Metabolic regulation of cellular plasticity in the pancreas
Identifieur interne : 002075 ( Pmc/Corpus ); précédent : 002074; suivant : 002076Metabolic regulation of cellular plasticity in the pancreas
Auteurs : Nikolay Ninov ; Daniel Hesselson ; Philipp Gut ; Amy Zhou ; Kevin Fidelin ; Didier Y. R. StainierSource :
- Current biology : CB [ 0960-9822 ] ; 2013.
Abstract
Obese individuals exhibit an increase in pancreatic β-cell mass; conversely, scarce nutrition during pregnancy has been linked to β-cell insufficiency in the offspring (reviewed in [
Url:
DOI: 10.1016/j.cub.2013.05.037
PubMed: 23791726
PubMed Central: 4206552
Links to Exploration step
PMC:4206552Le document en format XML
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<author><name sortKey="Ninov, Nikolay" sort="Ninov, Nikolay" uniqKey="Ninov N" first="Nikolay" last="Ninov">Nikolay Ninov</name>
<affiliation><nlm:aff id="A1">Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, the Diabetes Center, Institute for Regeneration Medicine and Liver Center, University of California, San Francisco, 1550 4th Street, San Francisco, CA 94158, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hesselson, Daniel" sort="Hesselson, Daniel" uniqKey="Hesselson D" first="Daniel" last="Hesselson">Daniel Hesselson</name>
<affiliation><nlm:aff id="A1">Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, the Diabetes Center, Institute for Regeneration Medicine and Liver Center, University of California, San Francisco, 1550 4th Street, San Francisco, CA 94158, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, NSW, Australia</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A4">St. Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia</nlm:aff>
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<author><name sortKey="Gut, Philipp" sort="Gut, Philipp" uniqKey="Gut P" first="Philipp" last="Gut">Philipp Gut</name>
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<author><name sortKey="Zhou, Amy" sort="Zhou, Amy" uniqKey="Zhou A" first="Amy" last="Zhou">Amy Zhou</name>
<affiliation><nlm:aff id="A1">Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, the Diabetes Center, Institute for Regeneration Medicine and Liver Center, University of California, San Francisco, 1550 4th Street, San Francisco, CA 94158, USA</nlm:aff>
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<author><name sortKey="Fidelin, Kevin" sort="Fidelin, Kevin" uniqKey="Fidelin K" first="Kevin" last="Fidelin">Kevin Fidelin</name>
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</affiliation>
<affiliation><nlm:aff id="A5">Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Université Pierre et Marie Curie UMP-S975, Paris, France</nlm:aff>
</affiliation>
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<author><name sortKey="Stainier, Didier Y R" sort="Stainier, Didier Y R" uniqKey="Stainier D" first="Didier Y. R." last="Stainier">Didier Y. R. Stainier</name>
<affiliation><nlm:aff id="A1">Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, the Diabetes Center, Institute for Regeneration Medicine and Liver Center, University of California, San Francisco, 1550 4th Street, San Francisco, CA 94158, USA</nlm:aff>
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<affiliation><nlm:aff id="A2">Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany</nlm:aff>
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<author><name sortKey="Ninov, Nikolay" sort="Ninov, Nikolay" uniqKey="Ninov N" first="Nikolay" last="Ninov">Nikolay Ninov</name>
<affiliation><nlm:aff id="A1">Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, the Diabetes Center, Institute for Regeneration Medicine and Liver Center, University of California, San Francisco, 1550 4th Street, San Francisco, CA 94158, USA</nlm:aff>
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<affiliation><nlm:aff id="A2">Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany</nlm:aff>
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<author><name sortKey="Hesselson, Daniel" sort="Hesselson, Daniel" uniqKey="Hesselson D" first="Daniel" last="Hesselson">Daniel Hesselson</name>
<affiliation><nlm:aff id="A1">Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, the Diabetes Center, Institute for Regeneration Medicine and Liver Center, University of California, San Francisco, 1550 4th Street, San Francisco, CA 94158, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, NSW, Australia</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A4">St. Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia</nlm:aff>
</affiliation>
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<author><name sortKey="Gut, Philipp" sort="Gut, Philipp" uniqKey="Gut P" first="Philipp" last="Gut">Philipp Gut</name>
<affiliation><nlm:aff id="A1">Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, the Diabetes Center, Institute for Regeneration Medicine and Liver Center, University of California, San Francisco, 1550 4th Street, San Francisco, CA 94158, USA</nlm:aff>
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<author><name sortKey="Zhou, Amy" sort="Zhou, Amy" uniqKey="Zhou A" first="Amy" last="Zhou">Amy Zhou</name>
<affiliation><nlm:aff id="A1">Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, the Diabetes Center, Institute for Regeneration Medicine and Liver Center, University of California, San Francisco, 1550 4th Street, San Francisco, CA 94158, USA</nlm:aff>
</affiliation>
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<author><name sortKey="Fidelin, Kevin" sort="Fidelin, Kevin" uniqKey="Fidelin K" first="Kevin" last="Fidelin">Kevin Fidelin</name>
<affiliation><nlm:aff id="A1">Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, the Diabetes Center, Institute for Regeneration Medicine and Liver Center, University of California, San Francisco, 1550 4th Street, San Francisco, CA 94158, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A5">Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Université Pierre et Marie Curie UMP-S975, Paris, France</nlm:aff>
</affiliation>
</author>
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</affiliation>
<affiliation><nlm:aff id="A2">Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany</nlm:aff>
</affiliation>
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<front><div type="abstract" xml:lang="en"><title>SUMMARY</title>
