Integration of CD45-positive leukocytes into newly forming lymphatics of adult mice
Identifieur interne : 000D39 ( Pmc/Corpus ); précédent : 000D38; suivant : 000D40Integration of CD45-positive leukocytes into newly forming lymphatics of adult mice
Auteurs : K. Buttler ; M. Lohrberg ; G. Gross ; H. A. Weich ; J. WiltingSource :
- Histochemistry and Cell Biology [ 0948-6143 ] ; 2016.
Abstract
The embryonic origin of lymphatic endothelial cells (LECs) has been a matter of controversy since more than a century. However, recent studies in mice have supported the concept that embryonic lymphangiogenesis is a complex process consisting of growth of lymphatics from specific venous segments as well as the integration of lymphangioblasts into the lymphatic networks. Similarly, the mechanisms of adult lymphangiogenesis are poorly understood and have rarely been studied. We have recently shown that endothelial progenitor cells isolated from the lung of adult mice have the capacity to form both blood vessels and lymphatics when grafted with Matrigel plugs into the skin of syngeneic mice. Here, we followed up on these experiments and studied the behavior of host leukocytes during lymphangiogenesis in the Matrigel plugs. We observed a striking co-localization of CD45+ leukocytes with the developing lymphatics. Numerous CD45+ cells expressed the LEC marker podoplanin and were obviously integrated into the lining of lymphatic capillaries. This indicates that, similar to inflammation-induced lymphangiogenesis in man, circulating CD45+ cells of adult mice are capable of initiating lymphangiogenesis and of adopting a lymphvasculogenic cellular differentiation program. The data are discussed in the context of embryonic and inflammation-induced lymphangiogenesis.
The online version of this article (doi:10.1007/s00418-015-1399-y) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1007/s00418-015-1399-y
PubMed: 26748643
PubMed Central: 4848334
Links to Exploration step
PMC:4848334Le document en format XML
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<front><div type="abstract" xml:lang="en"><p>The embryonic origin of lymphatic endothelial cells (LECs) has been a matter of controversy since more than a century. However, recent studies in mice have supported the concept that embryonic lymphangiogenesis is a complex process consisting of growth of lymphatics from specific venous segments as well as the integration of lymphangioblasts into the lymphatic networks. Similarly, the mechanisms of adult lymphangiogenesis are poorly understood and have rarely been studied. We have recently shown that endothelial progenitor cells isolated from the lung of adult mice have the capacity to form both blood vessels and lymphatics when grafted with Matrigel plugs into the skin of syngeneic mice. Here, we followed up on these experiments and studied the behavior of host leukocytes during lymphangiogenesis in the Matrigel plugs. We observed a striking co-localization of CD45<sup>+</sup>
leukocytes with the developing lymphatics. Numerous CD45<sup>+</sup>
cells expressed the LEC marker podoplanin and were obviously integrated into the lining of lymphatic capillaries. This indicates that, similar to inflammation-induced lymphangiogenesis in man, circulating CD45<sup>+</sup>
cells of adult mice are capable of initiating lymphangiogenesis and of adopting a lymphvasculogenic cellular differentiation program. The data are discussed in the context of embryonic and inflammation-induced lymphangiogenesis.</p>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (doi:10.1007/s00418-015-1399-y) contains supplementary material, which is available to authorized users.</p>
</sec>
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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">Histochem Cell Biol</journal-id>
<journal-id journal-id-type="iso-abbrev">Histochem. Cell Biol</journal-id>
<journal-title-group><journal-title>Histochemistry and Cell Biology</journal-title>
</journal-title-group>
<issn pub-type="ppub">0948-6143</issn>
<issn pub-type="epub">1432-119X</issn>
<publisher><publisher-name>Springer Berlin Heidelberg</publisher-name>
<publisher-loc>Berlin/Heidelberg</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26748643</article-id>
<article-id pub-id-type="pmc">4848334</article-id>
<article-id pub-id-type="publisher-id">1399</article-id>
<article-id pub-id-type="doi">10.1007/s00418-015-1399-y</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Original Paper</subject>
