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1.
Artigo em Inglês | MEDLINE | ID: mdl-31473306

RESUMO

Gastric chief cells differentiate from mucous neck cells and develop their mature state at the base of oxyntic glands with expression of secretory zymogen granules. After parietal cell loss, chief cells transdifferentiate into mucous cell metaplasia, designated spasmolytic polypeptide-expressing metaplasia (SPEM), which is considered a candidate precursor of gastric cancer. We examined the range of microRNA (miRNA) expression in chief cells and identified miRNAs involved in chief cell transdifferentiation into SPEM. Among them, miR-148a was strongly and specifically expressed in chief cells and significantly decreased during the process of chief cell transdifferentiation. Interestingly, suppression of miR-148a in a conditionally immortalized chief cell line induced up-regulation of CD44 variant 9 (CD44v9), one of the transcripts expressed at an early stage of SPEM development, and DNA methyltransferase 1 (Dnmt1), an established target of miR-148a. Immunostaining analyses showed that Dnmt1 was up-regulated in SPEM cells as well as in chief cells before the emergence of SPEM in mouse models of acute oxyntic atrophy using either DMP-777 or L635. In the cascade of events that leads to transdifferentiation, miR-148a was down-regulated after acute oxyntic atrophy either in xCT knockout mice or after sulfasalazine inhibition of xCT. These findings suggest that the alteration of miR-148a expression is an early event in the process of chief cell transdifferentiation into SPEM.

2.
Cell Mol Gastroenterol Hepatol ; 5(4): 678-690.e1, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29930985

RESUMO

Background & Aims: Atrophic gastritis caused by chronic inflammation in the gastric mucosa leads to the loss of gastric glandular cells, including acid-secreting parietal cells. Parietal cell atrophy in a setting of chronic inflammation induces spasmolytic polypeptide expressing metaplasia, a critical step in gastric carcinogenesis. However, the mechanisms by which inflammation causes parietal cell atrophy and spasmolytic polypeptide expressing metaplasia are not well defined. We investigated the role of interleukin-17A (IL-17A) in causing parietal cell atrophy. Methods: A mouse model of autoimmune atrophic gastritis was used to examine IL-17A production during early and late stages of disease. Organoids derived from corpus glands were used to determine the direct effects of IL-17A on gastric epithelial cells. Immunofluorescent staining was used to examine IL-17A receptors and the direct effect of signaling on parietal cells. Mice were infected with an IL-17A-producing adenovirus to determine the effects of IL-17A on parietal cells in vivo. Finally, IL-17A neutralizing antibodies were administered to mice with active atrophic gastritis to evaluate the effects on parietal cell atrophy and metaplasia. Results: Increased IL-17A correlated with disease severity in mice with chronic atrophic gastritis. IL-17A caused caspase-dependent gastric organoid degeneration, which could not be rescued with a necroptosis inhibitor. Parietal cells expressed IL-17A receptors and IL-17A treatment induced apoptosis in parietal cells. Overexpressing IL-17A in vivo induced caspase-3 activation and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining in parietal cells. Finally, IL-17A neutralizing antibody decreased parietal cell atrophy and metaplasia in mice with chronic atrophic gastritis. Conclusions: These data identify IL-17A as a cytokine that promotes parietal cell apoptosis during atrophic gastritis, a precursor lesion for gastric cancer.

