

RESUMO

Sleeve gastrectomy (SG) induces weight loss but its effects on body composition (BC) are less well known. The aims of this longitudinal study were to analyse the BC changes from the acute phase up to weight stabilization following SG. Variations in the biological parameters related to glucose, lipids, inflammation, and resting energy expenditure (REE) were concomitantly analysed. Fat mass (FM), lean tissue mass (LTM), and visceral adipose tissue (VAT) were determined by dual-energy X-ray absorptiometry in 83 obese patients (75.9% women) before SG and 1, 12 and 24 months later. After 1 month, LTM and FM losses were comparable, whereas at 12 months the loss of FM exceeded that of LTM. Over this period, VAT also decreased significantly, biological parameters became normalized, and REE was reduced. For most of the BC, biological and metabolic parameters, no substantial variation was demonstrated beyond 12 months. In summary, SG induced a modification in BC changes during the first 12 months following SG. Although the significant LTM loss was not associated with an increase in sarcopenia prevalence, the preservation of LTM might have limited the reduction in REE, which is a longer-term weight-regain criterion.


Assuntos
Composição Corporal , Obesidade , Humanos , Feminino , Masculino , Estudos Longitudinais , Obesidade/cirurgia , Metabolismo Energético , Gastrectomia
7.
Development ; 149(16)2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35912573

RESUMO

Gastrointestinal motor activity has been extensively studied in adults; however, only few studies have investigated fetal motor skills. It is unknown when the gastrointestinal tract starts to contract during the embryonic period and how this function evolves during development. Here, we adapted a non-invasive high-resolution echography technique combined with speckle tracking analysis to examine the gastrointestinal tract motor activity dynamics during chick embryo development. We provided the first recordings of fetal gastrointestinal motility in living embryos without anesthesia. We found that, although gastrointestinal contractions appear very early during development, they become synchronized only at the end of the fetal period. To validate this approach, we used various pharmacological inhibitors and BAPX1 gene overexpression in vivo. We found that the enteric nervous system determines the onset of the synchronized contractions in the stomach. Moreover, alteration of smooth muscle fiber organization led to an impairment of this functional activity. Altogether, our findings show that non-invasive high-resolution echography and speckle tracking analysis allows visualization and quantification of gastrointestinal motility during development and highlight the progressive acquisition of functional and coordinated gastrointestinal motility before birth.


Assuntos
Sistema Nervoso Entérico , Motilidade Gastrointestinal , Animais , Embrião de Galinha , Motilidade Gastrointestinal/fisiologia , Trato Gastrointestinal/diagnóstico por imagem , Miócitos de Músculo Liso , Ultrassonografia
8.
Redox Biol ; 56: 102431, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35988446

RESUMO

YAP1 and TAZ are transcriptional co-activator proteins that play fundamental roles in many biological processes, from cell proliferation and cell lineage fate determination to tumorigenesis. We previously demonstrated that Limb Expression 1 (LIX1) regulates YAP1 and TAZ activity and controls digestive mesenchymal progenitor proliferation. However, LIX1 mode of action remains elusive. Here, we found that endogenous LIX1 is localized in mitochondria and is anchored to the outer mitochondrial membrane through S-palmitoylation of cysteine 84, a residue conserved in all LIX1 orthologs. LIX1 downregulation altered the mitochondrial ultrastructure, resulting in a significantly decreased respiration and attenuated production of mitochondrial reactive oxygen species (mtROS). Mechanistically, LIX1 knock-down impaired the stability of the mitochondrial proteins PHB2 and OPA1 that are found in complexes with mitochondrial-specific phospholipids and are required for cristae organization. Supplementation with unsaturated fatty acids counteracted the effects of LIX1 knock-down on mitochondrial morphology and ultrastructure and restored YAP1/TAZ signaling. Collectively, our data demonstrate that LIX1 is a key regulator of cristae organization, modulating mtROS level and subsequently regulating the signaling cascades that control fate commitment of digestive mesenchyme-derived cells.