</subj-group>
</article-categories>
<title-group><article-title>Integration of CD45-positive leukocytes into newly forming lymphatics of adult mice</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Buttler</surname>
<given-names>K.</given-names>
</name>
<xref ref-type="aff" rid="Aff1"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lohrberg</surname>
<given-names>M.</given-names>
</name>
<xref ref-type="aff" rid="Aff1"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gross</surname>
<given-names>G.</given-names>
</name>
<xref ref-type="aff" rid="Aff2"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Weich</surname>
<given-names>H. A.</given-names>
</name>
<xref ref-type="aff" rid="Aff3"></xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Wilting</surname>
<given-names>J.</given-names>
</name>
<address><phone>49-551-397050</phone>
<email>joerg.wilting@med.uni-goettingen.de</email>
</address>
<xref ref-type="aff" rid="Aff1"></xref>
</contrib>
<aff id="Aff1"><label></label>
Department of Anatomy and Cell Biology, University Medical School Göttingen, Göttingen, Germany</aff>
<aff id="Aff2"><label></label>
Department of Gene Regulation, Helmholtz Centre for Infection Research, Brunswick, Germany</aff>
<aff id="Aff3"><label></label>
Department of Chemical Biology, Helmholtz Centre for Infection Research, Brunswick, Germany</aff>
</contrib-group>
<pub-date pub-type="epub"><day>9</day>
<month>1</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>9</day>
<month>1</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="ppub"><year>2016</year>
</pub-date>
<volume>145</volume>
<fpage>629</fpage>
<lpage>636</lpage>
<history><date date-type="accepted"><day>21</day>
<month>12</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s) 2016</copyright-statement>
<license license-type="OpenAccess"><license-p><bold>Open Access</bold>
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.</license-p>
</license>
</permissions>
<abstract id="Abs1"><p>The embryonic origin of lymphatic endothelial cells (LECs) has been a matter of controversy since more than a century. However, recent studies in mice have supported the concept that embryonic lymphangiogenesis is a complex process consisting of growth of lymphatics from specific venous segments as well as the integration of lymphangioblasts into the lymphatic networks. Similarly, the mechanisms of adult lymphangiogenesis are poorly understood and have rarely been studied. We have recently shown that endothelial progenitor cells isolated from the lung of adult mice have the capacity to form both blood vessels and lymphatics when grafted with Matrigel plugs into the skin of syngeneic mice. Here, we followed up on these experiments and studied the behavior of host leukocytes during lymphangiogenesis in the Matrigel plugs. We observed a striking co-localization of CD45<sup>+</sup>
leukocytes with the developing lymphatics. Numerous CD45<sup>+</sup>
cells expressed the LEC marker podoplanin and were obviously integrated into the lining of lymphatic capillaries. This indicates that, similar to inflammation-induced lymphangiogenesis in man, circulating CD45<sup>+</sup>
cells of adult mice are capable of initiating lymphangiogenesis and of adopting a lymphvasculogenic cellular differentiation program. The data are discussed in the context of embryonic and inflammation-induced lymphangiogenesis.</p>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (doi:10.1007/s00418-015-1399-y) contains supplementary material, which is available to authorized users.</p>
</sec>
</abstract>
<kwd-group xml:lang="en"><title>Keywords</title>
<kwd>Lymphatic endothelial cell</kwd>
<kwd>Lymphangioblast</kwd>
<kwd>Lymphangiogenesis</kwd>
<kwd>Lymphvasculogenesis</kwd>
<kwd>Endothelial progenitor cell</kwd>
<kwd>Mesenchymal stem cell</kwd>
</kwd-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© Springer-Verlag Berlin Heidelberg 2016</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
<body><sec id="Sec1"><title>Introduction</title>
<p>The embryonic origin of the lymphatic vascular system has been studied for more than a hundred years, but controversies still exist. Florence Sabin was among the first to study embryonic lymphangiogenesis, and stated that, in pigs, lymphatic vessel formation takes place via sprouting from specific segments of deep embryonic veins (Sabin <xref ref-type="bibr" rid="CR31">1909</xref>
