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Moghadamrad_2022_MDPI_Biomedicines_Paneth Cells Regulate
Journal article

Paneth cells regulate lymphangiogenesis under control of microbial signals during experimental portal hypertension

  • Hassan, Mohsin Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Germany - Department for Biomedical Research (DBMR), University of Bern, Switzerland
  • Juanola, Oriol ORCID Laboratories for Translational Research, Department of Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Bellinzona, Switzerland - Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Keller, Irene Interfaculty Bioinformatics Unit, Swiss Institute of Bioinformatics, University of Bern, Switzerland
  • Nanni, Paolo Functional Genomics Center Zurich, University/ETH Zurich, Switzerland
  • Wolski, Witold Functional Genomics Center Zurich, University/ETH Zurich, Switzerland
  • Martínez-López, Sebastián Hepatic and Intestinal Immunobiology Group, Departamento Medicina Clínica, Universidad Miguel Hernández, Alicante, Spain - Instituto de Investigación Sanitaria ISABIAL, Hospital General Universitario, Alicante, Spain
  • Caparrós, Esther Hepatic and Intestinal Immunobiology Group, Departamento Medicina Clínica, Universidad Miguel Hernández, Alicante, Spain - Instituto de Investigación Sanitaria ISABIAL, Hospital General Universitario, Alicante, Spain
  • Francés, Rubén Hepatic and Intestinal Immunobiology Group, Departamento Medicina Clínica, Universidad Miguel Hernández, Alicante, Spain - Instituto de Investigación Sanitaria ISABIAL, Hospital General Universitario, Alicante, Spain - Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain - CIBERehd, Instituto Salud Carlos III, Madrid, Spain
  • Moghadamrad, Sheida ORCID Department for Biomedical Research (DBMR), University of Bern, Switzerland - Laboratories for Translational Research, Department of Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Bellinzona, Switzerland - Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - University Clinic of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland
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  • 2022
Published in:
  • Biomedicines. - 2022, vol. 10, no. 7, p. 1503
Lymphatic vessels
Lymphangiogenesis
LYVE1
Paneth cells
Portal hypertension
English Intestinal microbiota can modulate portal hypertension through the regulation of the intestinal vasculature. We have recently demonstrated that bacterial antigens activate Paneth cells (PCs) to secrete products that regulate angiogenesis and portal hypertension. In the present work we hypothesized that Paneth cells regulate the development of lymphatic vessels under the control of intestinal microbiota during experimental portal hypertension. We used a mouse model of inducible PCs depletion (Math1Lox/LoxVilCreERT2) and performed partial portal vein ligation (PPVL) to induce portal hypertension. After 14 days, we performed mRNA sequencing and evaluated the expression of specific lymphangiogenic genes in small intestinal tissue. Intestinal and mesenteric lymphatic vessels proliferation was assessed by immunohistochemistry. Intestinal organoids with or without PCs were exposed to pathogen-associated molecular patterns, and conditioned media (CM) was used to stimulate human lymphatic endothelial cells (LECs). The lymphangiogenic activity of stimulated LECs was assessed by tube formation and wound healing assays. Secretome analysis of CM was performed using label-free proteomics quantification methods. Intestinal immune cell infiltration was evaluated by immunohistochemistry. We observed that the intestinal gene expression pattern was altered by the absence of PCs only in portal hypertensive mice. We found a decreased expression of specific lymphangiogenic genes in the absence of PCs during portal hypertension, resulting in a reduced proliferation of intestinal and mesenteric lymphatic vessels as compared to controls. In vitro analyses demonstrated that lymphatic tube formation and endothelial wound healing responses were reduced significantly in LECs treated with CM from organoids without PCs. Secretome analyses of CM revealed that PCs secrete proteins that are involved in lipid metabolism, cell growth and proliferation. Additionally, intestinal macrophages infiltrated the ileal mucosa and submucosa of mice with and without Paneth cells in response to portal hypertension. Our results suggest that intestinal microbiota signals stimulate Paneth cells to secrete factors that modulate the intestinal and mesenteric lymphatic vessels network during experimental portal hypertension.
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  • English
Classification
Medicine
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CC BY
Open access status
gold
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https://n2t.net/ark:/12658/srd1332020
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