Assuntos
Cisteína , Mitocôndrias , Cisteína/metabolismo , Mesoderma/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Fosfolipídeos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
9.
Bone ; 150: 116005, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33992821

RESUMO

BACKGROUND: Most obese women with low-trauma fractures present normal areal bone mineral density (aBMD), suggesting that other bone parameters are more determinant for fracture risk in these patients. OBJECTIVES: (i) Determine the effects of obesity in young women on areal bone mineral density (aBMD), bone geometry, strength, and volumetric BMD determined by advanced DXA-based methods; (ii) model the profiles of bone parameters for each population with age; and (iii) determine the factors related to body composition (i.e. lean tissue mass and fat mass) potentially implicated in the "bone adaptation" in the femoral region. SUBJECTS AND METHODS: Two hundred and twenty adolescent and young women from 18 to 35 years old were enrolled in this study: 128 patients with obesity and 92 age-matched (±6 months) normal-weight controls. aBMD was determined with DXA, whereas hip geometry and strength parameters were assessed by hip structural analysis (HSA) and volumetric BMD by 3D-SHAPER® software. RESULTS: Compared with controls, subjects with obesity presented significantly higher aBMD at all bone sites, but the difference was greater at hip compared with lumbar spine or radius. Bone size estimates (i.e. cortical thickness), as well as strength estimates (i.e. cross-sectional area) were higher at all femoral subregions including femoral neck, intertrochanteric region and femoral shaft in young women with obesity. In whole proximal femur and all femoral compartments, vBMD was also higher in subjects with obesity, but the difference between groups was greater for cortical vBMD compared with trabecular vBMD. When hip bone parameters were modelled for each group from individual values, maximal values were reached between 20 and 26 years in both groups but, whatever the age, subjects with obesity presented higher values than controls. In both groups, lean body mass (LBM) was the parameter most positively associated with the greatest number of bone parameters studied. CONCLUSION: Our study confirmed that young women with obesity presented higher aBMD, better hip geometry and greater strength compared with normal-weight controls. Additionally, cortical and trabecular compartments measured by 3D-SHAPER® were favourably and concomitantly modified. However, it remains to be demonstrated whether the evaluation of these new parameters would provide better prediction of fracture risk in this population than aBMD.


Assuntos
Densidade Óssea , Fraturas por Osteoporose , Absorciometria de Fóton , Adolescente , Adulto , Feminino , Colo do Fêmur , Humanos , Lactente , Obesidade , Adulto Jovem
10.
J Cell Mol Med ; 25(8): 4028-4039, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33656779

RESUMO

Smooth Muscle Cells (SMC) are unique amongst all muscle cells in their capacity to modulate their phenotype. Indeed, SMCs do not terminally differentiate but instead harbour a remarkable capacity to dedifferentiate, switching between a quiescent contractile state and a highly proliferative and migratory phenotype, a quality often associated to SMC dysfunction. However, phenotypic plasticity remains poorly examined in the field of gastroenterology in particular in pathologies in which gut motor activity is impaired. Here, we assessed SMC status in biopsies of infants with chronic intestinal pseudo-obstruction (CIPO) syndrome, a life-threatening intestinal motility disorder. We showed that CIPO-SMCs harbour a decreased level of contractile markers. This phenotype is accompanied by an increase in Platelet-Derived Growth Factor Receptor-alpha (PDGFRA) expression. We showed that this modulation occurs without origin-related differences in CIPO circular and longitudinal-derived SMCs. As we characterized PDGFRA as a marker of digestive mesenchymal progenitors during embryogenesis, our results suggest a phenotypic switch of the CIPO-SMC towards an undifferentiated stage. The development of CIPO-SMC culture and the characterization of SMC phenotypic switch should enable us to design therapeutic approaches to promote SMC differentiation in CIPO.


Assuntos
Diferenciação Celular , Pseudo-Obstrução Intestinal/patologia , Contração Muscular , Miócitos de Músculo Liso/patologia , Fenótipo , Adolescente , Proliferação de Células , Células Cultivadas , Criança , Feminino , Humanos , Pseudo-Obstrução Intestinal/metabolismo , Masculino , Miócitos de Músculo Liso/metabolismo , Transdução de Sinais
11.
Am J Physiol Gastrointest Liver Physiol ; 319(4): G519-G528, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32877218

