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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">M-CSF instructs myeloid lineage fate in single haematopoietic stem cells</title>
<author><name sortKey="Mossadegh Keller, Noushine" sort="Mossadegh Keller, Noushine" uniqKey="Mossadegh Keller N" first="Noushine" last="Mossadegh-Keller">Noushine Mossadegh-Keller</name>
<affiliation><nlm:aff id="A1">Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Institut National de la Santé et de la Recherche Médicale, U1104, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Centre National de la Recherche Scientifique, UMR7280, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sarrazin, Sandrine" sort="Sarrazin, Sandrine" uniqKey="Sarrazin S" first="Sandrine" last="Sarrazin">Sandrine Sarrazin</name>
<affiliation><nlm:aff id="A1">Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Institut National de la Santé et de la Recherche Médicale, U1104, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Centre National de la Recherche Scientifique, UMR7280, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kandalla, Prashanth K" sort="Kandalla, Prashanth K" uniqKey="Kandalla P" first="Prashanth K." last="Kandalla">Prashanth K. Kandalla</name>
<affiliation><nlm:aff id="A1">Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Institut National de la Santé et de la Recherche Médicale, U1104, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Centre National de la Recherche Scientifique, UMR7280, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Espinosa, Leon" sort="Espinosa, Leon" uniqKey="Espinosa L" first="Leon" last="Espinosa">Leon Espinosa</name>
<affiliation><nlm:aff id="A4">Laboratoire de Chimie Bactérienne, Centre National de la Recherche Scientifique, UMR 7283, 31 Chemin Joseph Aiguier, 13009 Marseille, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Stanley, E Richard" sort="Stanley, E Richard" uniqKey="Stanley E" first="E. Richard" last="Stanley">E. Richard Stanley</name>
<affiliation><nlm:aff id="A5">Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nutt, Stephen L" sort="Nutt, Stephen L" uniqKey="Nutt S" first="Stephen L." last="Nutt">Stephen L. Nutt</name>
<affiliation><nlm:aff id="A6">Walter and Eliza Hall Institute, 1G Royal Parade, Parkville, Victoria 3052, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Moore, Jordan" sort="Moore, Jordan" uniqKey="Moore J" first="Jordan" last="Moore">Jordan Moore</name>
<affiliation><nlm:aff id="A7">Fluidigm Corporation, South San Francisco, California 94080, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sieweke, Michael H" sort="Sieweke, Michael H" uniqKey="Sieweke M" first="Michael H." last="Sieweke">Michael H. Sieweke</name>
<affiliation><nlm:aff id="A1">Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Institut National de la Santé et de la Recherche Médicale, U1104, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Centre National de la Recherche Scientifique, UMR7280, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A8">Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Str. 10, 13125 Berlin, Germany</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">23575636</idno>
<idno type="pmc">3679883</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679883</idno>
<idno type="RBID">PMC:3679883</idno>
<idno type="doi">10.1038/nature12026</idno>
<date when="2013">2013</date>
<idno type="wicri:Area/Pmc/Corpus">001D34</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001D34</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">M-CSF instructs myeloid lineage fate in single haematopoietic stem cells</title>
<author><name sortKey="Mossadegh Keller, Noushine" sort="Mossadegh Keller, Noushine" uniqKey="Mossadegh Keller N" first="Noushine" last="Mossadegh-Keller">Noushine Mossadegh-Keller</name>
<affiliation><nlm:aff id="A1">Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Institut National de la Santé et de la Recherche Médicale, U1104, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Centre National de la Recherche Scientifique, UMR7280, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sarrazin, Sandrine" sort="Sarrazin, Sandrine" uniqKey="Sarrazin S" first="Sandrine" last="Sarrazin">Sandrine Sarrazin</name>
<affiliation><nlm:aff id="A1">Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Institut National de la Santé et de la Recherche Médicale, U1104, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Centre National de la Recherche Scientifique, UMR7280, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kandalla, Prashanth K" sort="Kandalla, Prashanth K" uniqKey="Kandalla P" first="Prashanth K." last="Kandalla">Prashanth K. Kandalla</name>
<affiliation><nlm:aff id="A1">Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Institut National de la Santé et de la Recherche Médicale, U1104, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Centre National de la Recherche Scientifique, UMR7280, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Espinosa, Leon" sort="Espinosa, Leon" uniqKey="Espinosa L" first="Leon" last="Espinosa">Leon Espinosa</name>