). In contrast, Kampmeier postulated an additional mesenchymal origin of lymphatics (Kampmeier <xref ref-type="bibr" rid="CR15">1912</xref>
). Our insight into the mechanisms regulating lymphatic vessel formation has greatly increased by the imaging of labeled cell lines in living animals, predominantly supporting Kampmeier’s hypothesis. For instance, in zebrafish embryos, precursor cells were found to migrate from the cardinal vein to the horizontal myoseptum to generate parachordal lymphangioblasts in this area (Küchler et al. <xref ref-type="bibr" rid="CR21">2006</xref>
; Yaniv et al. <xref ref-type="bibr" rid="CR45">2006</xref>
; Hogan et al. <xref ref-type="bibr" rid="CR12">2009</xref>
; Isogai et al. <xref ref-type="bibr" rid="CR14">2009</xref>
). These parachordal lymphangioblasts could be pursued to migrate along arteries and to remodel into major trunk lymphatic vessels thus forming the thoracic duct (Yaniv et al. <xref ref-type="bibr" rid="CR45">2006</xref>
; Bussmann et al. <xref ref-type="bibr" rid="CR3">2010</xref>
; Cha et al. <xref ref-type="bibr" rid="CR7">2012</xref>
). The data provided evidence for an intermediate mesenchymal phase of lymphangiogenesis in fish. Although a strong conservation of genes controlling lymphangiogenesis could be detected between zebrafish and mammals (Schulte-Merker et al. <xref ref-type="bibr" rid="CR35">2011</xref>
; Koltowska et al. <xref ref-type="bibr" rid="CR18">2013</xref>
), in higher vertebrates the lymphatic vascular system is more complex than in fish, which hardly possess any epifascial, dermal lymphatics. Moreover, organ-specific lymphatic vascular patterns can be seen in higher vertebrates, but the cellular origins of embryonic lymphatics in diverse compartments of the body are still subject of controversial discussions.</p>
<p>Apart from the embryo, lymphangiogenesis takes place under pathological conditions (Wilting et al. <xref ref-type="bibr" rid="CR44">2009</xref>
; Tammela and Alitalo <xref ref-type="bibr" rid="CR39">2010</xref>
). In murine experimental models employing the lung and the skin, it could be shown that acute inflammation is able to induce lymphangiogenesis effectively (Pullinger and Florey <xref ref-type="bibr" rid="CR29">1937</xref>
; Baluk et al. <xref ref-type="bibr" rid="CR1">2005</xref>
). Thereby, pro-inflammatory factors such as interleukin-1 and tumor necrosis factor-<italic>α</italic>
induce the up-regulation of the lymphangiogenic vascular endothelial growth factor-C (VEGF-C; Cha et al. <xref ref-type="bibr" rid="CR6">2007</xref>
). But also in man, acute inflammation is a strong pro-lymphangiogenic stimulus (Kerjaschki et al. <xref ref-type="bibr" rid="CR17">2006</xref>
), whereas chronic inflammation obviously has a deleterious effect on the lymphatics. After repeated inflammation collectors seem to loose their contractility, lymph then coagulates and the vessels subsequently obliterate (Földi and Földi <xref ref-type="bibr" rid="CR9">2003</xref>
). During inflammation-induced kidney transplant rejection in man, massive lymphangiogenesis into the parenchyma of the rejected kidneys has been observed; additionally, there was evidence for the integration of circulating cells into the lining of the newly developing lymphatics (Kerjaschki et al. <xref ref-type="bibr" rid="CR17">2006</xref>
). However, it is still a matter of debate, if the mechanisms of lymphangiogenesis in the mouse recapitulate those in man.</p>
<p>We have recently shown that endothelial progenitor cells (EPCs) isolated from the lungs of adult mice have the capacity to form both blood vessels and lymphatics, when grafted into the skin of mice using Matrigel<sup>®</sup>
plugs. Thereby, hem- and lymphangiogenesis were initiated via stimulation of the EPCs either by direct application of growth factors such as VEGF-A and basic fibroblast growth factor (FGF; Schniedermann et al. <xref ref-type="bibr" rid="CR33">2010</xref>
), or by co-injection of mesenchymal stem cells (MSCs), which secrete a variety of angiogenic factors. Thereby, we observed no participation of MSCs in the formation of the vascular wall (Buttler et al. <xref ref-type="bibr" rid="CR5">2014</xref>
). Here, we followed up on these experiments and studied the behavior of host leukocytes during lymphangiogenesis in the Matrigel<sup>®</sup>
plugs. We found a significant co-localization of CD45<sup>+</sup>