RESUMO

The first contractile waves in the developing embryonic gut are purely myogenic; they only involve smooth muscle. Here, we provide evidence for a transition from smooth muscle to interstitial cell of Cajal (ICC)-driven contractile waves in the developing chicken gut. In situ hybridization staining for anoctamin-1 (ANO1), a known ICC marker, shows that ICCs are already present throughout the gut, as from embryonic day (E)7. We devised a protocol to reveal ICC oscillatory and propagative calcium activity in embryonic gut whole mount and found that the first steady calcium oscillations in ICCs occur on (E14). We show that the activation of ICCs leads to an increase in contractile wave frequency, regularity, directionality, and velocity between E12 and E14. We finally demonstrate that application of the c-KIT antagonist imatinib mesylate in organ culture specifically depletes the ICC network and inhibits the transition to a regular rhythmic wave pattern. We compare our findings to existing results in the mouse and predict that a similar transition should take place in the human fetus between 12 and 14 wk of development. Together, our results point to an abrupt physiological transition from smooth muscle mesenchyme self-initiating waves to ICC-driven motility in the fetus and clarify the contribution of ICCs to the contractile wave pattern.NEW & NOTEWORTHY We reveal a sharp transition from smooth muscle to interstitial cell of Cajal (ICC)-driven motility in the chicken embryo, leading to higher-frequency, more rhythmic contractile waves. We predict the transition to happen between 12 and 14 embryonic wk in humans. We image for the first time the onset of ICC activity in an embryonic gut by calcium imaging. We show the first KIT and anoctamin-1 (ANO1) in situ hybridization micrographs in the embryonic chicken gut.


Assuntos
Motilidade Gastrointestinal/fisiologia , Células Intersticiais de Cajal/fisiologia , Intestinos/embriologia , Animais , Anoctamina-1/análise , Cálcio/metabolismo , Embrião de Galinha , Trato Gastrointestinal/embriologia , Trato Gastrointestinal/fisiologia , Humanos , Células Intersticiais de Cajal/química , Intestinos/fisiologia , Camundongos , Contração Muscular/fisiologia , Músculo Liso/embriologia , Músculo Liso/fisiologia , Fatores de Tempo
12.
J Cell Mol Med ; 24(16): 9244-9254, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32633461

RESUMO

Gastrointestinal stromal tumours (GISTs), the most common mesenchymal neoplasm of the gastrointestinal tract, result from deregulated proliferation of transformed KIT-positive interstitial cells of Cajal that share mesenchymal progenitors with smooth muscle cells. Despite the identification of selective KIT inhibitors, primary resistance and relapse remain a major concern. Moreover, most patients develop resistance partly through reactivation of KIT and its downstream signalling pathways. We previously identified the Limb Expression 1 (LIX1) gene as a unique marker of digestive mesenchyme immaturity. We also demonstrated that LIX1 regulates mesenchymal progenitor proliferation and differentiation by controlling the Hippo effector YAP1, which is constitutively activated in many sarcomas. Therefore, we wanted to determine LIX1 role in GIST development. We found that LIX1 is strongly up-regulated in GIST samples and this is associated with unfavourable prognosis. Moreover, LIX1 controls GIST cell proliferation in vitro and in vivo. Upon LIX1 inactivation in GIST cells, YAP1/TAZ activity is reduced, KIT (the GIST signature) is down-regulated, and cells acquire smooth muscle lineage features. Our data highlight LIX1 role in digestive mesenchyme-derived cell-fate decisions and identify this novel regulator as a target for drug design for GIST treatment by influencing its differentiation status.


Assuntos
Proteínas Relacionadas à Autofagia/metabolismo , Biomarcadores Tumorais/metabolismo , Proteínas de Ciclo Celular/metabolismo , Plasticidade Celular , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Recidiva Local de Neoplasia/patologia , Fatores de Transcrição/metabolismo , Animais , Proteínas Relacionadas à Autofagia/genética , Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular/genética , Proliferação de Células , Embrião de Galinha , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Taxa de Sobrevida , Fatores de Transcrição/genética , Células Tumorais Cultivadas
13.
J Comp Neurol ; 528(5): 879-889, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31658363

RESUMO

The enteric nervous system (ENS) is a complex network constituted of neurons and glial cells that ensures the intrinsic innervation of the gastrointestinal tract. ENS cells originate from vagal and sacral neural crest cells that are initially located at the border of the neural tube. In birds, sacral neural crest cells (sNCCs) first give rise to an extramural ganglionated structure (the so-called Nerve of Remak [NoR]) and to the pelvic plexus. Later, sNCCs enter the colon mesenchyme to colonize and contribute to the intrinsic innervation of the caudal part of the gut. However, no specific sNCC marker has been described. Here, we report the expression pattern of prospero-related homeobox 1 (PROX1) in the developing chick colon. PROX1 is a homeobox domain transcription factor that plays a role in cell type specification in various tissues. Using in situ hybridization and immunofluorescence techniques, we showed that PROX1 is expressed in sNCCs localized in the NoR and in the pelvic plexus. Then, using real-time quantitative PCR we found that PROX1 displays a strong and highly dynamic expression pattern during NoR development. Moreover, we demonstrated using in vivo cell tracing, that sNCCs are the source of the PROX1-positive cells within the NoR. Our results indicate that PROX1 is the first marker that specifically identifies sNCCs. This might help to better identify the role of the different neural crest cell populations in distal gut innervation, and consequently to improve the diagnosis of diseases linked to incomplete ENS formation, such as Hirschsprung's disease.


