Lymphatic endothelial progenitors originate from plastic myeloid cells activated by toll-like receptor-4
Identifieur interne : 009175 ( Ncbi/Merge ); précédent : 009174; suivant : 009176Lymphatic endothelial progenitors originate from plastic myeloid cells activated by toll-like receptor-4
Auteurs : Lisa D. Volk-Draper [États-Unis] ; Kelly L. Hall [États-Unis] ; Andrew C. Wilber [États-Unis] ; Sophia Ran [États-Unis]Source :
- PLoS ONE [ 1932-6203 ] ; 2017.
Abstract
Myeloid-derived lymphatic endothelial cells (M-LECP) are induced by inflammation and play an important role in adult lymphangiogenesis. However, the mechanisms driving M-LECP differentiation are currently unclear. We previously showed that activation of Toll-like receptor-4 (TLR4) induces myeloid-lymphatic transition (MLT) of immortalized mouse myeloid cells. Here the goals were to assess the potential of different TLR4 ligands to induce pro-lymphatic reprogramming in human and mouse primary myeloid cells and to identify transcriptional changes regulating this process.
Human and mouse myeloid cells were reprogrammed to the lymphatic phenotype by TLR4 ligands including lipopolysaccharide (LPS), recombinant high mobility group box 1 protein (HMGB1), and paclitaxel. TLR4 induced similar MLT in cells from mice of different strains and immune status. Commonly induced genes were detected by transcriptional profiling in human and mouse myeloid cells from either immunocompetent or immunodeficient mice. Shared trends included: (1) novel expression of lymphatic-specific markers vascular endothelial growth factor receptor-3 (VEGFR-3), lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and podoplanin (PDPN) largely absent prior to induction; (2) lack of notable changes in blood vessel-specific markers; (3) transient expression of VEGFR-3, but sustained increase of vascular endothelial growth factor-C (VEGF-C) and a variety of inflammatory cytokines; (4) dependency of VEGFR-3 upregulation and other LEC genes on NF-κB; and (5) novel expression of lymphatic-specific (e.g., PROX1) and stem/progenitor (e.g., E2F1) transcription factors known for their roles in adult and embryonic vascular formation. M-LECP generated by TLR4 ligands
We established a novel TLR4-dependent protocol for
Url:
DOI: 10.1371/journal.pone.0179257
PubMed: 28598999
PubMed Central: 5466303
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Hall</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL</wicri:regionArea><wicri:noRegion>IL</wicri:noRegion></affiliation></author><author><name sortKey="Wilber, Andrew C" sort="Wilber, Andrew C" uniqKey="Wilber A" first="Andrew C." last="Wilber">Andrew C. Wilber</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL</wicri:regionArea><wicri:noRegion>IL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL</wicri:regionArea><wicri:noRegion>IL</wicri:noRegion></affiliation></author><author><name sortKey="Ran, Sophia" sort="Ran, Sophia" uniqKey="Ran S" first="Sophia" last="Ran">Sophia Ran</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL</wicri:regionArea><wicri:noRegion>IL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL</wicri:regionArea><wicri:noRegion>IL</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28598999</idno><idno type="pmc">5466303</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466303</idno><idno type="RBID">PMC:5466303</idno><idno type="doi">10.1371/journal.pone.0179257</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">004424</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">004424</idno><idno type="wicri:Area/Pmc/Curation">004423</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">004423</idno><idno type="wicri:Area/Pmc/Checkpoint">000213</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000213</idno><idno type="wicri:Area/Ncbi/Merge">009175</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Lymphatic endothelial progenitors originate from plastic myeloid cells activated by toll-like receptor-4</title><author><name sortKey="Volk Draper, Lisa D" sort="Volk Draper, Lisa D" uniqKey="Volk Draper L" first="Lisa D." last="Volk-Draper">Lisa D. Volk-Draper</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL</wicri:regionArea><wicri:noRegion>IL</wicri:noRegion></affiliation></author><author><name sortKey="Hall, Kelly L" sort="Hall, Kelly L" uniqKey="Hall K" first="Kelly L." last="Hall">Kelly L. Hall</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL</wicri:regionArea><wicri:noRegion>IL</wicri:noRegion></affiliation></author><author><name sortKey="Wilber, Andrew C" sort="Wilber, Andrew C" uniqKey="Wilber A" first="Andrew C." last="Wilber">Andrew C. Wilber</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL</wicri:regionArea><wicri:noRegion>IL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL</wicri:regionArea><wicri:noRegion>IL</wicri:noRegion></affiliation></author><author><name sortKey="Ran, Sophia" sort="Ran, Sophia" uniqKey="Ran S" first="Sophia" last="Ran">Sophia Ran</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL</wicri:regionArea><wicri:noRegion>IL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL</wicri:regionArea><wicri:noRegion>IL</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="sec001"><title>Background</title><p>Myeloid-derived lymphatic endothelial cells (M-LECP) are induced by inflammation and play an important role in adult lymphangiogenesis. However, the mechanisms driving M-LECP differentiation are currently unclear. We previously showed that activation of Toll-like receptor-4 (TLR4) induces myeloid-lymphatic transition (MLT) of immortalized mouse myeloid cells. Here the goals were to assess the potential of different TLR4 ligands to induce pro-lymphatic reprogramming in human and mouse primary myeloid cells and to identify transcriptional changes regulating this process.