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1. Progastrin production transitions from Bmi1+/Prox1+ to Lgr5high cells during early intestinal tumorigenesis

Author

Bénédicte Brulin, Unmesh Jadhav, Philippe Crespy, Zeinab Homayed, Jihane Boubaker-Vitre, Fanny Grillet, J. Hazerbroucq, Frédéric Hollande, Cyril Breuker, Julie Giraud, Christine Pignodel, J-F. Bourgaux, Ramesh A. Shivdasani, Philippe Jay, Julie Pannequin, Momeneh Foroutan, MORNET, Dominique, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), University of Melbourne, Dana-Farber Cancer Institute [Boston], Harvard Medical School [Boston] (HMS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), and Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Cancer Research, FACS, Fluorescence-Activated Cell Sorting, [SDV]Life Sciences [q-bio], Intestinal polyp, Enteroendocrine cell, Biology, Tumor initiating cells, lcsh:RC254-282, Lgr5 (GPR49), 03 medical and health sciences, 0302 clinical medicine, Intestinal mucosa, Lgr5, leucine-rich repeat containing G protein-coupled receptor 5, Neoplastic transformation, APC, Adenomatous Polyposis Coli, Original Research, PG, progastrin, Progastrin, Intestinal stem cells, Wnt signaling pathway, LGR5, CBC, crypt base columnar cells, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Adenomas, 3. Good health, SPF, Specific Pathogen Free, [SDV] Life Sciences [q-bio], 030104 developmental biology, EGFP, Enhanced Green Fluorescence Protein, Oncology, BMI1, 030220 oncology & carcinogenesis, Cancer research, Stem cell, DAPI, 4′,6-diamidino-2-phenylindole
Abstract

Highlights • Secretion of progastrin is a signature event of early malignant transformation in the colon. • In the healthy epithelium, progastrin is produced by a subset of enteroendocrine cells expressing both Bmi1 and Prox1. • LGR5-high intestinal stem cells are a primary source of progastrin production in early mouse and human intestinal adenomas., Progastrin is an unprocessed soluble peptide precursor with a well-described tumor-promoting role in colorectal cancer. It is expressed at small levels in the healthy intestinal mucosa, and its expression is enhanced at early stages of intestinal tumor development, with high levels of this peptide in hyperplastic intestinal polyps being associated with poor neoplasm-free survival in patients. Yet, the precise type of progastrin-producing cells in the healthy intestinal mucosa and in early adenomas remains unclear. Here, we used a combination of immunostaining, RNAscope labelling and retrospective analysis of single cell RNAseq results to demonstrate that progastrin is produced within intestinal crypts by a subset of Bmi1+/Prox1+/LGR5low endocrine cells, previously shown to act as replacement stem cells in case of mucosal injury. In contrast, our findings indicate that intestinal stem cells, specified by expression of the Wnt signaling target LGR5, become the main source of progastrin production in early mouse and human intestinal adenomas. Collectively our results suggest that the previously identified feed-forward mechanisms between progastrin and Wnt signaling is a hallmark of early neoplastic transformation in mouse and human colonic adenomas.

Published
2020
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2. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites

Author

Valérie S. Zimmermann, Laure Garnier, Pierre Cesses, Danielle J. Smyth, Philippe Jay, Emmanuelle Sidot, Valerie Dardalhon, Marco Bruschi, Naomi Taylor, Makoto Ohmoto, François Gerbe, Ichiro Matsumoto, Bénédicte Brulin, Rick M. Maizels, Yvonne Harcus, Marie Pouzolles, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
0301 basic medicine, Male, Cell signaling, Mucosal/*immunology, Strongylida Infections/immunology, Goblet Cells/cytology/immunology, Physiological, [SDV]Life Sciences [q-bio], Biology, Feedback, 03 medical and health sciences, Mice, Immune system, Nippostrongylus/*immunology, Intestinal Mucosa/*cytology/*immunology/metabolism, Immunity, Interleukin-4/immunology, parasitic diseases, Receptors, Parasites/*immunology, Animals, Secretion, Cell Lineage, Progenitor cell, Cell Proliferation, Multidisciplinary, Signal Transduction/immunology, Th2 Cells/cytology/immunology, Stem Cells/cytology/immunology, Interleukin-13/immunology, Intestinal epithelium, 3. Good health, Interleukin-17/immunology/metabolism, 030104 developmental biology, Mucosal immunology, Immunology, Octamer Transcription Factors/deficiency, Female, Tuft cell
Abstract