Assuntos
Proteínas de Homeodomínio/metabolismo , Intestinos/inervação , Crista Neural/metabolismo , Animais , Biomarcadores/metabolismo , Embrião de Galinha , Sistema Nervoso Entérico/citologia , Crista Neural/citologia
14.
Int J Cardiol ; 240: 347-353, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28395979

RESUMO

BACKGROUND: Inflammation is deeply involved in the pathophysiology of ischemia-reperfusion (I/R) lesions and ventricular remodeling due to an acute myocardial infarction (AMI). Colchicine as a pleiotropic anti-inflammatory molecule may exert cardioprotective effects under acute ischemia. Here, we aimed to evaluate the impact of colchicine on reperfusion injury in a mouse model. METHOD: Myocardial ischemia/reperfusion (I/R) injury was induced in C57BL/6 male mice, after 45min ligation of the left coronary artery followed by reperfusion. 400µg/kg of colchicine or the vehicle was administrated intraperitoneally (i.p.) 25min before the reperfusion (blinded administration). Mice were sacrificed at 24h after the acute myocardial ischemia (AMI) and the infarct size was determined. Circulating level of troponin and cytokines profile were assessed 4h after the AMI. An echocardiography was performed in a follow-up group mice, 48h and 8weeks after the AMI. RESULTS: The infarct size was reduced in colchicine treated mice (39.8±3.5% versus 52.9±3.2%, p<0.05). Troponin was significantly lower in the colchicine treated mice (7015.7±1423.7pg/mL, n=5 vs 30,723.7±7959.9pg/mL in the placebo group, n=6; p<0.0001). Fibrosis was decreased in the Colchicine group (24.51±3.13% vs 11.38±2.46%, p=0.03). In the follow-up group mice (n=8), there were no differences between mice treated with placebo (n=9) and mice treated with colchicine (n=9) regarding to cardiac remodeling parameters but outflow approximated by the ITV was higher in the colchicine group. CONCLUSION: In conclusion, colchicine allowed a significant reduction of infarct size in mice, improves hemodynamic parameters and decrease cardiac fibrosis.


Assuntos
Colchicina/uso terapêutico , Modelos Animais de Doenças , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/patologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Animais , Insuficiência Cardíaca/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/complicações , Resultado do Tratamento , Moduladores de Tubulina/uso terapêutico
15.
Cell Tissue Res ; 368(3): 503-511, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28197779

RESUMO

During development, the gastrointestinal (GI) tract arises from a primary tube composed of mesoderm and endoderm. The mesoderm gives rise to the digestive mesenchyme, which in turn differentiates into multiple tissues, namely the submucosa, the interstitial cells of Cajal and the smooth muscle cells (SMCs). Concomitant with these early patterning events, the primitive GI tract is colonized by vagal enteric neural crest-derived cells (vENCDCs), a population of cells that gives rise to the enteric nervous system, the intrinsic innervation of the GI tract. Reciprocal neuro-mesenchymal interactions are essential for the coordinated development of GI musculature. The aim of this study is to examine and compare the kinetics of mesenchymal cell differentiation into SMCs along the anterior-posterior axis to the pattern of vENCDCs migration using whole-mount in situ hybridization and paraffin section immunofluorescence analyses on chick embryonic GI tracts from E4-Stage 23 to E7-Stages 30-31. We confirmed that gastric and pre-umbilical intestine mesenchyme differentiation into SMCs occurs after vENCDCs colonization. However, we found that colonic and post-umbilical intestine mesenchyme differentiation occurs before vENCDCs colonization. These findings suggest that regional-specific mechanisms are involved in the mesenchyme differentiation into SMCs along the GI anterior-posterior axis.


