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1. Discovery and 3D imaging of a novel ΔNp63-expressing basal cell type in human pancreatic ducts with implications in disease

Author

Pierre Lefesvre, Katarina Coolens, Farzad Esni, Nelson Dusetti, Harry Heimberg, Luc Bouwens, Jean-Luc Van Laethem, Yves Heremans, Gunter Leuckx, Patrick Jacquemin, Angel Fernandez Ruiz, Tatjana Arsenijevic, Meritxell Rovira, Christelle Bouchart, Peter In't Veld, Wim Waelput, Ilse Rooman, Sandrina Martens, Nicky D'Haene, Abdessamad El Kaoutari, Jaime Martinez de Villareal, Diedert Luc De Paep, Francisco X. Real, Joan Casamitjana, Hediel Madhloum, Mathias Van Bulck, Vrije Universiteit Brussel (VUB), Université libre de Bruxelles (ULB), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Spanish National Cancer Research Center (CNIO), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Université Catholique de Louvain = Catholic University of Louvain (UCL), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Institut Jules Bordet [Bruxelles], Centre de Recherche en Cancérologie de Marseille (CRCM), Basic (bio-) Medical Sciences, Experimental Pathology, Laboratory for Medical and Molecular Oncology, Faculty of Medicine and Pharmacy, Pathology/molecular and cellular medicine, Beta Cell Neogenesis, Cell Differentiation, Surgery, Diabetes Pathology & Therapy, Supporting clinical sciences, Pathology, Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UCL - SSS/DDUV - Institut de Duve, and UCL - SSS/DDUV/LPAD - Liver and pancreas differentiation

Subjects
0301 basic medicine, Pancreatic disease, Cellular differentiation, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, SOX9, Biology, Stem cell marker, 03 medical and health sciences, Basal (phylogenetics), 0302 clinical medicine, development genes, stem cells, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Gastro-entérologie, cancer, pancreas, Gastroenterology, imaging, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Stem cell, Pancreas
Abstract

Objective: The aggressive basal-like molecular subtype of pancreatic ductal adenocarcinoma (PDAC) harbours a ΔNp63 (p40) gene expression signature reminiscent of a basal cell type. Distinct from other epithelia with basal tumours, ΔNp63+ basal cells reportedly do not exist in the normal pancreas. Design: We evaluated ΔNp63 expression in human pancreas, chronic pancreatitis (CP) and PDAC. We further studied in depth the non-cancerous tissue and developed a three-dimensional (3D) imaging protocol (FLIP-IT, Fluorescence Light sheet microscopic Imaging of Paraffin-embedded or Intact Tissue) to study formalin-fixed paraffin-embedded samples at single cell resolution. Pertinent mouse models and HPDE cells were analysed. Results: In normal human pancreas, rare ΔNp63+ cells exist in ducts while their prevalence increases in CP and in a subset of PDAC. In non-cancer tissue, ΔNp63+ cells are atypical KRT19+ duct cells that overall lack SOX9 expression while they do express canonical basal markers and pertain to a niche of cells expressing gastrointestinal stem cell markers. 3D views show that the basal cells anchor on the basal membrane of normal medium to large ducts while in CP they exist in multilayer dome-like structures. In mice, ΔNp63 is not found in adult pancreas nor in selected models of CP or PDAC, but it is induced in organoids from larger Sox9low ducts. In HPDE, ΔNp63 supports a basal cell phenotype at the expense of a classical duct cell differentiation programme. Conclusion: In larger human pancreatic ducts, basal cells exist. ΔNp63 suppresses duct cell identity. These cells may play an important role in pancreatic disease, including PDAC ontogeny, but are not present in mouse models., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2021
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2. Long-Term GABA Administration Induces Alpha Cell-Mediated Beta-like Cell Neogenesis

Author

Noémie Druelle, Patrick Collombat, Sandra Lacas-Gervais, Andhira Vieira, Tiziana Napolitano, François Pattou, Biljana Hadzic, Decio L. Eizirik, Nouha Ben-Othman, Elisabet Gjernes, Gunter Leuckx, Monica Courtney, Julien Thevenet, Keith Al-Hasani, Anja Pfeifer, Ahmed Mansouri, Sergi Navarro-Sanz, Laura Marroquí, Fabio Avolio, Harry Heimberg, Serena Silvano, Ole D. Madsen, Julie Kerr-Conte, Fabien Record, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre Commun de Microscopie Appliquée (CCMA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Beta Cell Neogenesis Lab, Vrije Universiteit Brussel (VUB), Université libre de Bruxelles (ULB), Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Department of Molecular Cell Biology [Göttingen], Max Planck Institute for Biophysical Chemistry (MPI-BPC), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Pathology/molecular and cellular medicine, Beta Cell Neogenesis, Pathologic Biochemistry and Physiology, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)

