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

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Abstract
Oncogenic mutations in PIK3CA, encoding p110α-PI3K, are a common cause of venous and lymphatic malformations. Vessel type–specific disease pathogenesis is poorly understood, hampering development of efficient therapies. Here, we reveal a new immune-interacting subtype of Ptx3-positive dermal lymphatic capillary endothelial cells (iLECs) that recruit pro-lymphangiogenic macrophages to promote progressive lymphatic overgrowth. Mouse model of Pik3caH1047R-driven vascular malformations showed that proliferation was induced in both venous and lymphatic ECs but sustained selectively in LECs of advanced lesions. Single-cell transcriptomics identified the iLEC population, residing at lymphatic capillary terminals of normal vasculature, that was expanded in Pik3caH1047R mice. Expression of pro-inflammatory genes, including monocyte/macrophage chemokine Ccl2, in Pik3caH1047R-iLECs was associated with recruitment of VEGF-C–producing macrophages. Macrophage depletion, CCL2 blockade, or anti-inflammatory COX-2 inhibition limited Pik3caH1047R-driven lymphangiogenesis. Thus, targeting the paracrine crosstalk involving iLECs and macrophages provides a new therapeutic opportunity for lymphatic malformations. Identification of iLECs further indicates that peripheral lymphatic vessels not only respond to but also actively orchestrate inflammatory processes.
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Funding Information
  • Swedish Research Council (2018-05973, 2020-0269)
  • Knut and Alice Wallenberg Foundation (2018.0218, 2020.0057)
  • Göran Gustafsson Stiftelser
  • Swedish Cancer Society (19 0220 Pj, 19 0219 Us)
  • European Research Council (ERC-2014-CoG-646849)
  • H2020 Marie Skłodowska-Curie Actions (814316, 749731)
  • La Caixa Foundation (HR18-00120)
  • la Caixa Banking Foundation (LCF/BQ/PR20/11770002)
  • Deutsche Forschungsgemeinschaft (STR 1538/1-1)
  • European Molecular Biology Organization (ALTF 86-2017)

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