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MODELLING PIEZO1-MEDIATED PRESSURE-INDUCED INFLAMMATORY PHENOTYPE OF HUMAN PANCREATIC ORGANOIDS

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MODELLING PIEZO1-MEDIATED PRESSURE-INDUCED INFLAMMATORY PHENOTYPE OF HUMAN PANCREATIC ORGANOIDS

Aletta Kata Kiss 1, Arpad Varga 1, Petra Susánszki 2, György Lázár 3, Gergely Groma 2, Petra Pallagi 1, József Maléth 1

Affiliations

1 University of Szeged, Szeged, Hungary|||University of Szeged, Szeged, Hungary|||University of Szeged, Szeged, Hungary

2 University of Szeged, Szeged, Hungary|||University of Szeged, Szeged, Hungary

3 University of Szeged, Szeged, Hungary

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Abstract

Introduction

Pancreas inflammation is frequently brought on by sustained intraductal pressure, which is mostly caused by gallstones or ERCP, a minimally invasive diagnostic technique. It has been demonstrated that in mice, this brief pressure reduces tight junction integrity through calcineurin. Another effector protein of intraluminal pressure is the mechanosensitive Ca²⁺ channel PIEZO1, which senses cell elongation, increases Ca²⁺ influx, and hence controls both epithelial cell division and apoptosis. However, the development of treatment approaches that specifically target post-ERCP and gallstone-induced pancreatitis has been hampered in recent years due to challenges in in vitro modeling of pressure-related changes.

Aims & Methods

Therefore, our aim was to use apical-out organoids (hPOCs) generated from human pancreas to demonstrate the pressure-related disease processes ex vivo.
Pancreatic tissue samples were collected from 3 cadaver donors and used for establishment of hPOCs. Polarity switching of organoids was induced by Matrigel removal. Conventional and apical-out hPOCs were compared by RNA-sequencing and fluorescent live cell imaging. Gene expression changes in response of 1 µM PIEZO1 activator (YODA1) treatment were measured by qRT-PCR in apical-out hPOCs.

Results

Polarity switching reduced PIEZO1 expression, although decreasing intraluminal pressure and therefore cell elongation reduced expression of cytoskeletal and cell cycle related genes such as ACTB, VCL, LPXN, LMNA, and cyclin gene family members. In the same experiment, pro-inflammatory cytokines like CXCL1, CXCL2, CXCL3, and CXCL8 were found to be downregulated. We demonstrated that polarity switching resulted in enhanced Cl^- efflux via CFTR and ANO1 due to the absence of sustained intraluminal pressure maintained by basal secretion in the closed lumen of conventional organoids. The production of pro-inflammatory cytokines in apical-out hPOCs was reversed upon pharmacological activation of PIEZO1 by YODA1, indicating that PIEZO1 is responsible for the development of the inflammation-like pre-stimulated phenotype of apical-in hPOCs.

Conclusion

Altogether, our results suggest that conventional organoid cultures, previously used as physiologically relevant models, may represent a pressure-induced inflammatory state by overexpressing elements of the epithelial innate immune response, while polarity switching of organoids may overcome the previous limitations and open new perspectives in modelling pressure-induced pancreatitis in vitro.

Event

UEG Week Vienna 2024

Topics

Digestive Oncology Endoscopy Immunology Mechanisms & Personalised Medicine Pancreas Radiology & Imaging

Submission format

Abstract

Session

Pancreatic diseases: From models to precision medicine

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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Therapeutics: Endocopy, stentology, radiology and surgery

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Therapeutics: Endocopy, stentology, radiology and surgery

Arnaud Lemmers 1, Christian Toso 2

Affiliations

1 Hôpital Univ. Erasme (Gastro), Bruxelles, Belgium

2 University of Geneva Hospitals, Geneva, Switzerland

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Abstract

Event

UEG Postgraduate Teaching Programme Vienna 2024

Topics

Education & Training Endoscopy Hepatobiliary Radiology & Imaging Surgery

Session

Biliary strictures: Getting through without getting lost

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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ENDOSCOPIC CLOSURE OF A RECTAL FISTULA USING AMPLATZER™ CARDIAC SEPTAL DEFECT OCCLUDER

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ENDOSCOPIC CLOSURE OF A RECTAL FISTULA USING AMPLATZER™ CARDIAC SEPTAL DEFECT OCCLUDER

Renato Medas 1, Eduardo Rodrigues-Pinto 1, João Afonso 1, João Carlos Silva 1, Pedro Pereira 1, Guilherme Macedo 1

Affiliations

1 Centro Hospitalar e Universitário de São João, Porto, Portugal

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Abstract

Introduction

Cardiac septal ocludder device is an off-label device for closure of gastrointestinal fistulas and should be considered for chronic refractory fistulas to conventional endoscopic treatments.