Subjects
0301 basic medicine, Male, gamma-Aminobutyric Acid/administration & dosage, [SDV]Life Sciences [q-bio], Cell, Alpha cell, Neogenesis, GABA, Insulin-Secreting Cells/cytology, Insulin-Secreting Cells, Basic Helix-Loop-Helix Transcription Factors, Inducer, gamma-Aminobutyric Acid, geography.geographical_feature_category, diabetes, Cell Differentiation, Islet, 3. Good health, Cell biology, Islets of Langerhans/cytology, medicine.anatomical_structure, Arx, β cell regeneration, endocrine pancreas, medicine.medical_specialty, mice, Nerve Tissue Proteins, Biology, Diabetes Mellitus/chemically induced, General Biochemistry, Genetics and Molecular Biology, Glucagon-Secreting Cells/cytology, RATS, Islets of Langerhans, 03 medical and health sciences, In vivo, Internal medicine, Precursor cell, Diabetes Mellitus, medicine, Animals, Humans, Rats, Wistar, mouse, geography, Pax4, biology.organism_classification, 030104 developmental biology, Endocrinology, Glucagon-Secreting Cells, Cell Differentiation/drug effects, PAX4
Abstract

International audience; The recent discovery that genetically modified α cells can regenerate and convert into β-like cells in vivo holds great promise for diabetes research. However, to eventually translate these findings to human, it is crucial to discover compounds with similar activities. Herein, we report the identification of GABA as an inducer of α-to-β-like cell conversion in vivo. This conversion induces α cell replacement mechanisms through the mobilization of duct-lining precursor cells that adopt an α cell identity prior to being converted into β-like cells, solely upon sustained GABA exposure. Importantly, these neo-generated β-like cells are functional and can repeatedly reverse chemically induced diabetes in vivo. Similarly, the treatment of transplanted human islets with GABA results in a loss of α cells and a concomitant increase in β-like cell counts, suggestive of α-to-β-like cell conversion processes also in humans. This newly discovered GABA-induced α cell-mediated β-like cell neogenesis could therefore represent an unprecedented hope toward improved therapies for diabetes.

Published
2017
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3. STAT3 modulates β-cell cycling in injured mouse pancreas and protects against DNA damage

Author

Luc Baeyens, Willem Staels, S Roels, N. De Leu, Geert A. Martens, Gunter Leuckx, Yves Heremans, Mozhdeh Sojoodi, Ying Cai, Dries Renmans, Harry Heimberg, Gerard Gradwohl, M. Van de Casteele, S. De Groef, Vrije Universiteit Brussel (VUB), Ghent University Hospital, Universiteit Gent = Ghent University [Belgium] (UGENT), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), University of California [San Francisco] (UCSF), University of California, Universitair Ziekenhuis [Brussels, Belgium], Universitair Ziekenhus Brussel (UZ Brussel), Algemeen Stedelijk Ziekenhuis Aalst [Aalst, Belgium] (ASZ), Pathology/molecular and cellular medicine, Beta Cell Neogenesis, Basic (bio-) Medical Sciences, Faculty of Medicine and Pharmacy, Laboratory of Molecullar and Cellular Therapy, Pathologic Biochemistry and Physiology, Diabetes Pathology & Therapy, Cell Differentiation, Clinical sciences, Diabetes Clinic, Universiteit Gent = Ghent University (UGENT), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of California [San Francisco] (UC San Francisco), University of California (UC), Universitair Ziekenhuis Brussel = University Hospital of Brussels (UZ Brussel), and Gradwohl, Gérard

Subjects
0301 basic medicine, Male, Cancer Research, [SDV]Life Sciences [q-bio], UP-REGULATION, DUCT LIGATION, ACTIVATION, STAT3, Insulin-Secreting Cells, Mice, Knockout, Mice, Inbred BALB C, biology, diabetes, PROLIFERATION, FACTOR-ALPHA, Cell cycle, Recombinant Proteins, Cell biology, [SDV] Life Sciences [q-bio], cell death, Knockout mouse, GROWTH, Cytokines, Intercellular Signaling Peptides and Proteins, SIGNAL TRANSDUCER, Original Article, cell cycle, Beta cell, EXPRESSION, STAT3 Transcription Factor, medicine.medical_specialty, DNA damage, Cell Survival, Immunology, 03 medical and health sciences, Cellular and Molecular Neuroscience, Downregulation and upregulation, Internal medicine, medicine, Animals, Ligation, Interleukin-6, Pancreatic Ducts, Biology and Life Sciences, Cell Biology, beta cell, HISTONE H2AX, 030104 developmental biology, Endocrinology, Ki-67 Antigen, Cytoprotection, biology.protein, STAT protein, KNOCKOUT MICE, DNA Damage
Abstract