3.
Gut ; 67(5): 805-817, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28196875

RESUMO

OBJECTIVE: Alternatively activated macrophages (M2) are associated with the progression of spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach. However, the precise mechanism(s) and critical mediators that induce SPEM are unknown. DESIGN: To determine candidate genes important in these processes, macrophages from the stomach corpus of mice with SPEM (DMP-777-treated) or advanced SPEM (L635-treated) were isolated and RNA sequenced. Effects on metaplasia development after acute parietal cell loss induced by L635 were evaluated in interleukin (IL)-33, IL-33 receptor (ST2) and IL-13 knockout (KO) mice. RESULTS: Profiling of metaplasia-associated macrophages in the stomach identified an M2a-polarised macrophage population. Expression of IL-33 was significantly upregulated in macrophages associated with advanced SPEM. L635 induced metaplasia in the stomachs of wild-type mice, but not in the stomachs of IL-33 and ST2 KO mice. While IL-5 and IL-9 were not required for metaplasia induction, IL-13 KO mice did not develop metaplasia in response to L635. Administration of IL-13 to ST2 KO mice re-established the induction of metaplasia following acute parietal cell loss. CONCLUSIONS: Metaplasia induction and macrophage polarisation after parietal cell loss is coordinated through a cytokine signalling network of IL-33 and IL-13, linking a combined response to injury by both intrinsic mucosal mechanisms and infiltrating M2 macrophages.


Assuntos
Interleucina-13/metabolismo , Interleucina-33/metabolismo , Macrófagos/metabolismo , Metaplasia/metabolismo , Estômago/citologia , Animais , Citometria de Fluxo , Mucosa Gástrica/metabolismo , Imuno-Histoquímica , Interleucina-13/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Parietais Gástricas/citologia , Peptídeos/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Interleucina/genética , Transdução de Sinais
4.
United European Gastroenterol J ; 5(1): 37-44, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28405320

RESUMO

BACKGROUND: Autoimmune gastritis (AIG) and adenocarcinoma-associated chronic atrophic gastritis (CAG) are both associated with oxyntic atrophy, but AIG patients demonstrate an increased risk of carcinoid tumors rather than the elevated risk of adenocarcinoma observed with CAG. We therefore sought to compare the characteristics of the metaplastic mucosa in AIG and CAG patients. METHODS: We examined markers for metaplasia (spasmolytic polypeptide expressing metaplasia (SPEM) and intestinal metaplasia) as well as proliferation (Ki67) and immune cell populations (neutrophils, macrophages, and eosinophils) in gastric sections from 16 female patients with autoimmune thyroiditis and AIG and 17 patients with CAG associated with gastric adenocarcinoma. RESULTS: Both AIG and CAG patients demonstrated prominent SPEM and intestinal metaplasia. However, AIG patients displayed significantly lower numbers of infiltrating macrophages and significantly reduced mucosal cell proliferation as compared to CAG patients. CONCLUSIONS: These findings indicate that, while both AIG and CAG patients display prominent oxyntic atrophy and metaplasia, the AIG patients do not show proliferative metaplastic lineages that would predispose to adenocarcinoma.

5.
Cell Mol Gastroenterol Hepatol ; 3(1): 11-26, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28174755

RESUMO

Intestinal-type gastric adenocarcinoma evolves in a field of pre-existing metaplasia. Over the past 20 years, a number of murine models have been developed to address aspects of the physiology and pathophysiology of metaplasia induction. Although none of these models has achieved true recapitulation of the induction of adenocarcinoma, they have led to important insights into the factors that influence the induction and progression of metaplasia. Here, we review the pathologic definitions relevant to alterations in gastric corpus lineages and classification of metaplasia by specific lineage markers. In addition, we review present murine models of the induction and progression of spasmolytic polypeptide (TFF2)-expressing metaplasia, the predominant metaplastic lineage observed in murine models. These models provide a basis for the development of a broader understanding of the physiological and pathophysiological roles of metaplasia in the stomach.