leukocytes with the developing lymphatics, and a considerable number of these cells were obviously integrated into the lining of newly formed lymphatics. This led us to the conclusion that, similar to the mechanisms of inflammation-induced lymphangiogenesis in man, circulating CD45<sup>+</sup>
cells of adult mice are capable of initiating a lymphvasculogenic program.</p>
</sec>
<sec id="Sec2"><title>Materials and methods</title>
<sec id="Sec3"><title>Animals</title>
<p>Lung-derived EPCs and bone marrow-derived mesenchymal stem cells (MSCs) were isolated from C57/Bl.6 mice, and the cells were grafted into adult C57/Bl.6 mice. For the transplantation experiments, we used 8–12 weeks-old female mice. All experiments were approved by our local institutional animal care committee and the Lower Saxony state council on animal care (LAVES). The experiments corresponded to the requirements of the American Physiological Society.</p>
</sec>
<sec id="Sec4"><title>Isolation and culture of EPCs and MSCs</title>
<p>All cells were isolated from C57/Bl.6 mice. EPCs were isolated from mouse lungs using a magnetic cell separation method that has already been described by Schniedermann et al. (<xref ref-type="bibr" rid="CR33">2010</xref>
). Briefly, the lungs of adult mice were dissected after perfusion, minced and digested using collagenase A. A single cell suspension of the collected cells was produced with a 40 μm cell strainer, and CD31<sup>+</sup>
cells were cultivated after magnetic activated cell sorting using anti-CD31-coated Dynabeads<sup>®</sup>
(Thermo Fischer Scientific). After 8–10 days, cells were separated again using FACS sorting with anti-CD31 antibodies.</p>
<p>MSCs were isolated from bone marrow as described by Soleimani and Nadri (<xref ref-type="bibr" rid="CR36">2009</xref>
). Shortly, mice were killed by cervical dislocation and the hind limbs were separated from the trunk after removal of the skin. Muscles and connective tissue was then removed from the tibia and the femur under sterile conditions. To harvest bone marrow, the distal ends of tibia and femur were cut off and bone marrow was flushed out with PBS by insertion of a needle into the cancellous bone. The cell suspension was then filtered, and bone marrow cells were transferred into culture dishes. The cells were used between passages 6–10 (MSCs) and 8–24 (EPCs). As in our previous studies (Schniedermann et al. <xref ref-type="bibr" rid="CR33">2010</xref>
; Hoffmann et al. <xref ref-type="bibr" rid="CR11">2006</xref>
), MSCs and EPCs were cultured in DMEM enriched with FCS in 24- and 6-well plates (Nunc<sup>®</sup>
). EPCs were cultured in gelatine-coated wells or cell culture flasks.</p>
</sec>
<sec id="Sec5"><title>Assessment of vessel formation in vivo</title>
<p>For the in vivo experiments, MSCs and EPCs were trypsinized and counted. For the experiments with each single cell type, 1 × 10<sup>6</sup>
cells were used. When the two cell types were combined in a 1:1 mixture, 0.5–1 × 10<sup>6</sup>
cells were used for each cell type. Cells were centrifuged and the pellets were dissolved in 300 µl of cold Matrigel<sup>®</sup>
(Corning, Wiesbaden, Germany). The mice were shaved and mildly sedated by intraperitoneal injection of ketamine (100 mg/kg body weight). Matrigel plugs with or without cells were injected subcutaneously into the left and right dorsal lumbar region (two injections per animal). After 7–9 days, the animals were killed, the skin was dissected, the Matrigel plugs photographed in situ, excised and fixed with 4 % paraformaldehyde (PFA). The specimens were rinsed in PBS, immersed with saccharose and embedded in tissue freeze medium (Neg-50, Richard-Allan Scientific, Mi). The numbers of experiments were: Matrigel without cells (<italic>n</italic>
= 11), Matrigel with EPCs (5), Matrigel with MSCs (6), Matrigel with EPCs and MSCs (26).</p>
</sec>
<sec id="Sec6"><title>Histology and immunohistology</title>
<p>Frozen specimens were sectioned at 16 µm, mounted on slides, and stained with hematoxylin and eosin (HE). For the immunofluorescence studies, non-specific binding was blocked by the incubation with 2 % bovine serum albumin (BSA) for 1 h prior to the incubation with the primary antibodies. Primary antibodies were anti-mouse CD31 (rat clone MEC13.3; 1:50, BD), anti-podoplanin (syrian hamster clone 8.1.1, 1:1000, Hybridoma Bank, Iowa), anti-Prox1 (rabbit polyclonal, 1:500, Reliatech, Germany), and anti-mouse CD45 (rat monoclonal, 1:50, BD). After incubation with the primary antibodies for 1 h, sections were rinsed and the secondary antibodies were applied: goat anti-rat Alexa594/or Alexa488, donkey anti-rabbit Alexa488, goat anti-hamster Alexa594/or Alexa488 (all from Invitrogen). Dapi was used to counter-stain all nuclei. The sections were mounted under coverslips using Fluoromount-G (Southern Biotechnology, US) and studied with Axio Imager Z1 with ApoTome device (Zeiss, Göttingen, Germany).</p>