<p id="P1">Obese individuals exhibit an increase in pancreatic β-cell mass; conversely, scarce nutrition during pregnancy has been linked to β-cell insufficiency in the offspring (reviewed in [<xref rid="R1" ref-type="bibr">1</xref>
, <xref rid="R2" ref-type="bibr">2</xref>
]). These phenomena are thought to be mediated mainly through effects on β-cell proliferation, since a nutrient sensitive β-cell progenitor population in the pancreas has not been identified. Here, we employed the FUCCI (Fluorescent Ubiquitination-based Cell Cycle Indicator) system to investigate β-cell replication in real-time, and found that high nutrient concentrations induce rapid β-cell proliferation. Importantly, we found that high nutrient concentrations also stimulate β-cell differentiation from progenitors in the intrapancreatic duct (IPD). Using a new zebrafish line where β-cells are constitutively ablated, we further show that β-cell loss and high nutrient intake synergistically activate these progenitors. At the cellular level, this activation process causes ductal cell reorganization as it stimulates their proliferation and differentiation. Notably, we link the nutrient-dependent activation of these progenitors to a down-regulation of Notch signaling specifically within the IPD. Furthermore, we show that the nutrient sensor mechanistic Target Of Rapamycin (mTOR) is required for endocrine differentiation from the IPD under physiological conditions as well as in the diabetic state. This study thus reveals critical insights into how cells modulate their plasticity in response to metabolic cues and identifies nutrient sensitive progenitors in the mature pancreas.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9107782</journal-id>
<journal-id journal-id-type="pubmed-jr-id">8548</journal-id>
<journal-id journal-id-type="nlm-ta">Curr Biol</journal-id>
<journal-id journal-id-type="iso-abbrev">Curr. Biol.</journal-id>
<journal-title-group><journal-title>Current biology : CB</journal-title>
</journal-title-group>
<issn pub-type="ppub">0960-9822</issn>
<issn pub-type="epub">1879-0445</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">23791726</article-id>
<article-id pub-id-type="pmc">4206552</article-id>
<article-id pub-id-type="doi">10.1016/j.cub.2013.05.037</article-id>
<article-id pub-id-type="manuscript">NIHMS485509</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Metabolic regulation of cellular plasticity in the pancreas</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Ninov</surname>
<given-names>Nikolay</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref rid="FN1" ref-type="author-notes">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hesselson</surname>
<given-names>Daniel</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gut</surname>
<given-names>Philipp</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhou</surname>
<given-names>Amy</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fidelin</surname>
<given-names>Kevin</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Stainier</surname>
<given-names>Didier Y.R.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref rid="FN1" ref-type="author-notes">*</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, the Diabetes Center, Institute for Regeneration Medicine and Liver Center, University of California, San Francisco, 1550 4th Street, San Francisco, CA 94158, USA</aff>
<aff id="A2"><label>2</label>
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany</aff>
<aff id="A3"><label>3</label>
Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, NSW, Australia</aff>
<aff id="A4"><label>4</label>
St. Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia</aff>
<aff id="A5"><label>5</label>
Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Université Pierre et Marie Curie UMP-S975, Paris, France</aff>
<author-notes><corresp id="FN1"><label>*</label>
To whom correspondence should be addressed: (<email>nikolay.ninov@mpi-bn.mpg.de</email>
, <email>didier.stainier@mpi-bn.mpg.de</email>
)</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>1</day>
<month>7</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>20</day>
<month>6</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="ppub"><day>8</day>
<month>7</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>22</day>
<month>10</month>
<year>2014</year>
</pub-date>
<volume>23</volume>
<issue>13</issue>
<fpage>1242</fpage>
<lpage>1250</lpage>
<pmc-comment>elocation-id from pubmed: 10.1016/j.cub.2013.05.037</pmc-comment>
<permissions><copyright-statement>© 2013 Elsevier Inc. All rights reserved.</copyright-statement>
<copyright-year>2013</copyright-year>
</permissions>
<abstract><title>SUMMARY</title>
<p id="P1">Obese individuals exhibit an increase in pancreatic β-cell mass; conversely, scarce nutrition during pregnancy has been linked to β-cell insufficiency in the offspring (reviewed in [<xref rid="R1" ref-type="bibr">1</xref>
, <xref rid="R2" ref-type="bibr">2</xref>
]). These phenomena are thought to be mediated mainly through effects on β-cell proliferation, since a nutrient sensitive β-cell progenitor population in the pancreas has not been identified. Here, we employed the FUCCI (Fluorescent Ubiquitination-based Cell Cycle Indicator) system to investigate β-cell replication in real-time, and found that high nutrient concentrations induce rapid β-cell proliferation. Importantly, we found that high nutrient concentrations also stimulate β-cell differentiation from progenitors in the intrapancreatic duct (IPD). Using a new zebrafish line where β-cells are constitutively ablated, we further show that β-cell loss and high nutrient intake synergistically activate these progenitors. At the cellular level, this activation process causes ductal cell reorganization as it stimulates their proliferation and differentiation. Notably, we link the nutrient-dependent activation of these progenitors to a down-regulation of Notch signaling specifically within the IPD. Furthermore, we show that the nutrient sensor mechanistic Target Of Rapamycin (mTOR) is required for endocrine differentiation from the IPD under physiological conditions as well as in the diabetic state. This study thus reveals critical insights into how cells modulate their plasticity in response to metabolic cues and identifies nutrient sensitive progenitors in the mature pancreas.</p>
</abstract>
</article-meta>
</front>
</pmc>
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