<affiliation><nlm:aff id="A4">Laboratoire de Chimie Bactérienne, Centre National de la Recherche Scientifique, UMR 7283, 31 Chemin Joseph Aiguier, 13009 Marseille, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Stanley, E Richard" sort="Stanley, E Richard" uniqKey="Stanley E" first="E. Richard" last="Stanley">E. Richard Stanley</name>
<affiliation><nlm:aff id="A5">Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nutt, Stephen L" sort="Nutt, Stephen L" uniqKey="Nutt S" first="Stephen L." last="Nutt">Stephen L. Nutt</name>
<affiliation><nlm:aff id="A6">Walter and Eliza Hall Institute, 1G Royal Parade, Parkville, Victoria 3052, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Moore, Jordan" sort="Moore, Jordan" uniqKey="Moore J" first="Jordan" last="Moore">Jordan Moore</name>
<affiliation><nlm:aff id="A7">Fluidigm Corporation, South San Francisco, California 94080, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sieweke, Michael H" sort="Sieweke, Michael H" uniqKey="Sieweke M" first="Michael H." last="Sieweke">Michael H. Sieweke</name>
<affiliation><nlm:aff id="A1">Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Institut National de la Santé et de la Recherche Médicale, U1104, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Centre National de la Recherche Scientifique, UMR7280, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A8">Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Str. 10, 13125 Berlin, Germany</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Nature</title>
<idno type="ISSN">0028-0836</idno>
<idno type="eISSN">1476-4687</idno>
<imprint><date when="2013">2013</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="P1">Under stress conditions such as infection or inflammation the body rapidly needs to generate new blood cells that are adapted to the challenge. Haematopoietic cytokines are known to increase output of specific mature cells by affecting survival, expansion and differentiation of lineage-committed progenitors<sup><xref rid="R1" ref-type="bibr">1</xref>
,<xref rid="R2" ref-type="bibr">2</xref>
</sup>
, but it has been debated whether long-term haematopoietic stem cells (HSCs) are susceptible to direct lineage-specifying effects of cytokines. Although genetic changes in transcription factor balance can sensitize HSCs to cytokine instruction<sup><xref rid="R3" ref-type="bibr">3</xref>
</sup>
, the initiation of HSC commitment is generally thought to be triggered by stochastic fluctuation in cell-intrinsic regulators such as lineage-specific transcription factors<sup><xref rid="R4" ref-type="bibr">4</xref>
–<xref rid="R7" ref-type="bibr">7</xref>
</sup>
, leaving cytokines to ensure survival and proliferation of the progeny cells<sup><xref rid="R8" ref-type="bibr">8</xref>
,<xref rid="R9" ref-type="bibr">9</xref>
</sup>
. Here we show that macrophage colony-stimulating factor (M-CSF, also called CSF1), a myeloid cytokine released during infection and inflammation, can directly induce the myeloid master regulator PU.1 and instruct myeloid cell-fate change in mouse HSCs, independently of selective survival or proliferation. Video imaging and single-cell gene expression analysis revealed that stimulation of highly purified HSCs with M-CSF in culture resulted in activation of the <italic>PU.1</italic>
promoter and an increased number of PU.1<sup>+</sup>
cells with myeloid gene signature and differentiation potential. <italic>In vivo</italic>
, high systemic levels of M-CSF directly stimulated M-CSF-receptor-dependent activation of endogenous PU.1 protein in single HSCs and induced a PU.1-dependent myeloid differentiation preference. Our data demonstrate that lineage-specific cytokines can act directly on HSCs <italic>in vitro</italic>
and <italic>in vivo</italic>
to instruct a change of cell identity. This fundamentally changes the current view of how HSCs respond to environmental challenge and implicates stress-induced cytokines as direct instructors of HSC fate.</p>
</div>
</front>
</TEI>
<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">0410462</journal-id>
<journal-id journal-id-type="pubmed-jr-id">6011</journal-id>
<journal-id journal-id-type="nlm-ta">Nature</journal-id>
<journal-id journal-id-type="iso-abbrev">Nature</journal-id>
<journal-title-group><journal-title>Nature</journal-title>
</journal-title-group>
<issn pub-type="ppub">0028-0836</issn>
<issn pub-type="epub">1476-4687</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">23575636</article-id>
<article-id pub-id-type="pmc">3679883</article-id>
<article-id pub-id-type="doi">10.1038/nature12026</article-id>
<article-id pub-id-type="manuscript">NIHMS467359</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>M-CSF instructs myeloid lineage fate in single haematopoietic stem cells</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Mossadegh-Keller</surname>
<given-names>Noushine</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
<xref rid="FN2" ref-type="author-notes">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sarrazin</surname>
<given-names>Sandrine</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