Aims & Methods

We describe the off-label use of a cardiac septal defect occluder (CSDO, Amplatzer™, Abbott) for endoscopic closure of a lower gastrointestinal tract fistula between the rectum and post-cystectomy surgical site.

Results

An 84-year-old male with medical history of T1 bladder cancer underwent radical cystectomy complicated with surgical site abscess. Abdominal CT revealed free gas in surgical site and a rectum wall defect suggestive of fistula. Despite conservative treatment, patient persisted with penial and anal discharge. Patient was referred for endoscopic closure. Colonoscopy showed a 6mm fistulous tract between the cystectomy surgical site and the rectum wall. Two initial closure attempts with 12/6 over-the-scope clips (OTSC) after margin epithelial ablation were tried (second attempt with combined placement of a detachable snare below the OTSC), each 3 months apart. Despite initial technical and clinical success, fistula recurred after spontaneous detachment of OTSCs. Endoscopic
internal drainage with a double pigtail stent was also tried, however, fistula persisted after distal spontaneous migration 2 months later. Considering fistula persistence, patient was proposed for closure with a CSDO. After fluoroscopic characterization of the defect (surgical site: 20x25mm, fistulous tract length: 4mm: fistula orifice diameter: 3mm), a 16/4/12mm Amplatzer™ CSDO was chosen. After placement of a 0.035’AmplatzerTM guidewire from the rectum into the surgical site, guided by a 5.4-Fr angiography catheter, a delivery sheath was then advanced into the surgical site over the guidewire. After mounting the CSDO on the loading device, it was advanced inside the delivery sheath, and correctly deployed with the proximal flange in the surgical site and distal flange in the rectum. Patient remains well, without clinical recurrence.

Conclusion

To date, only 4 cases of lower gastrointestinal fistulas closure with CSDO, all rectovaginal fistulas, have been reported. To the best of our knowledge, this is the first case of endoscopic closure of a fistula between rectum and surgical site.

Event

UEG Week Copenhagen 2023

Topics

Colorectal Digestive Oncology Endoscopy

Submission format

Video Case

Session

Video Case Session

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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Tissue ablation: Endoluminal and EUS-guided

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Tissue ablation: Endoluminal and EUS-guided

D. Nageshwar Reddy 1

Affiliations

1 Asian Institute Of Gastroenterology, Gachibowli, India

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Abstract

Event

UEG Week Copenhagen 2023

Session

Advances in endoscopy: Biliopancreatic endoscopy

Published

2023

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Panel discussion: A 360-degree appraisal of acute pancreatitis

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Panel discussion: A 360-degree appraisal of acute pancreatitis

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Abstract

Event

UEG Postgraduate Teaching Programme Berlin 2025

Topics

Endoscopy Pancreas Radiology & Imaging

Session

A 360-degree appraisal of acute pancreatitis

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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THE PLACE OF ENDOSCOPIC DILATATION IN THE MANAGEMENT OF STENOSES IN STENOSING CROHN'S DISEASE.

Fatima zahra Mghyly 1, Salma Mechhor 2, Manal Cherkaoui Malki 3, Hicham El Bacha 4, Nadia Benzzoubeir 1, Ikram Errabih 5

Affiliations

1 Ibn Sina University Hospital, Mohammed V University, Rabat, Morocco

2 Ibn Sina Hospital, Rabat, Morocco

3 University Hospital Ibn Sina, Rabat, Morocco

4 Hopital ibn sina / universite mohamed v / faculte de medecine, Rabat, Morocco

5 Ibn Sina University Hospital, Rabat, Morocco

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Abstract

Introduction

Crohn's disease (CD) is a chronic inflammatory condition of the digestive tract characterized by a cyclical course, the most frequent and feared complication is the formation of stenoses. The management of these stenoses is often multidisciplinary medico-surgical as well as endoscopic.
Endoscopy plays an essential role in the diagnosis, monitoring, and treatment of these stenoses, particularly through endoscopic dilations. The objective of our work is to study the role of endoscopic dilations during stenosing Crohn's disease in addition to medical treatment.