</p></sec><sec id="sec002"><title>Methodology/Principal findings</title><p>Human and mouse myeloid cells were reprogrammed to the lymphatic phenotype by TLR4 ligands including lipopolysaccharide (LPS), recombinant high mobility group box 1 protein (HMGB1), and paclitaxel. TLR4 induced similar MLT in cells from mice of different strains and immune status. Commonly induced genes were detected by transcriptional profiling in human and mouse myeloid cells from either immunocompetent or immunodeficient mice. Shared trends included: (1) novel expression of lymphatic-specific markers vascular endothelial growth factor receptor-3 (VEGFR-3), lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and podoplanin (PDPN) largely absent prior to induction; (2) lack of notable changes in blood vessel-specific markers; (3) transient expression of VEGFR-3, but sustained increase of vascular endothelial growth factor-C (VEGF-C) and a variety of inflammatory cytokines; (4) dependency of VEGFR-3 upregulation and other LEC genes on NF-κB; and (5) novel expression of lymphatic-specific (e.g., PROX1) and stem/progenitor (e.g., E2F1) transcription factors known for their roles in adult and embryonic vascular formation. M-LECP generated by TLR4 ligands <italic>in vitro</italic> were functional <italic>in vivo</italic> as demonstrated by significantly increased lymphatic vessel density and lymphatic metastasis detected in orthotopic breast cancer models.</p></sec><sec id="sec003"><title>Conclusions/Significance</title><p>We established a novel TLR4-dependent protocol for <italic>in vitro</italic> production of functionally competent M-LECP from primary human or mouse myeloid cells and identified many potential regulators of this process. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28598999</article-id><article-id pub-id-type="pmc">5466303</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0179257</article-id><article-id pub-id-type="publisher-id">PONE-D-16-34645</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cellular Types</subject><subj-group><subject>Animal Cells</subject><subj-group><subject>Bone Marrow Cells</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject><subj-group><subject>Experimental Organism Systems</subject><subj-group><subject>Model Organisms</subject><subj-group><subject>Mouse Models</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject><subj-group><subject>Model Organisms</subject><subj-group><subject>Mouse Models</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject><subj-group><subject>Experimental Organism Systems</subject><subj-group><subject>Animal Models</subject><subj-group><subject>Mouse Models</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cellular Types</subject><subj-group><subject>Animal Cells</subject><subj-group><subject>Blood Cells</subject><subj-group><subject>White Blood Cells</subject><subj-group><subject>Monocytes</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cellular Types</subject><subj-group><subject>Animal Cells</subject><subj-group><subject>Immune Cells</subject><subj-group><subject>White Blood Cells</subject><subj-group><subject>Monocytes</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune Cells</subject><subj-group><subject>White Blood Cells</subject><subj-group><subject>Monocytes</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune Cells</subject><subj-group><subject>White Blood Cells</subject><subj-group><subject>Monocytes</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune Response</subject><subj-group><subject>Inflammation</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune Response</subject><subj-group><subject>Inflammation</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Diagnostic Medicine</subject><subj-group><subject>Signs and Symptoms</subject><subj-group><subject>Inflammation</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pathology and Laboratory Medicine</subject><subj-group><subject>Signs and Symptoms</subject><subj-group><subject>Inflammation</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Developmental Biology</subject><subj-group><subject>Cell Differentiation</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune System Proteins</subject><subj-group><subject>Immune Receptors</subject><subj-group><subject>Toll-like Receptors</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune System Proteins</subject><subj-group><subject>Immune