Publications
134 results found
Ferrer J, Jörs S, Jeliazkova P, et al., 2015, Lineage fate of ductular reactions in liver injury and carcinogenesis., Journal of Clinical Investigation, Vol: 125, Pages: 2445-2457, ISSN: 1558-8238
Ductular reactions (DRs) are observed in virtually all forms of human liver disease; however, the histogenesis and function of DRs in liver injury are not entirely understood. It is widely believed that DRs contain bipotential liver progenitor cells (LPCs) that serve as an emergency cell pool to regenerate both cholangiocytes and hepatocytes and may eventually give rise to hepatocellular carcinoma (HCC). Here, we used a murine model that allows highly efficient and specific lineage labeling of the biliary compartment to analyze the histogenesis of DRs and their potential contribution to liver regeneration and carcinogenesis. In multiple experimental and genetic liver injury models, biliary cells were the predominant precursors of DRs but lacked substantial capacity to produce new hepatocytes, even when liver injuries were prolonged up to 12 months. Genetic modulation of NOTCH and/or WNT/β-catenin signaling within lineage-tagged DRs impaired DR expansion but failed to redirect DRs from biliary differentiation toward the hepatocyte lineage. Further, lineage-labeled DRs did not produce tumors in genetic and chemical HCC mouse models. In summary, we found no evidence in our system to support mouse biliary-derived DRs as an LPC pool to replenish hepatocytes in a quantitatively relevant way in injury or evidence that DRs give rise to HCCs.
Marquard J, Otter S, Welters A, et al., 2015, Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment, Nature Medicine, Vol: 21, Pages: 363-372, ISSN: 1078-8956
In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and human islets enhanced their glucose-stimulated insulin secretion (GSIS) and survival of islet cells. Further, NMDAR inhibition prolonged the amount of time that glucose-stimulated beta cells spent in a depolarized state with high cytosolic Ca2+ concentrations. We also noticed that, in vivo, the NMDAR antagonist dextromethorphan (DXM) enhanced glucose tolerance in mice, and that in vitro dextrorphan, the main metabolite of DXM, amplified the stimulatory effect of exendin-4 on GSIS. In a mouse model of type 2 diabetes mellitus (T2DM), long-term treatment with DXM improved islet insulin content, islet cell mass and blood glucose control. Further, in a small clinical trial we found that individuals with T2DM treated with DXM showed enhanced serum insulin concentrations and glucose tolerance. Our data highlight the possibility that antagonists of NMDARs may provide a useful adjunct treatment for diabetes.
Kim YH, Larsen HL, Rue P, et al., 2015, Cell Cycle-Dependent Differentiation Dynamics Balances Growth and Endocrine Differentiation in the Pancreas, PLOS Biology, Vol: 13, ISSN: 1545-7885
Organogenesis relies on the spatiotemporal balancing of differentiation and proliferationdriven by an expanding pool of progenitor cells. In the mouse pancreas, lineage tracing atthe population level has shown that the expanding pancreas progenitors can initially giverise to all endocrine, ductal, and acinar cells but become bipotent by embryonic day 13.5,giving rise to endocrine cells and ductal cells. However, the dynamics of individual progenitorsbalancing self-renewal and lineage-specific differentiation has never been described.Using three-dimensional live imaging and in vivo clonal analysis, we reveal the contributionof individual cells to the global behaviour and demonstrate three modes of progenitor divisions:symmetric renewing, symmetric endocrinogenic, and asymmetric generating a progenitorand an endocrine progenitor. Quantitative analysis shows that the endocrinedifferentiation process is consistent with a simple model of cell cycle–dependent stochasticpriming of progenitors to endocrine fate. The findings provide insights to define control parametersto optimize the generation of β-cells in vitro.
