Mechanisms of Barrett's oesophagus: Intestinal differentiation, stem cells, and tissue models

Nakagawa, Hiroshi; Whelan, Kelly A.; Lynch, John P.

doi:10.1016/j.bpg.2014.11.001

Cited by 27 publications

(20 citation statements)

References 76 publications

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“…These L2-IL-1b mice develop a chronic [43] inflammatory esophagitis by 3 months ( Figure 1A) that is followed subsequently by the development of a columnar metaplasia with intestinal features that later progresses to dysplasia and cancer. The strength of this transgenic mouse model is that in many ways it strongly phenocopies the pathogenesis of the human BE as it is presently believed to occur [44,45]. This metaplasia is intestinalized, as confirmed by the presence of intestinal mucins established by Alcian blue staining, and immunohistochemistry for Muc2, an intestinal mucin [31].…”

Section: Autophagy In Human Normal Squamous Be and Eac Biopsiesmentioning

confidence: 91%

Autophagy levels are elevated in barrett's esophagus and promote cell survival from acid and oxidative stress

Kong

Whelan

Laczkó

et al. 2015

Molecular Carcinogenesis

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Autophagy is a highly conserved mechanism that is activated during cellular stress. We hypothesized that autophagy may be induced by acid reflux, which causes injury and inflammation, and therefore contributes to the pathogenesis of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). Currently, the role of autophagy in BE and EAC is poorly studied. We quantitatively define autophagy levels in human BE cell lines, a transgenic mouse model of BE, and human BE and EAC biopsies. Human non-dysplastic BE had the highest basal number of autophagic vesicles (AVs), while AVs were reduced in normal squamous cells and dysplastic BE cells, and nearly absent in EAC. To demonstrate a functional role for autophagy in BE pathogenesis, normal squamous (STR), non-dysplastic BE (CPA), dysplastic BE (CPD), and esophageal adenocarcinoma (OE19) cell lines were exposed to an acid pulse (pH3.5) followed by incubation in the presence or absence of chloroquine, an autophagy inhibitor. Acid exposure increased reactive oxygen species (ROS) levels in STR and CPA cells. Chloroquine alone had a small impact on intracellular ROS or cell survival. However, combination of chloroquine with the acid pulse resulted in a significant increase in ROS levels at 6 hours in STR and CPA cells, and increased cell death in all cell lines. These findings establish increased numbers of AVs in human BE compared to normal squamous or EAC, and suggest that autophagy functions to improve cell survival after acid reflux injury. Autophagy may thus play a critical role in BE pathogenesis and progression.

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Section: Autophagy In Human Normal Squamous Be and Eac Biopsiesmentioning

confidence: 91%

Autophagy levels are elevated in barrett's esophagus and promote cell survival from acid and oxidative stress

Kong

Whelan

Laczkó

et al. 2015

Molecular Carcinogenesis

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“…In addition to increased proliferation, spheroids compared with squamous epithelium also showed increased expression of genes related to responses to wound healing ( Figure 8 B ). Given the hypothesis that under certain circumstances BE may derive from ESMGs, we identified established BE markers from the literature (AGR2, MUC13, KRT18, MUC1, KRT8, and SOX9 32 , 33 , 34 ) that were represented on the porcine microarray. We found increased expression of these BE markers in 3D culture of ESMG spheroids compared with squamous epithelium ( Figure 8 C ), supporting the notion that cells within ESMGs have the potential to contribute to BE under certain conditions.…”

Section: Resultsmentioning

confidence: 99%

Porcine Esophageal Submucosal Gland Culture Model Shows Capacity for Proliferation and Differentiation