</sec>
</sec>
<sec id="Sec7"><title>Results</title>
<p>In all experiments performed with Matrigel<sup>®</sup>
plugs containing a 1:1 mixture of EPCs and MSCs, the stereomicroscopic inspection revealed the presence of blood vessels in the plugs already after 7–9 days. These vessels were obviously highly fragile since careful dissection of the skin always resulted in hemorrhage in the plug region. Matrigel<sup>®</sup>
controls and plugs containing only each single cell type were macroscopically and microscopically free of vessels, as it was shown in detail recently (Buttler et al. <xref ref-type="bibr" rid="CR5">2014</xref>
). The development of vessels in the EPC/MSC-containing plugs was verified by immunofluorescence using antibodies against CD31/PECAM1. In normal tissues, blood vascular endothelial cells (BECs) are strongly CD31/PECAM1-positive, whereas lymphatic endothelial cells (LECs) are just weakly positive and characterized by their nuclear expression of the Prox1 transcription factor (Wilting et al. <xref ref-type="bibr" rid="CR42">2002</xref>
). Both types of expression pattern could be found in EPC/MSC-containing Matrigel<sup>®</sup>
plugs, clearly documenting the development of blood vessels and lymphatic networks (Fig. <xref rid="Fig1" ref-type="fig">1</xref>
). The newly formed vessels were made up of a mosaic containing grafted EPCs and host endothelial cells. We did not find any signs for the integration of MSC into these vessels (Buttler et al. <xref ref-type="bibr" rid="CR5">2014</xref>
). Studies using antibodies against the pan-leukocyte marker CD45 revealed massive infiltration of leukocytes into the experimental plugs, indicating an inflammatory-type of lymphangiogenesis, although a syngeneic model was used in our grafting experiment. We observed a significant co-localization of host leukocytes with the podoplanin–positive lymphatic capillary networks in the plugs (Fig. <xref rid="Fig2" ref-type="fig">2</xref>
), indicating an active participation of the leukocytes in adult lymphangiogenesis. Interestingly, a subpopulation of CD45<sup>+</sup>
cells assumed endothelial-like morphology and was obviously integrated into the newly forming lymphatic networks (Fig. <xref rid="Fig3" ref-type="fig">3</xref>
). In many cases, like those shown in Figs. <xref rid="Fig2" ref-type="fig">2</xref>
and <xref rid="Fig3" ref-type="fig">3</xref>
, the new lymphatics formed delicate capillary-like networks, but we also observed sinusoid-like lymphatics. Again, round CD45<sup>+</sup>
leukocytes could clearly be distinguished from endothelial-like cells, which co-expressed CD45 and podoplanin (Fig. <xref rid="Fig4" ref-type="fig">4</xref>
). In rare case we found lymphatics with a wide lumen. In such cases we observed cells that obviously lined the lumen of the vessel (Fig. <xref rid="Fig5" ref-type="fig">5</xref>
; Suppl. Movie 1). Our data provide strong evidence for the existence of leukocytes with lymphvasculogenic potential in adult mice.<fig id="Fig1"><label>Fig. 1</label>
<caption><p>Verification of lymphatics in the Matrigel plugs with <italic>CD31</italic>
(<italic>green</italic>
) and <italic>Prox1</italic>
(<italic>red</italic>
) antibodies. The pan-endothelial marker <italic>CD31</italic>
stains blood vessels (<italic>BV</italic>
) strongly and lymphatics (<italic>LV</italic>
) weakly. <italic>Prox1</italic>
marks the nuclei of LECs (<italic>arrowheads</italic>
) as shown at higher magnification in the <italic>inset</italic>
. Nuclei are counter-stained with Dapi (<italic>blue</italic>
). <italic>Bar</italic>
30 µm</p>
</caption>
<graphic xlink:href="418_2015_1399_Fig1_HTML" id="MO1"></graphic>
</fig>
<fig id="Fig2"><label>Fig. 2</label>
<caption><p>Lymphatics in the Matrigel plugs are closely associated with leukocytes. Networks of lymphatic capillaries are demonstrated with the LEC marker podoplanin (<italic>red</italic>
). Note that the distribution of leukocytes, stained with anti-CD45 antibodies (<italic>green</italic>
), closely follows the pattern of the lymphatics. Nuclei are counter-stained with Dapi (<italic>blue</italic>