Rovira M, Ferrer J, 2015, Weaning gives beta cells license to regenerate, Developmental Cell, Vol: 32, Pages: 531-532, ISSN: 1534-5807
Mitchell RK, Mondragon A, Chen L, et al., 2015, Selective disruption of <i>Tcf7l2</i> in the pancreatic β cell impairs secretory function and lowers β cell mass, HUMAN MOLECULAR GENETICS, Vol: 24, Pages: 1390-1399, ISSN: 0964-6906
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- Citations: 75
Thorens B, Tarussio D, Maestro MA, et al., 2015, <i>Ins1</i> <SUP>Cre</SUP> knock-in mice for beta cell-specific gene recombination, DIABETOLOGIA, Vol: 58, Pages: 558-565, ISSN: 0012-186X
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- Citations: 123
Kone M, Sun G, Ibberson M, et al., 2014, LKB1 and AMPK differentially regulate pancreatic beta-cell identity, Faseb Journal, Vol: 28, Pages: 4972-4985, ISSN: 1530-6860
Fully differentiated pancreatic b cellsare essential for normal glucose homeostasis in mammals.Dedifferentiation of these cells has been suggestedto occur in type 2 diabetes, impairing insulinproduction. Since chronic fuel excess (“glucotoxicity”)is implicated in this process, we sought here to identifythe potential roles in b-cell identity of the tumor suppressorliver kinase B1 (LKB1/STK11) and the downstreamfuel-sensitive kinase, AMP-activated proteinkinase (AMPK). Highly b-cell-restricted deletion ofeach kinase in mice, using an Ins1-controlled Cre, wastherefore followed by physiological, morphometric,and massive parallel sequencing analysis. Loss of LKB1strikingly (2.0–12-fold, E<0.01) increased the expressionof subsets of hepatic (Alb, Iyd, Elovl2) and neuronal(Nptx2, Dlgap2, Cartpt, Pdyn) genes, enhancing glutamatesignaling. These changes were partially recapitulatedby the loss of AMPK, which also up-regulated b-cell“disallowed” genes (Slc16a1, Ldha, Mgst1, Pdgfra) 1.8- to3.4-fold (E<0.01). Correspondingly, targeted promoterswere enriched for neuronal (Zfp206; P51.3310233)and hypoxia-regulated (HIF1; P52.5310216) transcriptionfactors. In summary, LKB1 and AMPK, through onlypartly overlapping mechanisms, maintain b-cell identityby suppressing alternate pathways leading to neuronal,hepatic, and other characteristics. Selective targetingof these enzymes may provide a new approach tomaintaining b-cell function in some forms of diabetes.—Kone,M., Pullen, T. J., Sun, G., Ibberson, M.,Martinez-Sanchez, A., Sayers, S., Nguyen-Tu, M.-S.,Kantor, C., Swisa, A., Dor, Y., Gorman, T., Ferrer, J.,Thorens, B., Reimann, F., Gribble, F., McGinty, J. A.,Chen, L., French, P. M., Birzele, F., Hildebrandt, T.,Uphues, I., Rutter, G. A. LKB1 and AMPK differentiallyregulate pancreatic b-cell identity.
Shaw-Smith C, De Franco E, Allen HL, et al., 2014, GATA4 Mutations Are a Cause of Neonatal and Childhood-Onset Diabetes, Diabetes, Vol: 63, Pages: 2888-2894, ISSN: 0012-1797
The GATA family zinc finger transcription factors GATA4 and GATA6 are known to play important roles in the development of the pancreas. In mice, both Gata4 and Gata6 are required for pancreatic development. In humans, GATA6 haploinsufficiency can cause pancreatic agenesis and heart defects. Congenital heart defects also are common in patients with GATA4 mutations and deletions, but the role of GATA4 in the developing human pancreas is unproven. We report five patients with deletions (n = 4) or mutations of the GATA4 gene who have diabetes and a variable exocrine phenotype. In four cases, diabetes presented in the neonatal period (age at diagnosis 1–7 days). A de novo GATA4 missense mutation (p.N273K) was identified in a patient with complete absence of the pancreas confirmed at postmortem. This mutation affects a highly conserved residue located in the second zinc finger domain of the GATA4 protein. In vitro studies showed reduced DNA binding and transactivational activity of the mutant protein. We show that GATA4 mutations/deletions are a cause of neonatal or childhood-onset diabetes with or without exocrine insufficiency. These results confirm a role for GATA4 in normal development of the human pancreas.