6.
Am J Physiol Gastrointest Liver Physiol ; 312(1): G67-G76, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27881402

RESUMO

The plasticity of gastric chief cells is exemplified by their ability to transdifferentiate into spasmolytic polypeptide-expressing metaplasia (SPEM) after parietal cell loss. We sought to determine if chief cell maturity is a limiting factor in the capacity to transdifferentiate. Mist1-/- mice, previously shown to form only immature chief cells, were treated with DMP-777 or L635 to study the capability of these immature chief cells to transdifferentiate into a proliferative metaplastic lineage after acute parietal cell loss. Mist1-/- mice treated with DMP-777 showed fewer chief cell to SPEM transitions. Mist1-/- mice treated with L635 demonstrated significantly fewer proliferative SPEM cells compared with control mice. Thus immature chief cells were unable to transdifferentiate efficiently into SPEM after acute parietal cell loss. To determine whether chief cell age affects transdifferentiation into SPEM, we used tamoxifen to induce YFP expression in chief cells of Mist1CreER/+;RosaYFP mice and subsequently treated the cells with L635 to induce SPEM at 1 to 3.5 mo after tamoxifen treatment. After L635 treatment to induce acute parietal cell loss, 43% of all YFP-positive cells at 1 mo posttamoxifen were SPEM cells, of which 44% of these YFP-positive SPEM cells were proliferative. By 2 mo after tamoxifen induction, only 24% of marked SPEM cells were proliferating. However, by 3.5 mo after tamoxifen induction, only 12% of marked chief cells transdifferentiated into SPEM and none were proliferative. Thus, as chief cells age, they lose their ability to transdifferentiate into SPEM and proliferate. Therefore, both functional maturation and age limit chief cell plasticity. NEW & NOTEWORTHY: Previous investigations have indicated that spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach arises from transdifferentiation of chief cells. Nevertheless, the intrinsic properties of chief cells that influence transdifferentiation have been largely unknown. We now report that the ability to transdifferentiate into SPEM is impaired in chief cells that lack full functional maturation, and as chief cells age, they lose their ability to transdifferentiate. Thus chief cell plasticity is dependent on both cell age and maturation.


Assuntos
Linhagem da Célula/fisiologia , Transdiferenciação Celular/fisiologia , Celulas Principais Gástricas/patologia , Estômago/patologia , Fatores Etários , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proliferação de Células/fisiologia , Celulas Principais Gástricas/metabolismo , Mucosa Gástrica/metabolismo , Metaplasia/metabolismo , Metaplasia/patologia , Camundongos , Camundongos Knockout , Células Parietais Gástricas/metabolismo , Células Parietais Gástricas/patologia , Peptídeos/metabolismo
7.
J Histochem Cytochem ; 65(1): 47-58, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27872404

RESUMO

The glandular stomach has two major zones: the acid secreting corpus and the gastrin cell-containing antrum. Nevertheless, a single gland lies at the transition between the forestomach and corpus in the mouse stomach. We have sought to define the lineages that make up this gland unit at the squamocolumnar junction. The first gland in mice showed a notable absence of characteristic corpus lineages, including parietal cells and chief cells. In contrast, the gland showed strong staining of Griffonia simplicifolia-II (GSII)-lectin-positive mucous cells at the bases of glands, which were also positive for CD44 variant 9 and Clusterin. Prominent numbers of doublecortin-like kinase 1 (DCLK1) positive tuft cells were present in the first gland. The first gland contained Lgr5-expressing putative progenitor cells, and a large proportion of the cells were positive for Sox2. The cells of the first gland stained strongly for MUC4 and EpCAM, but both were absent in the normal corpus mucosa. The present studies indicate that the first gland in the corpus represents a unique anatomic entity. The presence of a concentration of progenitor cells and sensory tuft cells in this gland suggests that it may represent a source of reserve reparative cells for adapting to severe mucosal damage.