Receptors</subject><subj-group><subject>Toll-like Receptors</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Proteins</subject><subj-group><subject>Immune System Proteins</subject><subj-group><subject>Immune Receptors</subject><subj-group><subject>Toll-like Receptors</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Signal Transduction</subject><subj-group><subject>Immune Receptors</subject><subj-group><subject>Toll-like Receptors</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Oncology</subject><subj-group><subject>Cancers and Neoplasms</subject><subj-group><subject>Breast Tumors</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Physiology</subject><subj-group><subject>Immune Physiology</subject><subj-group><subject>Cytokines</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Physiology</subject><subj-group><subject>Immune Physiology</subject><subj-group><subject>Cytokines</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune System</subject><subj-group><subject>Innate Immune System</subject><subj-group><subject>Cytokines</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune System</subject><subj-group><subject>Innate Immune System</subject><subj-group><subject>Cytokines</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Developmental Biology</subject><subj-group><subject>Molecular Development</subject><subj-group><subject>Cytokines</subject></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Lymphatic endothelial progenitors originate from plastic myeloid cells activated by toll-like receptor-4</article-title><alt-title alt-title-type="running-head">TLR4 driven myeloid-lymphatic transition</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Volk-Draper</surname><given-names>Lisa D.</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Hall</surname><given-names>Kelly L.</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wilber</surname><given-names>Andrew C.</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-3958-6099</contrib-id><name><surname>Ran</surname><given-names>Sophia</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL, United States of America</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Bonecchi</surname><given-names>Raffaella</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Universita degli Studi di Milano, ITALY</addr-line></aff><author-notes><fn fn-type="COI-statement" id="coi001"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con"><p><list list-type="simple"><list-item><p><bold>Conceptualization:</bold> SR LVD KLH.</p></list-item><list-item><p><bold>Formal analysis:</bold> SR LDV KLH ACW.</p></list-item><list-item><p><bold>Funding acquisition:</bold> SR.</p></list-item><list-item><p><bold>Investigation:</bold> LDV KLH.</p></list-item><list-item><p><bold>Methodology:</bold> LDV KLH ACW.</p></list-item><list-item><p><bold>Project administration:</bold> SR.</p></list-item><list-item><p><bold>Resources:</bold> SR.</p></list-item><list-item><p><bold>Supervision:</bold> SR.</p></list-item><list-item><p><bold>Validation:</bold> LDV KLH.</p></list-item><list-item><p><bold>Visualization:</bold> SR LDV KLH.</p></list-item><list-item><p><bold>Writing – original draft:</bold> SR ACW.</p></list-item><list-item><p><bold>Writing – review & editing:</bold> SR ACW.</p></list-item></list></p></fn><corresp id="cor001">* E-mail: <email>sran@siumed.edu</email></corresp></author-notes><pub-date pub-type="epub"><day>9</day><month>6</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>12</volume><issue>6</issue><elocation-id>e0179257</elocation-id><history><date date-type="received"><day>29</day><month>8</month><year>2016</year></date><date date-type="accepted"><day>28</day><month>5</month><year>2017</year></date></history><permissions><copyright-statement>© 2017 Volk-Draper et al</copyright-statement><copyright-year>2017</copyright-year><copyright-holder>Volk-Draper et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="pone.0179257.pdf"></self-uri><abstract><sec id="sec001"><title>Background</title><p>Myeloid-derived lymphatic endothelial cells (M-LECP) are induced by inflammation and play an important role in adult lymphangiogenesis. However, the mechanisms driving M-LECP differentiation are currently unclear. We previously showed that activation of Toll-like receptor-4 (TLR4) induces myeloid-lymphatic transition (MLT) of immortalized mouse myeloid cells. Here the goals were to assess the potential of different TLR4 ligands to induce pro-lymphatic reprogramming in human and mouse primary myeloid cells and to identify transcriptional changes regulating this process.