Assuntos
Colo/embriologia , Sistema Nervoso Entérico/embriologia , Mesoderma/embriologia , Músculo Liso/embriologia , Crista Neural/embriologia , Animais , Padronização Corporal , Diferenciação Celular , Embrião de Galinha , Colo/citologia , Colo/inervação , Intestinos/citologia , Intestinos/embriologia , Mesoderma/citologia , Estômago/citologia , Estômago/embriologia
16.
Cell Rep ; 17(6): 1473-1481, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27806288

RESUMO

During spinal cord development, astrocyte precursors arise from neuroepithelial progenitors, delaminate from the ventricular zone, and migrate toward their final locations where they differentiate. Although the mechanisms underlying their early specification and late differentiation are being deciphered, less is known about the temporal control of their migration. Here, we show that the epithelial-mesenchymal transition regulator Zeb1 is expressed in glial precursors and report that loss of Zeb1 function specifically delays the onset of astrocyte precursor delamination from the ventricular zone, correlating with transient deregulation of the adhesion protein Cadherin-1. Consequently, astrocyte precursor invasion into the Zeb1-/- mutant white matter is delayed, and induction of their differentiation is postponed. These findings illustrate how fine regulation of adhesive properties influences the onset of neural precursor migration and further support the notion that duration of exposure of migrating astrocyte precursors to environmental cues and/or their correct positioning influence the timing of their differentiation.


Assuntos
Astrócitos/citologia , Astrócitos/metabolismo , Movimento Celular , Medula Espinal/citologia , Células-Tronco/citologia , Células-Tronco/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Envelhecimento/genética , Animais , Padronização Corporal , Diferenciação Celular , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Mutação/genética
17.
Dev Biol ; 414(2): 207-18, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27108394

RESUMO

In vertebrates, stomach smooth muscle development is a complex process that involves the tight transcriptional or post-transcriptional regulation of different signalling pathways. Here, we identified the RNA-binding protein Epithelial Splicing Regulatory Protein 1 (ESRP1) as an early marker of developing and undifferentiated stomach mesenchyme. Using a gain-of-function approach, we found that in chicken embryos, sustained expression of ESRP1 impairs stomach smooth muscle cell (SMC) differentiation and FGFR2 splicing profile. ESRP1 overexpression in primary differentiated stomach SMCs induced their dedifferentiation, promoted specific-FGFR2b splicing and decreased FGFR2c-dependent activity. Moreover, co-expression of ESRP1 and RBPMS2, another RNA-binding protein that regulates SMC plasticity and Bone Morphogenetic Protein (BMP) pathway inhibition, synergistically promoted SMC dedifferentiation. Finally, we also demonstrated that ESRP1 interacts with RBPMS2 and that RBPMS2-mediated SMC dedifferentiation requires ESRP1. Altogether, these results show that ESRP1 is expressed also in undifferentiated stomach mesenchyme and demonstrate its role in SMC development and plasticity.


Assuntos
Proteínas Aviárias/fisiologia , Moela das Aves/embriologia , Músculo Liso/embriologia , Proteínas de Ligação a RNA/fisiologia , Alelos , Sequência de Aminoácidos , Animais , Proteínas Aviárias/química , Proteínas Aviárias/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Embrião de Galinha , DNA Complementar/genética , Regulação da Expressão Gênica no Desenvolvimento , Moela das Aves/citologia , Humanos , Mesoderma/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Ressonância Magnética Nuclear Biomolecular , Cultura Primária de Células , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Mapeamento de Interação de Proteínas , Splicing de RNA/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Receptores Proteína Tirosina Quinases/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo
18.
BMC Biol ; 14: 34, 2016 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-27125505