International audience; Helminth parasitic infections are a major global health and social burden. The host defence against helminths such as Nippostrongylus brasiliensis is orchestrated by type 2 cell-mediated immunity. Induction of type 2 cytokines, including interleukins (IL) IL-4 and IL-13, induce goblet cell hyperplasia with mucus production, ultimately resulting in worm expulsion. However, the mechanisms underlying the initiation of type 2 responses remain incompletely understood. Here we show that tuft cells, a rare epithelial cell type in the steady-state intestinal epithelium, are responsible for initiating type 2 responses to parasites by a cytokine-mediated cellular relay. Tuft cells have a Th2-related gene expression signature and we demonstrate that they undergo a rapid and extensive IL-4Ralpha-dependent amplification following infection with helminth parasites, owing to direct differentiation of epithelial crypt progenitor cells. We find that the Pou2f3 gene is essential for tuft cell specification. Pou2f3(-/-) mice lack intestinal tuft cells and have defective mucosal type 2 responses to helminth infection; goblet cell hyperplasia is abrogated and worm expulsion is compromised. Notably, IL-4Ralpha signalling is sufficient to induce expansion of the tuft cell lineage, and ectopic stimulation of this signalling cascade obviates the need for tuft cells in the epithelial cell remodelling of the intestine. Moreover, tuft cells secrete IL-25, thereby regulating type 2 immune responses. Our data reveal a novel function of intestinal epithelial tuft cells and demonstrate a cellular relay required for initiating mucosal type 2 immunity to helminth infection.

Published
2016
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3. IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization

Author

Régis Brion, Stéphane Téletchéa, Bénédicte Brulin, Mike Maillasson, Dominique Heymann, Aude I. Segaliny, Céline Charrier, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes), Plateforme IMPACT Nantes (CRCINA-IMPACT), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Unité de fonctionnalité et ingénierie de protéines (UFIP), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), and This study was supported by the Region des Pays de la Loire (CIMATH II research project) and by the Ligue Nationale Contre le Cancer (Equipe LIGUE 2012).

Subjects
Macrophage colony-stimulating factor, Macrophage-Colony Stimulating Factor, Cell Survival, medicine.medical_treatment, Immunology, Molecular modeling, Receptor, Macrophage Colony-Stimulating Factor, [SDV.CAN]Life Sciences [q-bio]/Cancer, Interleukin-17 receptor, Proximity ligation assay, cFMS trafficking, Biology, Biochemistry, Monocytes, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Cell Line, Tumor, medicine, Immunology and Allergy, Humans, Phosphorylation, Receptor, Molecular Biology, 030304 developmental biology, Cell Proliferation, 0303 health sciences, Interleukins, Macrophage Colony-Stimulating Factor, Cell Differentiation, Hematology, Molecular biology, Interleukin-34, Cell biology, Molecular Docking Simulation, Cytokine, HEK293 Cells, Heteromeric cytokine, 030220 oncology & carcinogenesis, Interleukin 34, Cytokines, Signal transduction, Protein Multimerization, Signal Transduction
Abstract

