Human Dermal Fibroblasts Derived from Oculodentodigital Dysplasia Patients Suggest that Patients may have Wound Healing Defects
Identifieur interne : 002A32 ( Pmc/Corpus ); précédent : 002A31; suivant : 002A33Human Dermal Fibroblasts Derived from Oculodentodigital Dysplasia Patients Suggest that Patients may have Wound Healing Defects
Auteurs : Jared M. Churko ; Qing Shao ; Xiangqun Gong ; Kathryn J. Swoboda ; Donglin Bai ; Jacinda Sampson ; Dale W. LairdSource :
- Human mutation [ 1059-7794 ] ; 2011.
Abstract
Oculodentodigital dysplasia (ODDD) is primarily an autosomal dominant human disease caused by any one of over 60 mutations in the
Url:
DOI: 10.1002/humu.21472
PubMed: 21305658
PubMed Central: 3180923
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<author><name sortKey="Churko, Jared M" sort="Churko, Jared M" uniqKey="Churko J" first="Jared M." last="Churko">Jared M. Churko</name>
<affiliation><nlm:aff id="A1">Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada</nlm:aff>
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<author><name sortKey="Shao, Qing" sort="Shao, Qing" uniqKey="Shao Q" first="Qing" last="Shao">Qing Shao</name>
<affiliation><nlm:aff id="A1">Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada</nlm:aff>
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<author><name sortKey="Gong, Xiangqun" sort="Gong, Xiangqun" uniqKey="Gong X" first="Xiangqun" last="Gong">Xiangqun Gong</name>
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<author><name sortKey="Swoboda, Kathryn J" sort="Swoboda, Kathryn J" uniqKey="Swoboda K" first="Kathryn J." last="Swoboda">Kathryn J. Swoboda</name>
<affiliation><nlm:aff id="A3">Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA</nlm:aff>
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<author><name sortKey="Bai, Donglin" sort="Bai, Donglin" uniqKey="Bai D" first="Donglin" last="Bai">Donglin Bai</name>
<affiliation><nlm:aff id="A2">Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada</nlm:aff>
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<author><name sortKey="Sampson, Jacinda" sort="Sampson, Jacinda" uniqKey="Sampson J" first="Jacinda" last="Sampson">Jacinda Sampson</name>
<affiliation><nlm:aff id="A3">Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA</nlm:aff>
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<author><name sortKey="Laird, Dale W" sort="Laird, Dale W" uniqKey="Laird D" first="Dale W." last="Laird">Dale W. Laird</name>
<affiliation><nlm:aff id="A1">Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada</nlm:aff>
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<affiliation><nlm:aff id="A2">Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada</nlm:aff>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Human Dermal Fibroblasts Derived from Oculodentodigital Dysplasia Patients Suggest that Patients may have Wound Healing Defects</title>
<author><name sortKey="Churko, Jared M" sort="Churko, Jared M" uniqKey="Churko J" first="Jared M." last="Churko">Jared M. Churko</name>
<affiliation><nlm:aff id="A1">Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada</nlm:aff>
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<author><name sortKey="Shao, Qing" sort="Shao, Qing" uniqKey="Shao Q" first="Qing" last="Shao">Qing Shao</name>
<affiliation><nlm:aff id="A1">Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada</nlm:aff>
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<author><name sortKey="Gong, Xiangqun" sort="Gong, Xiangqun" uniqKey="Gong X" first="Xiangqun" last="Gong">Xiangqun Gong</name>
<affiliation><nlm:aff id="A2">Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada</nlm:aff>
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<author><name sortKey="Swoboda, Kathryn J" sort="Swoboda, Kathryn J" uniqKey="Swoboda K" first="Kathryn J." last="Swoboda">Kathryn J. Swoboda</name>
<affiliation><nlm:aff id="A3">Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA</nlm:aff>
</affiliation>
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<author><name sortKey="Bai, Donglin" sort="Bai, Donglin" uniqKey="Bai D" first="Donglin" last="Bai">Donglin Bai</name>
<affiliation><nlm:aff id="A2">Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada</nlm:aff>
</affiliation>
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<author><name sortKey="Sampson, Jacinda" sort="Sampson, Jacinda" uniqKey="Sampson J" first="Jacinda" last="Sampson">Jacinda Sampson</name>
<affiliation><nlm:aff id="A3">Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA</nlm:aff>
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<author><name sortKey="Laird, Dale W" sort="Laird, Dale W" uniqKey="Laird D" first="Dale W." last="Laird">Dale W. Laird</name>
<affiliation><nlm:aff id="A1">Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada</nlm:aff>
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<affiliation><nlm:aff id="A2">Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada</nlm:aff>
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<series><title level="j">Human mutation</title>
<idno type="ISSN">1059-7794</idno>
<idno type="eISSN">1098-1004</idno>
<imprint><date when="2011">2011</date>
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<front><div type="abstract" xml:lang="en"><p id="P1">Oculodentodigital dysplasia (ODDD) is primarily an autosomal dominant human disease caused by any one of over 60 mutations in the <italic>GJA1</italic>