Assuntos
Mucosa Gástrica/citologia , Células-Tronco/citologia , Estômago/citologia , Animais , Clusterina/análise , Mucosa Gástrica/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mucina-4/análise , Células Parietais Gástricas/citologia , Lectinas de Plantas/análise , Proteínas Serina-Treonina Quinases/análise , Receptores Acoplados a Proteínas-G/análise , Fatores de Transcrição SOXB1/análise , Células-Tronco/ultraestrutura , Estômago/ultraestrutura
8.
Cell Rep ; 17(11): 2955-2965, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27974209

RESUMO

Significant insights into disease pathogenesis have been gleaned from population-level genetic studies; however, many loci associated with complex genetic disease contain numerous genes, and phenotypic associations cannot be assigned unequivocally. In particular, a gene-dense locus on chromosome 11 (61.5-61.65 Mb) has been associated with inflammatory bowel disease, rheumatoid arthritis, and coronary artery disease. Here, we identify TMEM258 within this locus as a central regulator of intestinal inflammation. Strikingly, Tmem258 haploinsufficient mice exhibit severe intestinal inflammation in a model of colitis. At the mechanistic level, we demonstrate that TMEM258 is a required component of the oligosaccharyltransferase complex and is essential for N-linked protein glycosylation. Consequently, homozygous deficiency of Tmem258 in colonic organoids results in unresolved endoplasmic reticulum (ER) stress culminating in apoptosis. Collectively, our results demonstrate that TMEM258 is a central mediator of ER quality control and intestinal homeostasis.


Assuntos
Hexosiltransferases/genética , Doenças Inflamatórias Intestinais/genética , Proteínas de Membrana/genética , Animais , Apoptose , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Estresse do Retículo Endoplasmático/genética , Glicosilação , Hexosiltransferases/metabolismo , Humanos , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Intestinos/patologia , Proteínas de Membrana/metabolismo , Camundongos
9.
J Pathol ; 239(4): 399-410, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27125972

RESUMO

Spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia are considered neoplastic precursors of gastric adenocarcinoma in humans. Loss of parietal cells causes the development of SPEM in the gastric corpus and then chronic inflammation drives SPEM toward a more proliferative lineage. Mongolian gerbils infected with Helicobacter pylori develop chronic gastritis and metaplasia, mimicking aspects of human gastritis with H. pylori infection. We therefore examined metaplastic lineages in the gastric corpus mucosa of gerbils infected by H. pylori strain 7.13, which produces rapid onset of severe inflammation. Six weeks following H. pylori infection, Griffonia simplicifolia lectin II (GSII)-positive SPEM developed in the base of oxyntic glands in association with parietal cell loss and inflammation. In association with severe inflammation, SPEM glands evolved into aberrant phenotypes, including branched lesions, dilated lesions, and penetrating invasive glands. Mucin 4 (MUC4) was up-regulated in SPEM and progressive SPEM. Clusterin was expressed in the tips of branched and dilated lesions and throughout regions of invasive glands. Intriguingly, clusterin-positive regions in these lesions expressed Ki67 and matrix metalloproteinase 7 (MMP-7). These same regions were also positive for expression of phospho-IkBα, suggestive of activated NFkB signalling. These findings suggest that clusterin-positive regions in progressive phenotypes of SPEM have invasive characteristics. Thus, H. pylori infection in gerbils induces SPEM, which then can progress to further aberrant and invasive metaplastic phenotypes. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Mucosa Gástrica/patologia , Infecções por Helicobacter/patologia , Helicobacter pylori , Animais , Clusterina/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologia , Gerbillinae , Infecções por Helicobacter/complicações , Infecções por Helicobacter/microbiologia , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/patologia , Masculino , Metaplasia/etiologia , Metaplasia/microbiologia , Metaplasia/patologia , Mucina-4/metabolismo
10.
Gut ; 65(6): 914-24, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-25800782