Partial pancreatic duct ligation (PDL) of mouse pancreas induces a doubling of the β-cell mass mainly through proliferation of pre-existing and newly formed β-cells. The molecular mechanism governing this process is still largely unknown. Given the inflammatory nature of PDL and inflammation-induced signaling via the signal transducer and activator of transcription 3 (STAT3), the activation and the role of STAT3 in PDL-induced β-cell proliferation were investigated. Duct ligation stimulates the expression of several cytokines that can act as ligands inducing STAT3 signaling and phosphorylation in β-cells. β-Cell cycling increased by conditional β-cell-specific Stat3 knockout and decreased by STAT3 activation through administration of interleukin-6. In addition, the level of DNA damage in β-cells of PDL pancreas increased after deletion of Stat3. These data indicate a role for STAT3 in maintaining a steady state in the β-cell, by modulating its cell cycle and protection from DNA damage.

Published
2016
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4. Adult Duct-Lining Cells Can Reprogram into β-like Cells Able to Counter Repeated Cycles of Toxin-Induced Diabetes

Author

Pierre Gounon, Ahmed Mansouri, Anja Pfeifer, Philippe Ravassard, Nouha Ben-Othman, Emmanuel Benizri, Harry Heimberg, Monica Courtney, Damien Ambrosetti, Jorge Ferrer, Fabio Avolio, Noémie Druelle, Andhira Vieira, Elisabet Gjernes, Jacob Hecksher-Sørensen, Gunter Leuckx, Patrick Collombat, Keith Al-Hasani, Sandra Lacas-Gervais, Gerard Gradwohl, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and Beta Cell Neogenesis

Subjects
Blood Glucose, medicine.medical_specialty, endocrine system, Epithelial-Mesenchymal Transition, Nerve Tissue Proteins, Biology, Glucagon, General Biochemistry, Genetics and Molecular Biology, Streptozocin, Diabetes Mellitus, Experimental, 03 medical and health sciences, Mice, 0302 clinical medicine, Cell Movement, Precursor cell, Internal medicine, Insulin-Secreting Cells, medicine, Basic Helix-Loop-Helix Transcription Factors, Animals, Paired Box Transcription Factors, Cell Lineage, Molecular Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology, 030304 developmental biology, Homeodomain Proteins, 0303 health sciences, geography, geography.geographical_feature_category, diabetes, Pancreatic Ducts, Cell Differentiation, Cell Biology, Hypertrophy, Islet, Cellular Reprogramming, Embryonic stem cell, Cell biology, Endocrinology, medicine.anatomical_structure, Gene Expression Regulation, Glucagon-Secreting Cells, PAX4, Ectopic expression, Pancreas, Reprogramming, 030217 neurology & neurosurgery, Developmental Biology
Abstract

International audience; It was recently demonstrated that embryonic glucagon-producing cells in the pancreas can regenerate and convert into insulin-producing β-like cells through the constitutive/ectopic expression of the Pax4 gene. However, whether α cells in adult mice display the same plasticity is unknown. Similarly, the mechanisms underlying such reprogramming remain unclear. We now demonstrate that the misexpression of Pax4 in glucagon(+) cells age-independently induces their conversion into β-like cells and their glucagon shortage-mediated replacement, resulting in islet hypertrophy and in an unexpected islet neogenesis. Combining several lineage-tracing approaches, we show that, upon Pax4-mediated α-to-β-like cell conversion, pancreatic duct-lining precursor cells are continuously mobilized, re-express the developmental gene Ngn3, and successively adopt a glucagon(+) and a β-like cell identity through a mechanism involving the reawakening of the epithelial-to-mesenchymal transition. Importantly, these processes can repeatedly regenerate the whole β cell mass and thereby reverse several rounds of toxin-induced diabetes, providing perspectives to design therapeutic regenerative strategies.

Published
2013
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5. Correction : Clusters of Conserved Beta Cell Marker Genes for Assessment of Beta Cell Phenotype

Author

Geert A. Martens, Lei Jiang, Karine H. Hellemans, Geert Stangé, Harry Heimberg, Finn C. Nielsen, Olivier Sand, Jacques Van Helden, Leentje Van Lommel, Frans Schuit, Frans K. Gorus, Daniel G. Pipeleers, Laboratoire de Bioinformatique des Génomes et des Réseaux (BiGRe), and Université libre de Bruxelles (ULB)

Subjects
Cell type, Science, [SDV]Life Sciences [q-bio], lcsh:Medicine, Biology, 03 medical and health sciences, 0302 clinical medicine, Translation factor, Nuclear protein, lcsh:Science, Beta (finance), Genetics, Multidisciplinary, lcsh:R, Wnt signaling pathway, Correction, Protein phosphatase 1, TGF beta receptor 2, Molecular biology, 030220 oncology & carcinogenesis, Medicine, lcsh:Q, Beta cell, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], 030217 neurology & neurosurgery
Abstract

