ARAP3 Functions in Hematopoietic Stem Cells
Identifieur interne : 000459 ( Pmc/Curation ); précédent : 000458; suivant : 000460ARAP3 Functions in Hematopoietic Stem Cells
Auteurs : Yiwen Song [États-Unis] ; Jing Jiang [États-Unis] ; Sonja Vermeren [Royaume-Uni] ; Wei Tong [États-Unis]Source :
- PLoS ONE [ 1932-6203 ] ; 2014.
Abstract
ARAP3 is a GTPase-activating protein (GAP) that inactivates Arf6 and RhoA small GTPases. ARAP3 deficiency in mice causes a sprouting angiogenic defect resulting in embryonic lethality by E11. Mice with an ARAP3 R302,303A mutation (
Url:
DOI: 10.1371/journal.pone.0116107
PubMed: 25542002
PubMed Central: 4277471
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<author><name sortKey="Jiang, Jing" sort="Jiang, Jing" uniqKey="Jiang J" first="Jing" last="Jiang">Jing Jiang</name>
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<front><div type="abstract" xml:lang="en"><p>ARAP3 is a GTPase-activating protein (GAP) that inactivates Arf6 and RhoA small GTPases. ARAP3 deficiency in mice causes a sprouting angiogenic defect resulting in embryonic lethality by E11. Mice with an ARAP3 R302,303A mutation (<italic>Arap3<sup>KI/KI</sup>
</italic>
) that prevents activation by phosphoinositide-3-kinase (PI3K) have a similar angiogenic phenotype, although some animals survive to adulthood. Here, we report that hematopoietic stem cells (HSCs) from rare adult <italic>Arap3<sup>KI/KI</sup>
</italic>
bone marrow are compromised in their ability to reconstitute recipient mice and to self-renew. To elucidate the potential cell-autonomous and non-cell-autonomous roles of ARAP3 in hematopoiesis, we conditionally deleted <italic>Arap3</italic>
in hematopoietic cells and in several cell types within the HSC niche. Excision of <italic>Arap3</italic>
in hematopoietic cells using <italic>Vav1-Cre</italic>
does not alter the ability of ARAP3-deficient progenitor cells to proliferate and differentiate <italic>in vitro</italic>
or ARAP3-deficient HSCs to provide multi-lineage reconstitution and to undergo self-renewal <italic>in vivo</italic>
. Thus, our data suggest that ARAP3 does not play a cell-autonomous role in HSPCs. Deletion of <italic>Arap3</italic>
in osteoblasts and mesenchymal stromal cells using <italic>Prx1-Cre</italic>
resulted in no discernable phenotypes in hematopoietic development or HSC homeostasis in adult mice. In contrast, deletion of <italic>Arap3</italic>
using vascular endothelial cadherin (<italic>VEC</italic>
or <italic>Cdh5</italic>
)-driven <italic>Cre</italic>
resulted in embryonic lethality, however HSCs from surviving adult mice were largely normal. Reverse transplantations into <italic>VEC</italic>
-driven <italic>Arap3</italic>
conditional knockout mice revealed no discernable difference in HSC frequencies or function in comparison to control mice. Taken together, our investigation suggests that despite a critical role for ARAP3 in embryonic vascular development, its loss in endothelial cells minimally impacts HSCs in adult bone marrow.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<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, USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25542002</article-id>
<article-id pub-id-type="pmc">4277471</article-id>
<article-id pub-id-type="publisher-id">PONE-D-14-16771</article-id>
<article-id pub-id-type="doi">10.1371/journal.pone.0116107</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><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>Stem Cells</subject>
<subj-group><subject>Hematopoietic Stem Cells</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>ARAP3 Functions in Hematopoietic Stem Cells</article-title>
<alt-title alt-title-type="running-head">ARAP3 in HSCs</alt-title>
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<contrib-group><contrib contrib-type="author"><name><surname>Song</surname>
<given-names>Yiwen</given-names>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
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<xref ref-type="aff" rid="aff2"><sup>2</sup>
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<given-names>Jing</given-names>
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<xref ref-type="aff" rid="aff2"><sup>2</sup>
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<xref ref-type="aff" rid="aff3"><sup>3</sup>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
<addr-line>Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America</addr-line>
</aff>
