Journal
HISTOCHEMISTRY AND CELL BIOLOGY
Volume 135, Issue 6, Pages 603-613Publisher
SPRINGER
DOI: 10.1007/s00418-011-0819-x
Keywords
Foxc2 haploinsufficiency; Lymph node; Immunohistochemistry; Mouse
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Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan [21590217]
- Grants-in-Aid for Scientific Research [21590217] Funding Source: KAKEN
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Dysmorphogenesis of lymph nodes displayed in a fork head transcription factor Foxc2 haploinsufficient mice-a model for lymphedema-distichiasis syndrome-was studied by immunohistochemistry and electron microscopy. The Foxc2 heterozygous mice manifested lymph node hyperplasia composed of conspicuous proliferation of endothelial cells forming the lymphatic sinus and alpha-smooth muscle actin (SMA)-immunopositive fibroblast-like cells in the lymphatic pulp, particularly around the sinus. The hyperplastic sinus endothelial cells and the SMA-positive cells demonstrated distinct immunolocalization of platelet-derived growth factor (PDGF)-B, a crucial chemoattractant for vascular mural cell recruitment, and its receptor, PDGFR-beta, respectively. The observations suggest that the sinus endothelial cells elicit abnormal recruitment of the fibroblast-like cells as a type of vascular mural cells via PDGF-B/PDGFR-beta signaling in lymph nodes of the Foxc2 heterozygotes. Furthermore, in Foxc2 heterozygous lymph nodes, recruited SMA-positive cells displayed an intense immunoreaction for vascular endothelial growth factor (VEGF)-C, a highly specific lymphangiogenic factor, and its receptor, VEGFR-3, was preferentially distributed in the lymphatic sinus endothelial cells. These findings suggest that an interactive cycle between lymphatic sinus endothelial cells and the fibroblast-like cells, which involves PDGF-B/PDGFR-beta and VEGF-C/VEGFR-3 signaling, is essential for aberrant hyperplasia of the lymphatic sinus and the fibroblast-like cells in Foxc2 haploinsufficiency.
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