International audience; There is an error in the second paragraph in the "Limits to the concept of beta cell specificity: many shared traits with other cell types" section in the Discussion. The correct text is: "Among the conserved beta cell marker genes only 15% show a near absolute beta cell-selectivity. This gene cluster contains known beta cell markers (e.g. IAPP, INS1/2, PCSK1, INSM1, HADH), as well as novel ones, such as (i) ST18, a nuclear protein with tumor suppressor activity [22]; (ii) Protein phosphatase 1, regulatory (inhibitor) subunit 1A (PPP1R1A), was previously studied as regulator of muscle activity [30]. Ppp1r1a, also known as Inhibitor1 (I-1) protein was previously found to be abundantly expressed in mouse MIN6 beta cell line and mouse primary islets, where it forms a complex with translation factor eIF-alpha and protein phosphatase-1 [Reference added post-publication, Vander Mierde et al]. Our LC-MS analysis of purified beta and alpha cells, and in situ immunohistochemical analysis now further substantiate its specific and abundant expression in the beta cell lineage, and calls fur further exploration of how its association to protein phosphatase 1 mediates the latter proven action in glucose-regulation of insulin synthesis [Reference added post-publication, Vander Mierde et al]; (iii) FOSB gene products regulate neuronal plasticity [31] but are 20-times more abundant in beta cells than in brain and (iv) WNT4 , which was recently linked to the repressed state of canonical Wnt signaling in beta cells [32]."

Published
2012
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6. Ngn3 expression during postnatal in vitro beta cell neogenesis induced by the JAK/STAT pathway

Author

Luc Baeyens, Stefan Bonné, Philippe Ravassard, Michael S. German, Harry Heimberg, Luc Bouwens, Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Pathology/molecular and cellular medicine, Cell Differentiation, Beta Cell Neogenesis, Pathologic Biochemistry and Physiology, and Medical Biochemistry

Subjects
Male, MESH: Signal Transduction, transdifferentiation, neurogenin3, Neogenesis, MESH: Animals, Newborn, MESH: Janus Kinase 2, MESH: Growth Substances, MESH: Insulin-Secreting Cells, MESH: Lipase, 0302 clinical medicine, Epidermal growth factor, Hepatocyte Nuclear Factor 6, Insulin-Secreting Cells, MESH: Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Transcription Factors, MESH: Up-Regulation, MESH: Animals, MESH: Gene Silencing, MESH: Nerve Tissue Proteins, STAT3, Growth Substances, Cells, Cultured, 0303 health sciences, Gene knockdown, diabetes, Transdifferentiation, JAK-STAT signaling pathway, MESH: STAT3 Transcription Factor, 3. Good health, Cell biology, Up-Regulation, MESH: Models, Animal, Models, Animal, MESH: Hepatocyte Nuclear Factor 6, Beta cell, Signal Transduction, MESH: Cells, Cultured, Niacinamide, STAT3 Transcription Factor, medicine.medical_specialty, endocrine system, MESH: Rats, 030209 endocrinology & metabolism, Nerve Tissue Proteins, Biology, 03 medical and health sciences, MESH: Gene Expression Profiling, Internal medicine, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene Silencing, RNA, Messenger, Rats, Wistar, Molecular Biology, Pancreas, 030304 developmental biology, MESH: RNA, Messenger, MESH: Humans, Gene Expression Profiling, Cell Biology, Lipase, MESH: Rats, Wistar, Janus Kinase 2, biology.organism_classification, beta cell, MESH: Male, Rats, Endocrinology, Animals, Newborn, biology.protein, MESH: Niacinamide
Abstract

The basic helix-loop-helix protein Neurogenin3 specifies precursor cells of the endocrine pancreas during embryonic development, and is thought to be absent postnatally. We have studied Ngn3 expression during in vitro generation of beta-cells from adult rat exocrine pancreas tissue treated with epidermal growth factor and leukaemia inhibitory factor. This treatment induced a transient expression of both Ngn3 and its upstream activator hepatocyte nuclear factor 6. Inhibition of EGF and LIF signalling by pharmacological antagonists of the JAK2/STAT3 pathway, or knockdown of Ngn3 by RNA interference prevented the generation of new insulin-positive cells. This study demonstrates that in vitro growth factor stimulation can induce recapitulation of an embryonic endocrine differentiation pathway in adult dedifferentiated exocrine cells. This could prove to be important for understanding the mechanism of beta-cell regeneration and for therapeutic ex vivo neogenesis of beta cells.

Published
2006
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