International audience; Interleukin-34 (IL-34) is a newly-discovered homodimeric cytokine that regulates, like Macrophage Colony-Stimulating Factor (M-CSF), the differentiation of the myeloid lineage through M-CSF receptor (M-CSFR) signaling pathways. To date, both cytokines have been considered as competitive cytokines with regard to the M-CSFR. The aim of the present work was to study the functional relationships of these cytokines on cells expressing the M-CSFR. We demonstrate that simultaneous addition of M-CSF and IL-34 led to a specific activation pattern on the M-CSFR, with higher phosphorylation of the tyrosine residues at low concentrations. Similarly, both cytokines showed an additive effect on cellular proliferation or viability. In addition, BIAcore experiments demonstrated that M-CSF binds to IL-34, and molecular docking studies predicted the formation of a heteromeric M-CSF/IL-34 cytokine. A proximity ligation assay confirmed this interaction between the cytokines. Finally, co-expression of the M-CSFR and its ligands differentially regulated M-CSFR trafficking into the cell. This study establishes a new foundation for the understanding of the functional relationship between IL-34 and M-CSF, and gives a new vision for the development of therapeutic approaches targeting the IL-34/M-CSF/M-CSFR axis.

Published
2015
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4. Pathogenic potential of Escherichia coli clinical strains from orthopedic implant infections towards human osteoblastic cells

Author

Bénédicte Brulin, Lise Crémet, Régis Brion, Karim Asehnoune, Nathalie Caroff, Stéphane Corvec, Cédric Jacqueline, Alexis Broquet, Dominique Heymann, Sandie Dauvergne, Thérapeutiques cliniques et expérimentales des infections (EA 3826) (EA 3826), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Département de bactériologie-hygiénique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité de Soins Intensifs [CHU Nantes] (Département d'anesthésie et de soins intensifs), This work was supported by the French 'Ministère de l’Enseignement Supérieur et de la Recherche'., maurice, sandrine, and Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)

Subjects
medicine.disease_cause, Bacterial Adhesion, Hemolysin Proteins, Immunology and Allergy, human osteoblasts, Pathogen, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Microscopy, Confocal, Escherichia coli Proteins, alpha-hemolysin, Hemolysin, General Medicine, E coli, Endocytosis, 3. Good health, Infectious Diseases, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Staphylococcus aureus, Surgical Procedures, Operative, Pseudomonas aeruginosa, cytotoxicity, Gentamicin, Research Article, medicine.drug, Microbiology (medical), Prosthesis-Related Infections, Cell Survival, Population, Biology, Cell Line, Microbiology, Gentamicin protection assay, Escherichia coli, medicine, Humans, education, Osteoblasts, L-Lactate Dehydrogenase, General Immunology and Microbiology, Interleukin-6, Tumor Necrosis Factor-alpha, Gene Expression Profiling, Coculture Techniques, internalization, Orthopedics, TNF-α, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; One sentence summary: This study describes the interaction of Escherichia coli clinical strains with an osteoblastic cell line, showing no internalization unlike Staphylococcus aureus, but a strong cytotoxicity of the Hly-A producing strains. Editor: Patrik M. Bavoil ABSTRACT Escherichia coli is one of the first causes of Gram-negative orthopedic implant infections (OII), but little is known about the pathogenicity of this species in such infections that are increasing due to the ageing of the population. We report how this pathogen interacts with human osteoblastic MG-63 cells in vitro, by comparing 20 OII E. coli strains to two Staphylococcus aureus and two Pseudomonas aeruginosa strains. LDH release assay revealed that 6/20 (30%) OII E. coli induced MG-63 cell lysis whereas none of the four control strains was cytotoxic after 4 h of coculture. This high cytotoxicity was associated with hemolytic properties and linked to hlyA gene expression. We further showed by gentamicin protection assay and confocal microscopy that the non-cytotoxic E. coli were not able to invade MG-63 cells unlike S. aureus strains (internalization rate

Published
2015
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5. Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium

Author

Béatrice Romagnolo, François Gerbe, Leila Makrini, Noah F. Shroyer, Johan H. van Es, Christine Pignodel, Sylvie Robine, Georg Mellitzer, Philippe Jay, Bénédicte Brulin, Hans Clevers, Jean-François Bourgaux, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Division of Gastroenterology, Hepatology and Nutrition, University of Cincinnati (UC)-Cincinnati Children's Hospital Medical Center, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service d'Anatomopathologie, Hubrecht Institute for Developmental Biology and Stem Cell Research, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adenoma, Cell type, Cellular differentiation, Nerve Tissue Proteins, Enteroendocrine cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, SOX9, Adenocarcinoma, Protein Serine-Threonine Kinases, Biology, Article, Mice, 03 medical and health sciences, Doublecortin-Like Kinases, 0302 clinical medicine, Intestinal mucosa, Intestinal Neoplasms, Intestine, Small, Basic Helix-Loop-Helix Transcription Factors, Animals, Humans, Intestine, Large, Intestinal Mucosa, Isomerases, Research Articles, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Membrane Proteins, Cell Differentiation, SOX9 Transcription Factor, Cell Biology, Intestinal epithelium, Cell biology, Intramolecular Oxidoreductases, Mice, Inbred C57BL, Cyclooxygenase 2, 030220 oncology & carcinogenesis, Cyclooxygenase 1, Tuft cell, Stem cell, Biomarkers
Abstract

Tuft cells represent a fourth type of intestinal secretory cell that constitutes the primary source of endogenous intestinal opioids and are the only epithelial cell that constitutively express cyclooxygenases., The unique morphology of tuft cells was first revealed by electron microscopy analyses in several endoderm-derived epithelia. Here, we explore the relationship of these cells with the other cell types of the intestinal epithelium and describe the first marker signature allowing their unambiguous identification. We demonstrate that although mature tuft cells express DCLK1, a putative marker of quiescent stem cells, they are post-mitotic, short lived, derive from Lgr5-expressing epithelial stem cells, and are found in mouse and human tumors. We show that whereas the ATOH1/MATH1 transcription factor is essential for their differentiation, Neurog3, SOX9, GFI1, and SPDEF are dispensable, which distinguishes these cells from enteroendocrine, Paneth, and goblet cells, and raises from three to four the number of secretory cell types in the intestinal epithelium. Moreover, we show that tuft cells are the main source of endogenous intestinal opioids and are the only epithelial cells that express cyclooxygenase enzymes, suggesting important roles for these cells in the intestinal epithelium physiopathology.

Published
2011
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6. DCAMKL-1 expression identifies Tuft cells rather than stem cells in the adult mouse intestinal epithelium

Author

Bénédicte Brulin, François Gerbe, Philippe Jay, Catherine Legraverend, Leila Makrini, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular and Medical Genetics, University of Toronto, Jay, Philippe, and Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Pathology, medicine.medical_specialty, Cellular differentiation, [SDV.CAN]Life Sciences [q-bio]/Cancer, colon carcinoma, MESH: Stem Cells, Biology, Stem cell marker, MESH: Protein-Serine-Threonine Kinases, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cancer stem cell, stem cells, medicine, tuft cells, intestinal epithelium, MESH: Animals, Dcamkl-1, cell lineage, MESH: Mice, 030304 developmental biology, 0303 health sciences, Hepatology, Gastroenterology, MESH: Biological Markers, brush cells, Amniotic stem cells, MESH: Immunohistochemistry, differentiation, 3. Good health, Cell biology, Dcamkl1, MESH: Reproducibility of Results, Dclk1, colon cancer, 030220 oncology & carcinogenesis, Amniotic epithelial cells, MESH: Intestinal Mucosa, Stem cell, Tuft cell, Adult stem cell, Sox9
Abstract

International audience; In an editorial of the last issue of Gastroenterology, Montgomery and Shivdasani comment on the known markers of mammalian intestinal epithelial stem cells. We wish to caution that staining for doublecortin and calcium/calmodulin-dependent protein kinase-like-1 (DCAMKL-1), one of the putative stem cell markers mentioned in this editorial, is a highly specific and robust marker of postmitotic, differentiated, tuft cells, a minority cell lineage of the intestinal epithelium, rather than a marker for intestinal epithelial stem cells. This is important since candidate markers of intestinal stem cell are scarce and DCAMKL-1 might be especially attractive to researchers because of the availability of good antibodies, which is not the case for other, functionally validated, markers, such as Lgr5.

Published
2009
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