von Figura G, Fukuda A, Roy N, et al., 2014, The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma, Nature Cell Biology, Vol: 16, Pages: 255-267, ISSN: 1476-4679
Pancreatic ductal adenocarcinoma (PDA) develops through distinct precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). However, genetic features resulting in IPMN-associated PDA (IPMN–PDA) versus PanIN-associated PDA (PanIN-PDA) are largely unknown. Here we find that loss of Brg1, a core subunit of SWI/SNF chromatin remodelling complexes, cooperates with oncogenic Kras to form cystic neoplastic lesions that resemble human IPMN and progress to PDA. Although Brg1-null IPMN–PDA develops rapidly, it possesses a distinct transcriptional profile compared with PanIN-PDA driven by mutant Kras and hemizygous p53 deletion. IPMN–PDA also is less lethal, mirroring prognostic trends in PDA patients. In addition, Brg1 deletion inhibits Kras-dependent PanIN development from adult acinar cells, but promotes Kras-driven preneoplastic transformation in adult duct cells. Therefore, this study implicates Brg1 as a determinant of context-dependent Kras-driven pancreatic tumorigenesis and suggests that chromatin remodelling may underlie the development of distinct PDA subsets.
Pasquali L, Gaulton KJ, Rodriguez-Segui SA, et al., 2014, Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants, Nature Genetics, Vol: 46, Pages: 136-+, ISSN: 1546-1718
Type 2 diabetes affects over 300 million people, causing severe complications and premature death, yet the underlying molecular mechanisms are largely unknown. Pancreatic islet dysfunction is central in type 2 diabetes pathogenesis, and understanding islet genome regulation could therefore provide valuable mechanistic insights. We have now mapped and examined the function of human islet cis-regulatory networks. We identify genomic sequences that are targeted by islet transcription factors to drive islet-specific gene activity and show that most such sequences reside in clusters of enhancers that form physical three-dimensional chromatin domains. We find that sequence variants associated with type 2 diabetes and fasting glycemia are enriched in these clustered islet enhancers and identify trait-associated variants that disrupt DNA binding and islet enhancer activity. Our studies illustrate how islet transcription factors interact functionally with the epigenome and provide systematic evidence that the dysregulation of islet enhancers is relevant to the mechanisms underlying type 2 diabetes.
Tattikota SG, Rathjen T, McAnulty SJ, et al., 2014, Argonaute2 mediates compensatory expansion of the pancreatic beta cell, Cell Metabolism, Vol: 19, Pages: 122-134, ISSN: 1932-7420
Pancreatic β cells adapt to compensate for increased metabolic demand during insulin resistance. Although the microRNA pathway has an essential role in β cell proliferation, the extent of its contribution is unclear. Here, we report that miR-184 is silenced in the pancreatic islets of insulin-resistant mouse models and type 2 diabetic human subjects. Reduction of miR-184 promotes the expression of its target Argonaute2 (Ago2), a component of the microRNA-induced silencing complex. Moreover, restoration of miR-184 in leptin-deficient ob/ob mice decreased Ago2 and prevented compensatory β cell expansion. Loss of Ago2 during insulin resistance blocked β cell growth and relieved the regulation of miR-375-targeted genes, including the growth suppressor Cadm1. Lastly, administration of a ketogenic diet to ob/ob mice rescued insulin sensitivity and miR-184 expression and restored Ago2 and β cell mass. This study identifies the targeting of Ago2 by miR-184 as an essential component of the compensatory response to regulate proliferation according to insulin sensitivity.
Weedon MN, Cebola I, Patch AM, et al., 2014, Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis, Nature Genetics, Vol: 46, ISSN: 1061-4036
The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutations in a previously uncharacterized ∼400-bp sequence located 25 kb downstream of PTF1A (encoding pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome sequencing and epigenomic annotation in a disease-relevant cell type can thus uncover new noncoding elements underlying human development and disease.