gene encoding the gap junction protein Cx43. In the present study, wound healing was investigated in a G60S ODDD mutant mouse model and by using dermal fibroblasts isolated from two ODDD patients harboring the p.D3N and p.V216L mutants along with dermal fibroblasts isolated from their respective unaffected relatives. Punch biopsies revealed a delay in wound closure in the G60S mutant mice in comparison to wild type littermates and this delay appeared to be due to defects in the dermal fibroblasts. While both the p.D3N and p.V216L mutants reduced gap junctional intercellular communication in human dermal fibroblasts, immunolocalization studies revealed that Cx43 gap junctions were prevalent at the cell surface of p.D3N expressing fibroblasts but greatly reduced in p.V216L expressing fibroblasts. Mutant expressing fibroblasts were further found to have reduced proliferation and migration capabilities. Finally, in response to TGFβ1, mutant expressing fibroblasts expressed significantly less alpha smooth muscle actin suggesting they were inefficient in their ability to differentiate into myofibroblasts. Collectively, our results suggest that ODDD patients may have subclinical defects in wound healing due to impaired function of dermal fibroblasts.</p>
</div>
</front>
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<pmc article-type="research-article" xml:lang="en"><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">9215429</journal-id>
<journal-id journal-id-type="pubmed-jr-id">2408</journal-id>
<journal-id journal-id-type="nlm-ta">Hum Mutat</journal-id>
<journal-title-group><journal-title>Human mutation</journal-title>
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<issn pub-type="ppub">1059-7794</issn>
<issn pub-type="epub">1098-1004</issn>
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<article-id pub-id-type="manuscript">NIHMS318180</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
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<title-group><article-title>Human Dermal Fibroblasts Derived from Oculodentodigital Dysplasia Patients Suggest that Patients may have Wound Healing Defects</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Churko</surname>
<given-names>Jared M.</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
<xref rid="FN2" ref-type="author-notes">#</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Shao</surname>
<given-names>Qing</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
<xref rid="FN2" ref-type="author-notes">#</xref>
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<contrib contrib-type="author"><name><surname>Gong</surname>
<given-names>Xiangqun</given-names>
</name>
<xref rid="A2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Swoboda</surname>
<given-names>Kathryn J.</given-names>
</name>
<xref rid="A3" ref-type="aff">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bai</surname>
<given-names>Donglin</given-names>
</name>
<xref rid="A2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sampson</surname>
<given-names>Jacinda</given-names>
</name>
<xref rid="A3" ref-type="aff">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Laird</surname>
<given-names>Dale W.</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
<xref rid="A2" ref-type="aff">2</xref>
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<aff id="A1"><label>1</label>
Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada</aff>
<aff id="A2"><label>2</label>
Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada</aff>
<aff id="A3"><label>3</label>
Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA</aff>
<author-notes><corresp id="FN1">Address Correspondence to: Dale W. Laird, Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada, N6A-5C1, Tel: 001 (519) 661-2111 x86827, Fax: 001 (519) 850-2562, <email>Dale.laird@schulich.uwo.ca</email>
</corresp>
<fn id="FN2" fn-type="equal"><label>#</label>
<p>Both authors contributed equally</p>
</fn>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>31</day>
<month>8</month>
<year>2011</year>
</pub-date>
<pub-date pub-type="ppub"><month>4</month>
<year>2011</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>1</day>
<month>4</month>
<year>2012</year>
</pub-date>
<volume>32</volume>
<issue>4</issue>
<fpage>456</fpage>
<lpage>466</lpage>
<abstract><p id="P1">Oculodentodigital dysplasia (ODDD) is primarily an autosomal dominant human disease caused by any one of over 60 mutations in the <italic>GJA1</italic>
gene encoding the gap junction protein Cx43. In the present study, wound healing was investigated in a G60S ODDD mutant mouse model and by using dermal fibroblasts isolated from two ODDD patients harboring the p.D3N and p.V216L mutants along with dermal fibroblasts isolated from their respective unaffected relatives. Punch biopsies revealed a delay in wound closure in the G60S mutant mice in comparison to wild type littermates and this delay appeared to be due to defects in the dermal fibroblasts. While both the p.D3N and p.V216L mutants reduced gap junctional intercellular communication in human dermal fibroblasts, immunolocalization studies revealed that Cx43 gap junctions were prevalent at the cell surface of p.D3N expressing fibroblasts but greatly reduced in p.V216L expressing fibroblasts. Mutant expressing fibroblasts were further found to have reduced proliferation and migration capabilities. Finally, in response to TGFβ1, mutant expressing fibroblasts expressed significantly less alpha smooth muscle actin suggesting they were inefficient in their ability to differentiate into myofibroblasts. Collectively, our results suggest that ODDD patients may have subclinical defects in wound healing due to impaired function of dermal fibroblasts.</p>
</abstract>
<kwd-group><kwd>Cx43</kwd>
<kwd>GJA1</kwd>
<kwd>oculodentodigital dysplasia</kwd>
<kwd>ODDD</kwd>
<kwd>fibroblasts</kwd>
<kwd>gap junctions</kwd>
<kwd>phosphorylation</kwd>
</kwd-group>
</article-meta>
</front>
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