Aims & Methods

This is a single-center descriptive retrospective study carried out within our department over a period of 6 years: from January 2018 to January 2024, including all patients followed for stenosing Crohn's disease who underwent endoscopic dilation. We collected data related to age, history, location, phenotype, clinical symptoms, endoscopic data as well as evolution.

Results

We included 19 patients followed in our training for stenosing Crohn's disease who benefited from endoscopic dilation out of a total of 109 patients followed for Crohn's disease with a stenosing phenotype (17.4%). The average age was 45 years with extremes ranging from 20 to 71, with a male predominance and a M/F sex ratio: 2.8 (14 M and 5 F).
Three patients were smokers (15.8%), 6 patients underwent anterior ileocecal resection (31.6%) and a total colectomy ATCD in one patient (5.3%). The median time from diagnosis of Crohn's disease to formation of symptomatic stenosis was 9.3 years.
Clinically, abdominal pain was present in 8 patients (42.1%), Koenig syndrome in 7 patients (36.8%), diarrhea in 3 patients (21%), 4 patients (28.5%). had defecatory pain, evacuation constipation in 3 patients (15.8%) and late postprandial vomiting was present in 1 patient (5.3%).
The stenosis was at the last ileal loop in 5 cases (26.3%), 4 (21%) at the rectal level, 1 stenosis respectively at the colonic, anal, esophageal, pyloric and duodenal level (5.3% each) and 5 stenoses at the level of the anastomosis including 4 (21%) at the level of the ileocolic anastomosis and 1 at the level of the ileorectal anastomosis (5.3%).
The average length of the stenoses was 19.2 mm with extremes ranging from 5 to 40 mm. Dilations were carried out using hydrostatic dilation balloons whose caliber varied between 10 and 16.5 mm, 3 (15.8%) patients benefited from dilation to 16.5 mm, 7 (36.8%) at 12mm, 6 (31.6%) at 15mm, and 2 (10.5%) at 11mm.
11 patients benefited (57.9%) from a single dilation session, 7 patients benefited from 2 dilations (36.8%) and 1 patient (5.3%) had recourse to 5 dilations.
Primary success defined by the passage of the endoscope was possible in 15 patients (78.9%). Only one perforation type complication was noted, treated surgically.
The secondary success rate defined by the disappearance of symptoms was in 9 patients (47%). The average follow-up was 31.8 months and the clinical recurrence rate was 37.5% at 6 months. 4 patients (21%) benefited from additional surgery.

Conclusion

Endoscopic dilation is a minimally invasive treatment which constitutes an effective alternative to surgery in the management of stenoses during Crohn's disease; in our study more than half of our patients only had recourse to a single dilation session with a primary success of more than 78.9%, and a disappearance of symptoms at 6 months in almost half of the patients, thus making the use of surgery less frequent.

Conference

UEG Week Vienna 2024

Topics

IBD

Submission format

Abstract

Session

IBD (Posters)

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

A New Era in MASH: How Disease-Specific Therapies Are Changing the Game and Best Practices for Clinical Integration (Catalyst Medical Education, LLC) (Complete Session)

This content is part of Gutflix. Log in with your myUEG account, or create one free, to watch it.

Not sure what you can access? Learn more about account types.

A New Era in MASH: How Disease-Specific Therapies Are Changing the Game and Best Practices for Clinical Integration (Catalyst Medical Education, LLC) (Complete Session)

Naim Alkhouri 1, Jörn Schattenberg 2, Frank Tacke 3

Affiliations

1 Transplant Hepatology Arizona Liver Health Phoenix, AZ, None, United States of America

2 Department of Internal Medicine II, Saarland University Medical Center, Homburg, Germany

3 Charité Universitaetsmedizin Berlin, Dept of Hepatology & Gastroenterology, Berlin, Germany

Summary

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Abstract

Publisher

Catalyst Medical Education

Event

UEG Week Berlin 2025

Session

A New Era in MASH: How Disease-Specific Therapies Are Changing the Game and Best Practices for Clinical Integration (Catalyst Medical Education, LLC)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Christian Toso

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Pedro Pereira

Tissue ablation: Endoluminal and EUS-guided

D. Nageshwar Reddy

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THE PLACE OF ENDOSCOPIC DILATATION IN THE MANAGEMENT OF STENOSES IN STENOSING CROHN'S DISEASE.

Ikram Errabih

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Naim Alkhouri

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