<xref rid="FN2" ref-type="author-notes">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kandalla</surname>
<given-names>Prashanth K.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Espinosa</surname>
<given-names>Leon</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Stanley</surname>
<given-names>E. Richard</given-names>
</name>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nutt</surname>
<given-names>Stephen L.</given-names>
</name>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Moore</surname>
<given-names>Jordan</given-names>
</name>
<xref ref-type="aff" rid="A7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sieweke</surname>
<given-names>Michael H.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="aff" rid="A8">8</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</aff>
<aff id="A2"><label>2</label>
Institut National de la Santé et de la Recherche Médicale, U1104, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</aff>
<aff id="A3"><label>3</label>
Centre National de la Recherche Scientifique, UMR7280, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France</aff>
<aff id="A4"><label>4</label>
Laboratoire de Chimie Bactérienne, Centre National de la Recherche Scientifique, UMR 7283, 31 Chemin Joseph Aiguier, 13009 Marseille, France</aff>
<aff id="A5"><label>5</label>
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA</aff>
<aff id="A6"><label>6</label>
Walter and Eliza Hall Institute, 1G Royal Parade, Parkville, Victoria 3052, Australia</aff>
<aff id="A7"><label>7</label>
Fluidigm Corporation, South San Francisco, California 94080, USA</aff>
<aff id="A8"><label>8</label>
Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Str. 10, 13125 Berlin, Germany</aff>
<author-notes><corresp id="FN1">Correspondence and requests for materials should be addressed to M.H.S. (<email>sieweke@ciml.univ-mrs.fr</email>
) or S.S. (<email>sarrazin@ciml.univ-mrs.fr</email>
)</corresp>
<fn id="FN2" fn-type="equal"><label>*</label>
<p>These authors contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>30</day>
<month>4</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>10</day>
<month>4</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="ppub"><day>9</day>
<month>5</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>12</day>
<month>6</month>
<year>2013</year>
</pub-date>
<volume>497</volume>
<issue>7448</issue>
<fpage>239</fpage>
<lpage>243</lpage>
<permissions><copyright-statement>©2013 Macmillan Publishers Limited. All rights reserved</copyright-statement>
<copyright-year>2013</copyright-year>
</permissions>
<abstract><p id="P1">Under stress conditions such as infection or inflammation the body rapidly needs to generate new blood cells that are adapted to the challenge. Haematopoietic cytokines are known to increase output of specific mature cells by affecting survival, expansion and differentiation of lineage-committed progenitors<sup><xref rid="R1" ref-type="bibr">1</xref>
,<xref rid="R2" ref-type="bibr">2</xref>
</sup>
, but it has been debated whether long-term haematopoietic stem cells (HSCs) are susceptible to direct lineage-specifying effects of cytokines. Although genetic changes in transcription factor balance can sensitize HSCs to cytokine instruction<sup><xref rid="R3" ref-type="bibr">3</xref>
</sup>
, the initiation of HSC commitment is generally thought to be triggered by stochastic fluctuation in cell-intrinsic regulators such as lineage-specific transcription factors<sup><xref rid="R4" ref-type="bibr">4</xref>
–<xref rid="R7" ref-type="bibr">7</xref>
</sup>
, leaving cytokines to ensure survival and proliferation of the progeny cells<sup><xref rid="R8" ref-type="bibr">8</xref>
,<xref rid="R9" ref-type="bibr">9</xref>
</sup>
. Here we show that macrophage colony-stimulating factor (M-CSF, also called CSF1), a myeloid cytokine released during infection and inflammation, can directly induce the myeloid master regulator PU.1 and instruct myeloid cell-fate change in mouse HSCs, independently of selective survival or proliferation. Video imaging and single-cell gene expression analysis revealed that stimulation of highly purified HSCs with M-CSF in culture resulted in activation of the <italic>PU.1</italic>
promoter and an increased number of PU.1<sup>+</sup>
cells with myeloid gene signature and differentiation potential. <italic>In vivo</italic>
, high systemic levels of M-CSF directly stimulated M-CSF-receptor-dependent activation of endogenous PU.1 protein in single HSCs and induced a PU.1-dependent myeloid differentiation preference. Our data demonstrate that lineage-specific cytokines can act directly on HSCs <italic>in vitro</italic>
and <italic>in vivo</italic>
to instruct a change of cell identity. This fundamentally changes the current view of how HSCs respond to environmental challenge and implicates stress-induced cytokines as direct instructors of HSC fate.</p>
</abstract>
<funding-group><award-group><funding-source country="United States">National Cancer Institute : NCI</funding-source>
<award-id>R01 CA032551 || CA</award-id>
</award-group>
</funding-group>
</article-meta>
</front>
</pmc>
</record>
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