Paneth cells promote angiogenesis and regulate portal hypertension in response to microbial signals.

Mohsin Hassan, Mohsin Hassan; Moghadamrad, Sheida; Sorribas, Marcel; G. Muntet, Sergi; Kellmann, Philipp; Trentesaux, Coralie; Fraudeau, Marie; Nanni, Paolo; Wolski, Witold; Keller, Irene; Hapfelmeier, Siegfried; Shroyer, Noah F; Wiest, Reiner; Romagnolo, Beatrice; De Gottardi, Andrea (2020). Paneth cells promote angiogenesis and regulate portal hypertension in response to microbial signals. Journal of hepatology, 73(3), pp. 628-639. Elsevier 10.1016/j.jhep.2020.03.019

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BACKGROUND & AIMS

Paneth cells (PCs) synthesize and secrete antimicrobial peptides that are key mediators of host-microbe interactions, establishing a balance between intestinal microflora and enteric pathogens. We observed that their number increases in experimental portal hypertension and aimed to investigate the mechanisms by which these cells can contribute to the regulation of portal pressure.

METHODS

We first treated Math1Lox/LoxVilcreERT2 mice with tamoxifen to induce the complete depletion of intestinal PCs. Subsequently, we performed partial portal vein or bile duct ligation. We then studied the effects of these interventions on hemodynamic parameters, proliferation of blood vessels and the expression of genes regulating angiogenesis. Intestinal organoids were cultured and exposed to different microbial products to study the composition of their secreted products (by proteomics) and their effects on the proliferation and tube formation of endothelial cells (ECs). In vivo confocal laser endomicroscopy was used to confirm the findings on blood vessel proliferation.

RESULTS

Portal hypertension was significantly attenuated in PC-depleted mice compared to control mice and was associated with a decrease in portosystemic shunts. Depletion of PCs also resulted in a significantly decreased density of blood vessels in the intestinal wall and mesentery. Furthermore, we observed reduced expression of intestinal genes regulating angiogenesis in Paneth cell depleted mice using arrays and next generation sequencing. Tube formation and wound healing responses were significantly decreased in ECs treated with conditioned media from PC-depleted intestinal organoids exposed to intestinal microbiota-derived products. Proteomic analysis of conditioned media in the presence of PCs revealed an increase in factors regulating angiogenesis and additional metabolic processes. In vivo endomicroscopy showed decreased vascular proliferation in the absence of PCs.

CONCLUSIONS

These results suggest that in response to intestinal flora and microbiota-derived factors, PCs secrete not only antimicrobial peptides, but also pro-angiogenic signaling molecules, thereby promoting intestinal and mesenteric angiogenesis and regulating portal hypertension.

LAY SUMMARY

Paneth cells are present in the lining of the small intestine. They prevent the passage of bacteria from the intestine into the blood circulation by secreting substances to fight bacteria. In this paper, we discovered that these substances not only act against bacteria, but also increase the quantity of blood vessels in the intestine and blood pressure in the portal vein. This is important, because high blood pressure in the portal vein may result in several complications which could be targeted with novel approaches.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases > Research
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Gastroenterology
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Gastroenterologie / Mukosale Immunologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Gastroenterologie / Mukosale Immunologie

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie

UniBE Contributor:

Mohsin Hassan, Mohsin Hassan; Moghadamrad, Sheida; Sorribas Olivera, Marcel; Guixé Muntet, Sergi; Kellmann, Philipp; Keller, Irene; Hapfelmeier, Siegfried Hektor; Wiest, Reiner and De Gottardi, Andrea

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0168-8278

Publisher:

Elsevier

Language:

English

Submitter:

Rahel Fuhrer

Date Deposited:

15 Dec 2020 17:11

Last Modified:

15 Dec 2020 17:11

Publisher DOI:

10.1016/j.jhep.2020.03.019

PubMed ID:

32205193

Uncontrolled Keywords:

Antimicrobial peptides Bacterial-derived products Intestinal microflora Intestinal organoids Proteomics

BORIS DOI:

10.7892/boris.148411

URI:

https://boris.unibe.ch/id/eprint/148411

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