RESUMO

BACKGROUND: Smooth muscle cell (SMC) plasticity maintains the balance between differentiated SMCs and proliferative mesenchymal progenitors, crucial for muscular tissue homeostasis. Studies on the development of mesenchymal progenitors into SMCs have proven useful in identifying molecular mechanisms involved in digestive musculature plasticity in physiological and pathological conditions. RESULTS: Here, we show that Limb Expression 1 (LIX1) molecularly defines the population of mesenchymal progenitors in the developing stomach. Using in vivo functional approaches in the chick embryo, we demonstrate that LIX1 is a key regulator of stomach SMC development. We show that LIX1 is required for stomach SMC determination to regulate the expression of the pro-proliferative gene YAP1 and mesenchymal cell proliferation. However, as stomach development proceeds, sustained LIX1 expression has a negative impact on further SMC differentiation and this is associated with a decrease in YAP1 activity. CONCLUSIONS: We demonstrate that expression of LIX1 must be tightly regulated to allow fine-tuning of the transcript levels and state of activation of the pro-proliferative transcriptional coactivator YAP1 to regulate proliferation rates of stomach mesenchymal progenitors and their differentiation. Our data highlight dual roles for LIX1 and YAP1 and provide new insights into the regulation of cell density-dependent proliferation, which is essential for the development and homeostasis of organs.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Diferenciação Celular , Proliferação de Células , Células-Tronco Mesenquimais/citologia , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linhagem Celular , Embrião de Galinha , Regulação da Expressão Gênica , Inativação Gênica , Marcadores Genéticos , Miócitos de Músculo Liso/citologia , Fosfoproteínas/genética , Proteínas de Ligação a RNA/genética , Transdução de Sinais , Estômago/citologia
19.
Cell Mol Life Sci ; 72(20): 3883-96, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26126787

RESUMO

The gastrointestinal tract develops from a simple and uniform tube into a complex organ with specific differentiation patterns along the anterior-posterior and dorso-ventral axes of asymmetry. It is derived from all three germ layers and their cross-talk is important for the regulated development of fetal and adult gastrointestinal structures and organs. Signals from the adjacent mesoderm are essential for the morphogenesis of the overlying epithelium. These mesenchymal-epithelial interactions govern the development and regionalization of the different gastrointestinal epithelia and involve most of the key morphogens and signaling pathways, such as the Hedgehog, BMPs, Notch, WNT, HOX, SOX and FOXF cascades. Moreover, the mechanisms underlying mesenchyme differentiation into smooth muscle cells influence the regionalization of the gastrointestinal epithelium through interactions with the enteric nervous system. In the neonatal and adult gastrointestinal tract, mesenchymal-epithelial interactions are essential for the maintenance of the epithelial regionalization and digestive epithelial homeostasis. Disruption of these interactions is also associated with bowel dysfunction potentially leading to epithelial tumor development. In this review, we will discuss various aspects of the mesenchymal-epithelial interactions observed during digestive epithelium development and differentiation and also during epithelial stem cell regeneration.


Assuntos
Mucosa Intestinal/embriologia , Mesoderma/embriologia , Comunicação Celular , Diferenciação Celular , Trato Gastrointestinal/citologia , Trato Gastrointestinal/embriologia , Trato Gastrointestinal/metabolismo , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Mesoderma/citologia , Mesoderma/metabolismo , Miócitos de Músculo Liso/citologia , Transdução de Sinais , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia
20.
Development ; 142(2): 331-42, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25519241

RESUMO

In vertebrates, the digestive tract develops from a uniform structure where reciprocal epithelial-mesenchymal interactions pattern this complex organ into regions with specific morphologies and functions. Concomitant with these early patterning events, the primitive GI tract is colonized by the vagal enteric neural crest cells (vENCCs), a population of cells that will give rise to the enteric nervous system (ENS), the intrinsic innervation of the GI tract. The influence of vENCCs on early patterning and differentiation of the GI tract has never been evaluated. In this study, we report that a crucial number of vENCCs is required for proper chick stomach development, patterning and differentiation. We show that reducing the number of vENCCs by performing vENCC ablations induces sustained activation of the BMP and Notch pathways in the stomach mesenchyme and impairs smooth muscle development. A reduction in vENCCs also leads to the transdifferentiation of the stomach into a stomach-intestinal mixed phenotype. In addition, sustained Notch signaling activity in the stomach mesenchyme phenocopies the defects observed in vENCC-ablated stomachs, indicating that inhibition of the Notch signaling pathway is essential for stomach patterning and differentiation. Finally, we report that a crucial number of vENCCs is also required for maintenance of stomach identity and differentiation through inhibition of the Notch signaling pathway. Altogether, our data reveal that, through the regulation of mesenchyme identity, vENCCs act as a new mediator in the mesenchymal-epithelial interactions that control stomach development.


Assuntos
Diferenciação Celular/fisiologia , Sistema Nervoso Entérico/embriologia , Morfogênese/fisiologia , Crista Neural/embriologia , Transdução de Sinais/fisiologia , Estômago/embriologia , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Embrião de Galinha , Imunofluorescência , Hibridização In Situ , Músculo Liso/embriologia , Técnicas de Cultura de Órgãos , Receptores Notch/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estômago/inervação
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