). <italic>Bar</italic>
50 µm</p>
</caption>
<graphic xlink:href="418_2015_1399_Fig2_HTML" id="MO2"></graphic>
</fig>
<fig id="Fig3"><label>Fig. 3</label>
<caption><p>A subpopulation of cells in the lymphatic networks are positive for both podoplanin and CD45. <bold>a</bold>
<italic>Podoplanin</italic>
(<italic>red</italic>
). <bold>b</bold>
<italic>CD45</italic>
(<italic>green</italic>
). <bold>c</bold>
<italic>Merged</italic>
picture. Besides round CD45-positive cells, there are endothelial-like cells that co-express podoplanin and CD45 (<italic>arrows</italic>
). Nuclei are counter-stained with Dapi (<italic>blue</italic>
). <italic>Bar</italic>
25 µm. (Modified from: Buttler et al. <xref ref-type="bibr" rid="CR5">2014</xref>
; Springer license no.: 3699330937457). <bold>d</bold>
Higher magnification of (<bold>c</bold>
) note endothelial-like cells that co-express podoplanin and CD45 (<italic>arrows</italic>
), indicating integration of leukocytes into developing lymphatic networks. <italic>Bar</italic>
10 µm</p>
</caption>
<graphic xlink:href="418_2015_1399_Fig3_HTML" id="MO3"></graphic>
</fig>
<fig id="Fig4"><label>Fig. 4</label>
<caption><p>Endothelial-like cells in the lymphatic sinusoids are positive for both podoplanin and CD45. <bold>a</bold>
<italic>Merged</italic>
picture of a <italic>podoplanin</italic>
<sup>+</sup>
(<italic>green</italic>
) lymphatic sinus. <italic>CD45</italic>
is shown in <italic>red</italic>
. Besides <italic>round</italic>
CD45<sup>+</sup>
leukocytes (<italic>arrowheads</italic>
), there are endothelial-like cells (<italic>yellow</italic>
) that co-express the two markers. <bold>b</bold>
–<bold>d</bold>
Merged picture and separate channels showing the cell marked with an <italic>arrow</italic>
in (<bold>a</bold>
). <italic>Bar</italic>
10 µm</p>
</caption>
<graphic xlink:href="418_2015_1399_Fig4_HTML" id="MO4"></graphic>
</fig>
<fig id="Fig5"><label>Fig. 5</label>
<caption><p>Cells lining newly formed lymphatics express podoplanin and CD45. <bold>a</bold>
Merged picture of a lymphatic vessel (<italic>LV</italic>
) in the Matrigel plug, stained for <italic>podoplanin</italic>
(<italic>green</italic>
) and <italic>CD45</italic>
(<italic>red</italic>
). Nuclei are counter-stained with <italic>Dapi</italic>
(<italic>blue</italic>
). The vessels are lumenized and have two branches to the <italic>left</italic>
. <italic>Bar</italic>
20 µm. <bold>b</bold>
–<bold>e</bold>
<italic>Merged</italic>
picture and separate channels showing the cell marked with an <italic>arrow</italic>
in (<bold>a</bold>
). The cell lining the vessels expresses both <italic>podoplanin</italic>
and <italic>CD45</italic>
. <italic>Bar</italic>
8 µm</p>
</caption>
<graphic xlink:href="418_2015_1399_Fig5_HTML" id="MO5"></graphic>
</fig>
</p>
</sec>
<sec id="Sec8"><title>Discussion</title>
<sec id="Sec9"><title>Lymphangiogenic potential of endothelial progenitor cells</title>
<p>We have previously shown that the lung of mice contains EPCs that possess the potential to differentiate into both BECs and LECs (Schniedermann et al. <xref ref-type="bibr" rid="CR33">2010</xref>
; Buttler et al. <xref ref-type="bibr" rid="CR5">2014</xref>
). Thereby, the EPCs exert their hem- and lymphangiogenic program only after exogenous stimulation, either by direct application with VEGF-A and FGF, or after co-transplantation with MSCs (Melero-Martin et al. <xref ref-type="bibr" rid="CR25">2008</xref>
; Schniedermann et al. <xref ref-type="bibr" rid="CR33">2010</xref>
; Lin et al. <xref ref-type="bibr" rid="CR22">2012</xref>
; Buttler et al. <xref ref-type="bibr" rid="CR5">2014</xref>
). It has to be pointed out that rodents have the capacity to regenerate lung tissue after resection, which has not been observed in the human. Regeneration of mouse lung is accompanied by the formation of new blood vessels (Konerding et al. <xref ref-type="bibr" rid="CR19">2012</xref>
); however, the development of lymphatics has not been studied in this model. In our experiments, the lymphatics in the Matrigel plugs are formed by a mosaic of grafted EPCs and host-derived LECs, which was shown by the use of GFP-labeled EPCs (Buttler et al. <xref ref-type="bibr" rid="CR5">2014</xref>
). Since we used a syngeneic mouse model, it is admissible to speculate that autologous patient-derived EPCs may behave in a similar way and integrate into newly developing lymphatic networks, which might provide a therapeutic option for the treatment of lymphedema.</p>