</p></sec><sec id="sec002"><title>Methodology/Principal findings</title><p>Human and mouse myeloid cells were reprogrammed to the lymphatic phenotype by TLR4 ligands including lipopolysaccharide (LPS), recombinant high mobility group box 1 protein (HMGB1), and paclitaxel. TLR4 induced similar MLT in cells from mice of different strains and immune status. Commonly induced genes were detected by transcriptional profiling in human and mouse myeloid cells from either immunocompetent or immunodeficient mice. Shared trends included: (1) novel expression of lymphatic-specific markers vascular endothelial growth factor receptor-3 (VEGFR-3), lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and podoplanin (PDPN) largely absent prior to induction; (2) lack of notable changes in blood vessel-specific markers; (3) transient expression of VEGFR-3, but sustained increase of vascular endothelial growth factor-C (VEGF-C) and a variety of inflammatory cytokines; (4) dependency of VEGFR-3 upregulation and other LEC genes on NF-κB; and (5) novel expression of lymphatic-specific (e.g., PROX1) and stem/progenitor (e.g., E2F1) transcription factors known for their roles in adult and embryonic vascular formation. M-LECP generated by TLR4 ligands <italic>in vitro</italic> were functional <italic>in vivo</italic> as demonstrated by significantly increased lymphatic vessel density and lymphatic metastasis detected in orthotopic breast cancer models.</p></sec><sec id="sec003"><title>Conclusions/Significance</title><p>We established a novel TLR4-dependent protocol for <italic>in vitro</italic> production of functionally competent M-LECP from primary human or mouse myeloid cells and identified many potential regulators of this process. This information can be further exploited for research and therapeutic purposes.</p></sec></abstract><funding-group><award-group id="award001"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000054</institution-id><institution>National Cancer Institute</institution></institution-wrap></funding-source><award-id>R01CA140732</award-id><principal-award-recipient><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-3958-6099</contrib-id><name><surname>Ran</surname><given-names>Sophia</given-names></name></principal-award-recipient></award-group><award-group id="award002"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000054</institution-id><institution>National Cancer Institute</institution></institution-wrap></funding-source><award-id>R01CA199649-01A1</award-id><principal-award-recipient><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-3958-6099</contrib-id><name><surname>Ran</surname><given-names>Sophia</given-names></name></principal-award-recipient></award-group><award-group id="award003"><funding-source><institution>Illinois William E. McElroy Charitable Foundation</institution></funding-source><principal-award-recipient><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-3958-6099</contrib-id><name><surname>Ran</surname><given-names>Sophia</given-names></name></principal-award-recipient></award-group><award-group id="award004"><funding-source><institution>Simmons Cancer Institute at Southern Illinois University School of Medicine</institution></funding-source><principal-award-recipient><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-3958-6099</contrib-id><name><surname>Ran</surname><given-names>Sophia</given-names></name></principal-award-recipient></award-group><funding-statement>This work was supported by grants numbers 5R01CA140732, 1R01CA199649-01A1 from National Institute of Health and by awards from the Illinois William E. McElroy Charitable Foundation and the Simmons Cancer Institute at Southern Illinois University School of Medicine, Illinois, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><fig-count count="11"></fig-count><table-count count="1"></table-count><page-count count="29"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>All relevant data are within the paper and its Supporting Information files. Additionally, all data from qPCR analyses reported in this manuscript are deposited in the Gene Expression Omnibus (GEO) in The National Center for Biotechnology Information (NCBI) library. The relevant datasets are identified by numbers GSE75518 and GSE78162.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>All relevant data are within the paper and its Supporting Information files. Additionally, all data from qPCR analyses reported in this manuscript are deposited in the Gene Expression Omnibus (GEO) in The National Center for Biotechnology Information (NCBI) library. The relevant datasets are identified by numbers GSE75518 and GSE78162.</p></notes></front></pmc><affiliations><list><country><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Volk Draper, Lisa D" sort="Volk Draper, Lisa D" uniqKey="Volk Draper L" first="Lisa D." last="Volk-Draper">Lisa D. Volk-Draper</name></noRegion><name sortKey="Hall, Kelly L" sort="Hall, Kelly L" uniqKey="Hall K" first="Kelly L." last="Hall">Kelly L. Hall</name><name sortKey="Ran, Sophia" sort="Ran, Sophia" uniqKey="Ran S" first="Sophia" last="Ran">Sophia Ran</name><name sortKey="Ran, Sophia" sort="Ran, Sophia" uniqKey="Ran S" first="Sophia" last="Ran">Sophia Ran</name><name sortKey="Wilber, Andrew C" sort="Wilber, Andrew C" uniqKey="Wilber A" first="Andrew C." last="Wilber">Andrew C. Wilber</name><name sortKey="Wilber, Andrew C" sort="Wilber, Andrew C" uniqKey="Wilber A" first="Andrew C." last="Wilber">Andrew C. Wilber</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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