<aff id="aff2"><label>2</label>
<addr-line>Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America</addr-line>
</aff>
<aff id="aff3"><label>3</label>
<addr-line>MRC Centre for Inflammation Research, The Queen's Medical Research Institute, The University of Edinburgh, United Kingdom</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Ivanovic</surname>
<given-names>Zoran</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>French Blood Institute, France</addr-line>
</aff>
<author-notes><corresp id="cor1">* E-mail: <email>tongw@email.chop.edu</email>
</corresp>
<fn fn-type="conflict"><p><bold>Competing Interests: </bold>
The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con"><p>None. Conceived and designed the experiments: WT YS. Performed the experiments: YS JJ. Analyzed the data: WT YS. Contributed reagents/materials/analysis tools: SV. Wrote the paper: WT YS SV.</p>
</fn>
</author-notes>
<pub-date pub-type="collection"><year>2014</year>
</pub-date>
<pub-date pub-type="epub"><day>26</day>
<month>12</month>
<year>2014</year>
</pub-date>
<volume>9</volume>
<issue>12</issue>
<elocation-id>e116107</elocation-id>
<history><date date-type="received"><day>14</day>
<month>4</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>5</day>
<month>12</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-year>2014</copyright-year>
<copyright-holder>Song et al</copyright-holder>
<license><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>
<abstract><p>ARAP3 is a GTPase-activating protein (GAP) that inactivates Arf6 and RhoA small GTPases. ARAP3 deficiency in mice causes a sprouting angiogenic defect resulting in embryonic lethality by E11. Mice with an ARAP3 R302,303A mutation (<italic>Arap3<sup>KI/KI</sup>
</italic>
) that prevents activation by phosphoinositide-3-kinase (PI3K) have a similar angiogenic phenotype, although some animals survive to adulthood. Here, we report that hematopoietic stem cells (HSCs) from rare adult <italic>Arap3<sup>KI/KI</sup>
</italic>
bone marrow are compromised in their ability to reconstitute recipient mice and to self-renew. To elucidate the potential cell-autonomous and non-cell-autonomous roles of ARAP3 in hematopoiesis, we conditionally deleted <italic>Arap3</italic>
in hematopoietic cells and in several cell types within the HSC niche. Excision of <italic>Arap3</italic>
in hematopoietic cells using <italic>Vav1-Cre</italic>
does not alter the ability of ARAP3-deficient progenitor cells to proliferate and differentiate <italic>in vitro</italic>
or ARAP3-deficient HSCs to provide multi-lineage reconstitution and to undergo self-renewal <italic>in vivo</italic>
. Thus, our data suggest that ARAP3 does not play a cell-autonomous role in HSPCs. Deletion of <italic>Arap3</italic>
in osteoblasts and mesenchymal stromal cells using <italic>Prx1-Cre</italic>
resulted in no discernable phenotypes in hematopoietic development or HSC homeostasis in adult mice. In contrast, deletion of <italic>Arap3</italic>
using vascular endothelial cadherin (<italic>VEC</italic>
or <italic>Cdh5</italic>
)-driven <italic>Cre</italic>
resulted in embryonic lethality, however HSCs from surviving adult mice were largely normal. Reverse transplantations into <italic>VEC</italic>
-driven <italic>Arap3</italic>
conditional knockout mice revealed no discernable difference in HSC frequencies or function in comparison to control mice. Taken together, our investigation suggests that despite a critical role for ARAP3 in embryonic vascular development, its loss in endothelial cells minimally impacts HSCs in adult bone marrow.</p>
</abstract>
<funding-group><funding-statement>WT is supported by National Institutes of Health (NIH) grants R01HL095675 and R01HL110806. WT received a New Investigator Award from the Myeloproliferative Neoplasm Research Foundation and Gabrielle's Angel Foundation for Cancer Research, and is a Leukemia Lymphoma Society (LLS) Scholar. YS is supported by NIH training grant T32-DK007780-09. SV is supported by the Biotechnology and Biological Sciences Research Council (BB/C520712). 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><page-count count="21"></page-count>
</counts>
<custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name>
<meta-value>The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes><title>Data Availability</title>
<p>The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.</p>
</notes>
</front>
</pmc>
</record>
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