RESUMO

OBJECTIVE: Intestinal metaplasia and spasmolytic polypeptide-expressing metaplasia (SPEM) are considered neoplastic precursors of gastric adenocarcinoma and are both marked by gene expression alterations in comparison to normal stomach. Since miRNAs are important regulators of gene expression, we sought to investigate the role of miRNAs on the development of stomach metaplasias. DESIGN: We performed miRNA profiling using a quantitative reverse transcription-PCR approach on laser capture microdissected human intestinal metaplasia and SPEM. Data integration of the miRNA profile with a previous mRNA profile from the same samples was performed to detect potential miRNA-mRNA regulatory circuits. Transfection of gastric cancer cell lines with selected miRNA mimics and inhibitors was used to evaluate their effects on the expression of putative targets and additional metaplasia markers. RESULTS: We identified several genes as potential targets of miRNAs altered during metaplasia progression. We showed evidence that HNF4γ (upregulated in intestinal metaplasia) is targeted by miR-30 and that miR-194 targets a known co-regulator of HNF4 activity, NR2F2 (downregulated in intestinal metaplasia). Intestinal metaplasia markers such as VIL1, TFF2 and TFF3 were downregulated after overexpression of miR-30a in a HNF4γ-dependent manner. In addition, overexpression of HNF4γ was sufficient to induce the expression of VIL1 and this effect was potentiated by downregulation of NR2F2. CONCLUSIONS: The interplay of the two transcription factors HNF4γ and NR2F2 and their coordinate regulation by miR-30 and miR-194, respectively, represent a miRNA to transcription factor network responsible for the expression of intestinal transcripts in stomach cell lineages during the development of intestinal metaplasia.


Assuntos
Biomarcadores Tumorais/genética , Fator 4 Nuclear de Hepatócito/genética , MicroRNAs/genética , Regulação para Cima/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Fator II de Transcrição COUP/genética , Mucosa Gástrica/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Metaplasia/genética , Proteínas dos Microfilamentos/genética , Peptídeos/genética , Estômago/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Transfecção , Fator Trefoil-2/genética , Fator Trefoil-3/genética
11.
Am J Pathol ; 185(8): 2219-31, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26073039

RESUMO

Doublecortin-like kinase 1 (Dclk1) is considered a reliable marker for tuft cells in the gastrointestinal tract. We investigated the dynamic changes of tuft cells associated with mouse models of oxyntic atrophy and metaplasia in the stomach. Increases in the numbers of Dclk1-positive tuft cells were observed in several models of parietal cell loss. However, the expanded population of Dclk1-expressing cells showed a morphologically distinct structure in apical microvilli and acetylated microtubules, which was not seen in the tuft cells present in the normal gastric mucosa. These microvillar sensory cells (MVSCs) showed no evidence of proliferation. The expansion of the MVSCs induced by oxyntic atrophy was reversible after the return of parietal cells. More important, expansion of MVSCs after induced parietal cell loss was not observed in Gast(-/-) mice. Although the Dclk1-expressing cells in the normal gastric mucosa were in part derived from Lrig1-expressing stem cells, the Lrig1-lineaged cells did not produce the expanded Dclk1-expressing cells associated with oxyntic atrophy. These studies indicate that loss of parietal cells leads to the reversible emergence of a novel Dclk1-expressing sensory cell population in the gastric mucosa.


Assuntos
Mucosa Gástrica/metabolismo , Gastrinas/metabolismo , Células Parietais Gástricas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Atrofia/metabolismo , Atrofia/patologia , Mucosa Gástrica/patologia , Metaplasia , Camundongos , Células Parietais Gástricas/patologia , Proteínas Serina-Treonina Quinases/genética , Estômago/patologia
12.
Am J Physiol Gastrointest Liver Physiol ; 307(8): G777-92, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25190476

