Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation

Area of Science:

• Vascular biology
• Immunology
• Cell biology

Background:

• PIK3CA mutations cause vascular malformations, but disease mechanisms remain unclear.
• Understanding vessel type-specific pathogenesis is crucial for developing effective therapies.

Purpose of the Study:

• To investigate the role of PIK3CA mutations in lymphatic malformation pathogenesis.
• To identify specific cell types and interactions driving lymphatic overgrowth.

Main Methods:

• Utilized a mouse model with Pik3caH1047R mutation.
• Performed single-cell transcriptomics to identify cell populations.
• Analyzed gene expression, including chemokine Ccl2.
• Investigated the effect of macrophage depletion, CCL2 blockade, and COX-2 inhibition.

Main Results:

• Identified a novel subtype of Ptx3-positive immune-interacting lymphatic endothelial cells (iLECs).
• Pik3caH1047R mutations induced proliferation in both venous and lymphatic endothelial cells, sustained in lymphatic endothelial cells.
• iLECs in mutant mice overexpressed pro-inflammatory genes, including Ccl2, recruiting VEGF-C-producing macrophages.
• Targeting macrophages, CCL2, or COX-2 inhibited lymphangiogenesis.

Conclusions:

• PIK3CA-driven lymphatic malformations involve crosstalk between iLECs and macrophages.
• Targeting this iLEC-macrophage interaction offers a potential therapeutic strategy.
• Peripheral lymphatic vessels actively participate in orchestrating inflammatory processes.