Baeyens L, Lemper M, Leuckx G, et al., 2014, Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice, NATURE BIOTECHNOLOGY, Vol: 32, Pages: 76-+, ISSN: 1087-0156
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- Citations: 141
Al-Hasani K, Pfeifer A, Courtney M, et al., 2013, Adult Duct-Lining Cells Can Reprogram into β-like Cells Able to Counter Repeated Cycles of Toxin-Induced Diabetes, DEVELOPMENTAL CELL, Vol: 26, Pages: 86-100, ISSN: 1534-5807
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- Citations: 146
Jeliazkova P, Joers S, Lee M, et al., 2013, Canonical Notch2 signaling determines biliary cell fates of embryonic hepatoblasts and adult hepatocytes independent of Hes1, HEPATOLOGY, Vol: 57, Pages: 2469-2479, ISSN: 0270-9139
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- Citations: 71
van de Bunt M, Gaulton KJ, Parts L, et al., 2013, The miRNA Profile of Human Pancreatic Islets and Beta-Cells and Relationship to Type 2 Diabetes Pathogenesis, PLOS ONE, Vol: 8, ISSN: 1932-6203
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- Citations: 122
van Arensbergen J, Garcia-Hurtado J, Angel Maestro M, et al., 2013, Ring1b bookmarks genes in pancreatic embryonic progenitors for repression in adult β cells, GENES & DEVELOPMENT, Vol: 27, Pages: 52-63, ISSN: 0890-9369
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- Citations: 27
Tundidor Rengel D, Torres Grajales JL, Oriola J, et al., 2013, Cinacalcet for management of hypercalcemia secondary to calcium-sensing receptor mutation., Endocrinol Nutr, Vol: 60, Pages: 40-41
Mito JK, Ferrer JM, Brigman BE, et al., 2012, Intraoperative detection and removal of microscopic residual sarcoma using wide-field imaging., Cancer, Vol: 118, Pages: 5320-5330
BACKGROUND: The goal of limb-sparing surgery for a soft tissue sarcoma of the extremity is to remove all malignant cells while preserving limb function. After initial surgery, microscopic residual disease in the tumor bed will cause a local recurrence in approximately 33% of patients with sarcoma. To help identify these patients, the authors developed an in vivo imaging system to investigate the suitability of molecular imaging for intraoperative visualization. METHODS: A primary mouse model of soft tissue sarcoma and a wide field-of-view imaging device were used to investigate a series of exogenously administered, near-infrared (NIR) fluorescent probes activated by cathepsin proteases for real-time intraoperative imaging. RESULTS: The authors demonstrated that exogenously administered cathepsin-activated probes can be used for image-guided surgery to identify microscopic residual NIR fluorescence in the tumor beds of mice. The presence of residual NIR fluorescence was correlated with microscopic residual sarcoma and local recurrence. The removal of residual NIR fluorescence improved local control. CONCLUSIONS: The authors concluded that their technique has the potential to be used for intraoperative image-guided surgery to identify microscopic residual disease in patients with cancer.
Moran I, Akerman I, van de Bunt M, et al., 2012, Human β Cell Transcriptome Analysis Uncovers IncRNAs That Are Tissue-Specific, Dynamically Regulated, and Abnormally Expressed in Type 2 Diabetes, CELL METABOLISM, Vol: 16, Pages: 435-448, ISSN: 1550-4131
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- Citations: 354
Rodriguez-Segui S, Akerman I, Ferrer J, 2012, GATA believe it: new essential regulators of pancreas development, JOURNAL OF CLINICAL INVESTIGATION, Vol: 122, Pages: 3469-3471, ISSN: 0021-9738
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- Citations: 21
Molero X, Cristina Vaquero E, Flandez M, et al., 2012, Gene expression dynamics after murine pancreatitis unveils novel roles for Hnf1α in acinar cell homeostasis, GUT, Vol: 61, Pages: 1187-1196, ISSN: 0017-5749
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- Citations: 33
Swales N, Martens GA, Bonné S, et al., 2012, Plasticity of adult human pancreatic duct cells by neurogenin3-mediated reprogramming., PLOS One, Vol: 7, Pages: e37055-e37055, ISSN: 1932-6203
AIMS/HYPOTHESIS: Duct cells isolated from adult human pancreas can be reprogrammed to express islet beta cell genes by adenoviral transduction of the developmental transcription factor neurogenin3 (Ngn3). In this study we aimed to fully characterize the extent of this reprogramming and intended to improve it. METHODS: The extent of the Ngn3-mediated duct-to-endocrine cell reprogramming was measured employing genome wide mRNA profiling. By modulation of the Delta-Notch signaling or addition of pancreatic endocrine transcription factors Myt1, MafA and Pdx1 we intended to improve the reprogramming. RESULTS: Ngn3 stimulates duct cells to express a focused set of genes that are characteristic for islet endocrine cells and/or neural tissues. This neuro-endocrine shift however, is incomplete with less than 10% of full duct-to-endocrine reprogramming achieved. Transduction of exogenous Ngn3 activates endogenous Ngn3 suggesting auto-activation of this gene. Furthermore, pancreatic endocrine reprogramming of human duct cells can be moderately enhanced by inhibition of Delta-Notch signaling as well as by co-expressing the transcription factor Myt1, but not MafA and Pdx1. CONCLUSIONS/INTERPRETATION: The results provide further insight into the plasticity of adult human duct cells and suggest measurable routes to enhance Ngn3-mediated in vitro reprogramming protocols for regenerative beta cell therapy in diabetes.