Furstenberg

Stolarchuk

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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Background & AimsAlthough cells comprising esophageal submucosal glands (ESMGs) represent a potential progenitor cell niche, new models are needed to understand their capacity to proliferate and differentiate. By histologic appearance, ESMGs have been associated with both overlying normal squamous epithelium and columnar epithelium. Our aim was to assess ESMG proliferation and differentiation in a 3-dimensional culture model.MethodsWe evaluated proliferation in human ESMGs from normal and diseased tissue by proliferating cell nuclear antigen immunohistochemistry. Next, we compared 5-ethynyl-2′-deoxyuridine labeling in porcine ESMGs in vivo before and after esophageal injury with a novel in vitro porcine organoid ESMG model. Microarray analysis of ESMGs in culture was compared with squamous epithelium and fresh ESMGs.ResultsMarked proliferation was observed in human ESMGs of diseased tissue. This activated ESMG state was recapitulated after esophageal injury in an in vivo porcine model, ESMGs assumed a ductal appearance with increased proliferation compared with control. Isolated and cultured porcine ESMGs produced buds with actively cycling cells and passaged to form epidermal growth factor–dependent spheroids. These spheroids were highly proliferative and were passaged multiple times. Two phenotypes of spheroids were identified: solid squamous (P63+) and hollow/ductal (cytokeratin 7+). Microarray analysis showed spheroids to be distinct from parent ESMGs and enriched for columnar transcripts.ConclusionsOur results suggest that the activated ESMG state, seen in both human disease and our porcine model, may provide a source of cells to repopulate damaged epithelium in a normal manner (squamous) or abnormally (columnar epithelium). This culture model will allow the evaluation of factors that drive ESMGs in the regeneration of injured epithelium. The raw microarray data have been uploaded to the National Center for Biotechnology Information Gene Expression Omnibus (accession number: GSE100543).

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“…Due to the dual action of bupropion with regards to the inhibition of norepinephrine and dopamine reuptake, it is thought to be effective for reducing impulsive behaviors in both IGD and ibGD patients ( 33 , 34 ). Impulsivity is a well-known correlate of prototypical behavioral addictions with steep discounting of delayed rewards ( 35 ). This steep discounting of delayed rewards is associated with the dopamine-based neuromodulatory system ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Bupropion Shows Different Effects on Brain Functional Connectivity in Patients With Internet-Based Gambling Disorder and Internet Gaming Disorder

et al. 2018

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IntroductionInternet gaming disorder (IGD) and gambling disorder (GD) share similar clinical characteristics but show different brain functional connectivity patterns. Bupropion is known to be effective for the treatment of patients with IGD and GD. We hypothesized that bupropion may be effective for the treatment of Internet-based gambling disorder (ibGD) and IGD and that the connections between the default mode network (DMN) and cognitive control network (CCN) would be different between ibGD and IGD patients after 12 weeks of bupropion treatment.Methods16 patients with IGD, 15 patients with ibGD, and 15 healthy subjects were recruited in this study. At baseline and after 12 weeks of bupropion treatment, the clinical symptoms of patients with IGD or ibGD were assessed, and brain activity was evaluated using resting state functional magnetic resonance imaging.ResultsAfter the 12-week bupropion treatment, clinical symptoms, including the severity of IGD or GD, depressive symptoms, attention, and impulsivity improved in both groups. In the IGD group, the functional connectivity (FC) within the posterior DMN as well as the FC between the DMN and the CCN decreased following treatment. Moreover, the FC within the DMN in the IGD group was positively correlated with changes in Young Internet Addiction Scale scores after the bupropion treatment period. In the ibGD group, the FC within the posterior DMN decreased while the FC within the CCN increased after the bupropion treatment period. Moreover, the FC within the CCN in the ibGD group was significantly greater than that in the IGD group.ConclusionBupropion was effective in improving clinical symptoms in patients with IGD and ibGD. However, there were differences in the pharmacodynamics between the two groups. After 12 weeks of bupropion treatment, the FC within the DMN as well as between the DMN and CCN decreased in patients with IGD, whereas the FC within the CCN increased in patients with ibGD.

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Mechanisms of Barrett's oesophagus: Intestinal differentiation, stem cells, and tissue models

Cited by 27 publications

References 76 publications

Autophagy levels are elevated in barrett's esophagus and promote cell survival from acid and oxidative stress

Autophagy levels are elevated in barrett's esophagus and promote cell survival from acid and oxidative stress

Porcine Esophageal Submucosal Gland Culture Model Shows Capacity for Proliferation and Differentiation

Bupropion Shows Different Effects on Brain Functional Connectivity in Patients With Internet-Based Gambling Disorder and Internet Gaming Disorder

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