RESUMO

Oxyntic atrophy in the stomach leads to chief cell transdifferentiation into spasmolytic polypeptide expressing metaplasia (SPEM). Investigations of preneoplastic metaplasias in the stomach are limited by the sole reliance on in vivo mouse models, owing to the lack of in vitro models for distinct normal mucosal lineages and metaplasias. Utilizing the Immortomouse, in vitro cell models of chief cells and SPEM were developed to study the characteristics of normal chief cells and metaplasia. Chief cells and SPEM cells isolated from Immortomice were cultured and characterized at both the permissive (33°C) and the nonpermissive temperature (39°C). Clones were selected on the basis of their transcriptional expression of specific stomach lineage markers (named ImChief and ImSPEM) and protein expression and growth were analyzed. The transcriptional expression profiles of ImChief and ImSPEM cells were compared further by using gene microarrays. ImChief cells transcriptionally express most chief cell markers and contain pepsinogen C and RAB3D-immunostaining vesicles. ImSPEM cells express the SPEM markers TFF2 and HE4 and constitutively secrete HE4. Whereas ImChief cells cease proliferation at the nonpermissive temperature, ImSPEM cells continue to proliferate at 39°C. Gene expression profiling of ImChief and ImSPEM revealed myelin and lymphocyte protein 2 (MAL2) as a novel marker of SPEM lineages. Our results indicate that the expression and proliferation profiles of the novel ImChief and ImSPEM cell lines resemble in vivo chief and SPEM cell lineages. These cell culture lines provide the first in vitro systems for studying the molecular mechanisms of the metaplastic transition in the stomach.


Assuntos
Celulas Principais Gástricas/metabolismo , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/metabolismo , Peptídeos/metabolismo , Estômago/patologia , Animais , Biomarcadores/metabolismo , Células Cultivadas , Mucosa Gástrica/metabolismo , Metaplasia/diagnóstico , Camundongos , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Pepsinogênio C/genética , Pepsinogênio C/metabolismo , Peptídeos/genética , Proteínas/genética , Proteínas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteínas rab3 de Ligação ao GTP/genética , Proteínas rab3 de Ligação ao GTP/metabolismo
13.
Lab Invest ; 94(5): 517-27, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24638272

RESUMO

Normal pancreatic epithelium progresses through various stages of pancreatic intraepithelial neoplasms (PanINs) in the development of pancreatic ductal adenocarcinoma (PDAC). Transcriptional regulation of this progression is poorly understood. In mouse, the hepatic nuclear factor 6 (Hnf6) transcription factor is expressed in ductal cells and at lower levels in acinar cells of the adult pancreas, but not in mature endocrine cells. Hnf6 is critical for terminal differentiation of the ductal epithelium during embryonic development and for pancreatic endocrine cell specification. We previously showed that, in mice, loss of Hnf6 from the pancreatic epithelium during organogenesis results in increased duct proliferation and altered duct architecture, increased periductal fibrosis and acinar-to-ductal metaplasia. Here we show that decreased expression of HNF6 is strongly correlated with increased severity of PanIN lesions in samples of human pancreata and is absent from >90% of PDAC. Mouse models in which cancer progression can be analyzed from the earliest stages that are seldom accessible in humans support a role for Hnf6 loss in progression from early- to late-stage PanIN and PDAC. In addition, gene expression analyses of human pancreatic cancer reveal decreased expression of HNF6 and its direct and indirect target genes compared with normal tissue and upregulation of genes that act in opposition to HNF6 and its targets. The negative correlation between HNF6 expression and pancreatic cancer progression suggests that HNF6 maintains pancreatic epithelial homeostasis in humans, and that its loss contributes to the progression from PanIN to ductal adenocarcinoma. Insight on the role of HNF6 in pancreatic cancer development could lead to its use as a biomarker for early detection and prognosis.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Fator 6 Nuclear de Hepatócito/deficiência , Fator 6 Nuclear de Hepatócito/genética , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Pancreáticas/metabolismo , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Progressão da Doença , Fator 6 Nuclear de Hepatócito/metabolismo , Homeostase/genética , Humanos , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia
14.
Gastroenterology ; 146(7): 1727-38.e8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24534633