Allen HL, Flanagan SE, Shaw-Smith C, et al., 2012, GATA6 haploinsufficiency causes pancreatic agenesis in humans, NATURE GENETICS, Vol: 44, Pages: 20-22, ISSN: 1061-4036
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- Citations: 183
Kirkpatrick CL, Wiederkehr A, Baquie M, et al., 2011, Hepatic Nuclear Factor 1α (HNF1α) Dysfunction Down-regulates X-box-binding Protein 1 (XBP1) and Sensitizes β-Cells to Endoplasmic Reticulum Stress, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 32300-32312
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- Citations: 21
Akerman I, van Arensbergen J, Ferrer J, 2011, Removing the Brakes on Cell Identity, DEVELOPMENTAL CELL, Vol: 20, Pages: 411-412, ISSN: 1534-5807
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- Citations: 5
Ferrer J, 2011, Glucose as a Mitogenic Hormone, CELL METABOLISM, Vol: 13, Pages: 357-358, ISSN: 1550-4131
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- Citations: 5
Hunter CS, Angel Maestro M, Raum JC, et al., 2011, Hnf1α (MODY3) Regulates β-Cell-Enriched MafA Transcription Factor Expression, MOLECULAR ENDOCRINOLOGY, Vol: 25, Pages: 339-347, ISSN: 0888-8809
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- Citations: 13
Nammo T, Rodriguez-Segui SA, Ferrer J, 2011, Mapping Open Chromatin with Formaldehyde-Assisted Isolation of Regulatory Elements, EPIGENETICS PROTOCOLS, SECOND EDITION, Vol: 791, Pages: 287-296, ISSN: 1064-3745
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- Citations: 10
Liechti R, Csardi G, Bergmann S, et al., 2010, EuroDia: a beta-cell gene expression resource, Database : the Journal of Biological Databases and Curation, Vol: 2010, ISSN: 1758-0463
Type 2 diabetes mellitus (T2DM) is a major disease affecting nearly 280 million people worldwide. Whilst the pathophysiological mechanisms leading to disease are poorly understood, dysfunction of the insulin-producing pancreatic beta-cells is key event for disease development. Monitoring the gene expression profiles of pancreatic beta-cells under several genetic or chemical perturbations has shed light on genes and pathways involved in T2DM. The EuroDia database has been established to build a unique collection of gene expression measurements performed on beta-cells of three organisms, namely human, mouse and rat. The Gene Expression Data Analysis Interface (GEDAI) has been developed to support this database. The quality of each dataset is assessed by a series of quality control procedures to detect putative hybridization outliers. The system integrates a web interface to several standard analysis functions from R/Bioconductor to identify differentially expressed genes and pathways. It also allows the combination of multiple experiments performed on different array platforms of the same technology. The design of this system enables each user to rapidly design a custom analysis pipeline and thus produce their own list of genes and pathways. Raw and normalized data can be downloaded for each experiment. The flexible engine of this database (GEDAI) is currently used to handle gene expression data from several laboratory-run projects dealing with different organisms and platforms.
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