</sec>
<sec id="Sec10"><title>Leukocytes in murine lymphangiogenesis</title>
<p>Here, we studied lymphangiogenesis in adult mice and observed a striking co-localization of new lymphatics with CD45<sup>+</sup>
leukocytes. In an embryonic mouse model of lymphangiogenesis, a population of myeloid cells, characterized by the expression of the tyrosine kinase Syk, was found to express the lymphangiogenic factors VEGF-C and -D, as well as various chemokines. The Syk<sup>+</sup>
cell population comprises M2-polarized mononuclear cells and regulates developmental lymphangiogenesis (Böhmer et al. <xref ref-type="bibr" rid="CR2">2010</xref>
). The effect of the Syk<sup>+</sup>
cells could be inhibited in vivo by the application of soluble VEGFR-3, a specific inhibitor for VEGF-C and -D (Böhmer et al. <xref ref-type="bibr" rid="CR2">2010</xref>
). An important function for VEGF-C-secreting macrophages and neutrophils has been reported in various murine lymphangiogenesis models (Schoppmann et al. <xref ref-type="bibr" rid="CR34">2002</xref>
; Baluk et al. <xref ref-type="bibr" rid="CR1">2005</xref>
; Gordon et al. <xref ref-type="bibr" rid="CR10">2010</xref>
).</p>
</sec>
<sec id="Sec11"><title>Inflammation-induced lymphangiogenesis</title>
<p>Our studies revealed an obvious co-localization of CD45<sup>+</sup>
leukocytes with the newly forming lymphatic networks. The accumulation of leukocytes is known as a characteristic feature of inflammation. Consistent with this, EPCs and MSCs secrete chemoattractants such as CXCL1, 10 and 16, as well as MCP1 (Buttler et al. <xref ref-type="bibr" rid="CR5">2014</xref>
). Among others, these factors attract macrophages, which can release angiogenic proteins such as VEGF-A and VEGF-C (Schoppmann et al. <xref ref-type="bibr" rid="CR34">2002</xref>
; Mantovani et al. <xref ref-type="bibr" rid="CR23">2006</xref>
). The contribution of macrophages to inflammation-induced lymphangiogenesis could, among others, be demonstrated in a macrophage-deficient mouse model (Kubota et al. <xref ref-type="bibr" rid="CR20">2009</xref>
). Since we did neither observe any significant numbers of leukocytes in the Matrigel controls, nor in the experiments with EPCs, it is obvious that the attraction of leukocytes is induced by the grafted MSCs. As we have used a syngeneic C57/Bl.6 mouse model, it is unlikely that leukocyte immigration is a sign for host-versus-graft reactions.</p>
<p>Human cornea and kidney transplant rejection shows most clearly that inflammation is a potent inducer of lymphangiogenesis. In the cornea, inflammation induces growth of lymphatics, which remain clinically invisible. Lymphangiogenesis then facilitates trafficking of antigen-presenting cells from the cornea to draining lymph nodes, induction of hypersensitivity and corneal rejection (Chen et al. <xref ref-type="bibr" rid="CR8">2007</xref>
). Similarly, in renal transplant rejection, inflammation is associated with a 50-fold increase in lymphatic vessel density and invasion of lymphatics into the tubulointerstitial stroma (Kerjaschki et al. <xref ref-type="bibr" rid="CR16">2004</xref>
). Thereby, host cells, which obviously represent circulating lymphendothelial progenitor cells, integrate into the endothelial lining and contribute to the newly developing lymphatic networks (Kerjaschki et al. <xref ref-type="bibr" rid="CR17">2006</xref>
). In this respect, the mouse model presented in our study deeply reflects the mechanisms of human inflammation-induced lymphangiogenesis.</p>
</sec>
<sec id="Sec12"><title>Embryonic lymphangiogenesis</title>
<p>Regarding the embryonic development of the lymphovascular system, it is generally accepted that lymph sacs, the first histologically detectable structures of the lymphatic system, are formed by outgrowth of pre-lymphatic clusters from the cardinal veins (Sabin <xref ref-type="bibr" rid="CR31">1909</xref>
; Pollmann et al. <xref ref-type="bibr" rid="CR28">2014</xref>
). In recent years, the lymph sacs were proposed to represent the sole origin of the whole lymphatic system of mice (Srinivasan et al. <xref ref-type="bibr" rid="CR37">2007</xref>
). However, an opposing theory claiming the existence of mesenchymal precursor cells, so-called lymphangioblasts, as a second source for the lymphatic vasculature is getting more and more conceivable. In 1910, Huntington and McClure were the first to speculate on the existence of mesenchymal precursor cells for LECs (Huntington and McClure <xref ref-type="bibr" rid="CR13">1910</xref>