RESUMO

BACKGROUND & AIMS: Loss of parietal cells causes the development of spasmolytic polypeptide-expressing metaplasia (SPEM) through transdifferentiation of chief cells. In the presence of inflammation, SPEM can advance into a more proliferative metaplasia with increased expression of intestine-specific transcripts. We used L635 to induce acute SPEM with inflammation in mice and investigated the roles of inflammatory cells in the development of SPEM. METHODS: To study the adaptive immune system, Rag1 knockout, interferon-γ-deficient, and wild-type (control) mice received L635 for 3 days. To study the innate immune system, macrophages were depleted by intraperitoneal injection of clodronate liposomes 2 days before and throughout L635 administration. Neutrophils were depleted by intraperitoneal injection of an antibody against Ly6G 2 days before and throughout L635 administration. Pathology and immunohistochemical analyses were used to determine depletion efficiency, metaplasia, and proliferation. To characterize SPEM in each model, gastric tissues were collected and levels of Cftr, Dmbt1, and Gpx2 mRNAs were measured. Markers of macrophage polarization were used to identify subpopulations of macrophages recruited to the gastric mucosa. RESULTS: Administration of L635 to Rag1 knockout, interferon-γ-deficient, and neutrophil-depleted mice led to development of proliferative SPEM and up-regulation of intestine-specific transcripts in SPEM cells, similar to controls. However, macrophage-depleted mice given L635 showed significant reductions in numbers of SPEM cells, SPEM cell proliferation, and expression of intestine-specific transcripts, compared with control mice given L635. In mice given L635, as well as patients with intestinal metaplasia, M2 macrophages were the primary inflammatory component. CONCLUSIONS: Results from studies of mouse models and human metaplastic tissues indicate that M2 macrophages promote the advancement of SPEM in the presence of inflammation.


Assuntos
Transformação Celular Neoplásica/metabolismo , Gastrite/metabolismo , Macrófagos/metabolismo , Células Parietais Gástricas/metabolismo , Peptídeos/metabolismo , Neoplasias Gástricas/metabolismo , Imunidade Adaptativa , Animais , Atrofia , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Modelos Animais de Doenças , Gastrite/induzido quimicamente , Gastrite/genética , Gastrite/imunologia , Gastrite/patologia , Regulação Neoplásica da Expressão Gênica , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Imunidade Inata , Mediadores da Inflamação/metabolismo , Interferon gama/deficiência , Interferon gama/genética , Macrófagos/imunologia , Masculino , Metaplasia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucinas/genética , Mucinas/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Células Parietais Gástricas/imunologia , Células Parietais Gástricas/patologia , Fenótipo , RNA Mensageiro/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Regulação para Cima
15.
Proc Natl Acad Sci U S A ; 108(37): 15242-7, 2011 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-21876171

RESUMO

Type 1 and type 2 diabetes result from an absolute or relative reduction in functional ß-cell mass. One approach to replacing lost ß-cell mass is transplantation of cadaveric islets; however, this approach is limited by lack of adequate donor tissue. Therefore, there is much interest in identifying factors that enhance ß-cell differentiation and proliferation in vivo or in vitro. Connective tissue growth factor (CTGF) is a secreted molecule expressed in endothelial cells, pancreatic ducts, and embryonic ß cells that we previously showed is required for ß-cell proliferation, differentiation, and islet morphogenesis during development. The current study investigated the tissue interactions by which CTGF promotes normal pancreatic islet development. We found that loss of CTGF from either endothelial cells or ß cells results in decreased embryonic ß-cell proliferation, making CTGF unique as an identified ß cell-derived factor that regulates embryonic ß-cell proliferation. Endothelial CTGF inactivation was associated with decreased islet vascularity, highlighting the proposed role of endothelial cells in ß-cell proliferation. Furthermore, CTGF overexpression in ß cells during embryogenesis using an inducible transgenic system increased islet mass at birth by promoting proliferation of immature ß cells, in the absence of changes in islet vascularity. Together, these findings demonstrate that CTGF acts in an autocrine manner during pancreas development and suggest that CTGF has the potential to enhance expansion of immature ß cells in directed differentiation or regeneration protocols.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Animais , Comunicação Autócrina , Linhagem da Célula , Proliferação de Células , Tamanho Celular , Desenvolvimento Embrionário , Camundongos , Modelos Biológicos , Morfogênese , Ratos
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