). Further evidence was found by analyzing the expression patterns of the LEC marker Prox1 in mesenchymal cells of <italic>Xenopus</italic>
, chicken and mouse embryos, revealing scattered cells of lymphatic character supposed to represent lymphangioblasts (Schneider et al. <xref ref-type="bibr" rid="CR32">1999</xref>
; Ny et al. <xref ref-type="bibr" rid="CR26">2005</xref>
; Buttler et al. <xref ref-type="bibr" rid="CR4">2006</xref>
). Evidence for lymphangioblasts in both the intra-embryonic and the extra-embryonic mesoderm of avian embryos was provided with quail-chick-transplantation experiments. Mesodermal cells of 2- to 3-day-old quail embryos are able to integrate into the host’s lymph sacs, lymph hearts and allantoic lymphatics when transplanted into corresponding regions of chick embryos (Papoutsi et al. <xref ref-type="bibr" rid="CR27">2001</xref>
; Wilting et al. <xref ref-type="bibr" rid="CR41">2000</xref>
, <xref ref-type="bibr" rid="CR43">2006</xref>
; Valasek et al. <xref ref-type="bibr" rid="CR40">2007</xref>
). As cells of the macrophage/monocyte lineage were found to contribute to lymphangiogenesis in inflammation, they were suggested to participate in the embryonic formation of the lymphatic system, too. Trans-differentiation of macrophages to LECs was suggested, but, although Lyve-1-positive macrophages were found capable of integrating into the wall of developing lymphatics, Prox1 expression was not detected. Hereby, trans-differentiation could be excluded (Gordon et al. <xref ref-type="bibr" rid="CR10">2010</xref>
).</p>
<p>In mammals, the formation of embryonic blood vessels in a bipartite way is generally accepted, meaning there is (1) de novo formation of vessels from angioblasts (vasculogenesis) and (2) growth of vessels from preexisting ones by sprouting, splitting and intercalation (angiogenesis; Risau <xref ref-type="bibr" rid="CR30">1997</xref>
). The existence of lymphangioblasts in mammals has been negated by a number of researchers in the field. However, recently elegant studies on mice have shown that a significant part of the dermal lymphatic vasculature is formed independently of venous sprouts. Using lineage-tracing experiments they could depict a non-venous origin of LECs in the lumbar skin and along the dorsal midline. In a process referred to as lymphvasculogenesis, these cells were found to assemble into clusters, subsequently generating vessels (Martinez-Corral et al. <xref ref-type="bibr" rid="CR24">2015</xref>
). In a second study the same group could show that parts of the mesenteric lymphatic vasculature are formed from progenitors of hemogenic endothelial origin, thus representing further evidence for the lymphatic system being of multiple origin (Stanczuk et al. <xref ref-type="bibr" rid="CR38">2015</xref>
). The hemogenic endothelium is the intra-embryonic source of blood cells. Together, the data show that murine lymphatics are derived from venous and non-venous origin, and the development of blood cells and LECs is closely connected. As shown in our study, the mechanisms of adult lymphangiogenesis recapitulate to a great extent those of the embryo. Lymphvasculogenic and lymphangiogenic mechanisms exist side by side. Thereby, adult lymphangioblasts like their embryonic counterparts may also be derived from hemogenic precursor cells.</p>
</sec>
</sec>
<sec sec-type="supplementary-material"><title>Electronic supplementary material</title>
<sec id="Sec13"><p>Below is the link to the electronic supplementary material.
<supplementary-material content-type="local-data" id="MOESM1"><media xlink:href="418_2015_1399_MOESM1_ESM.mov"><label>Suppl. Movie 1</label>
<caption><p>Movie of the specimen shown in Fig. 5. Note that numerous CD45<sup>+</sup>
cells (red) are found in the wall of the podoplanin<sup>+</sup>
(green) lymphatic vessel (MOV 8732 kb)</p>
</caption>
</media>
</supplementary-material>
</p>
</sec>
</sec>
</body>
<back><ack><p>We thank Mrs. B. Pawletta and Mrs. I. Hollatz for their expert technical assistance in progenitor cell culture, and Mr. B. Manshausen for his valuable assistance in the preparation of immunohistological specimens.</p>
</ack>
<notes notes-type="conflict-interest"><title>Compliance with ethical standards</title>
<sec id="FPar1"><title>Conflict of interest</title>
<p>The authors declare no conflicts of interest.</p>
</sec>
</notes>
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