Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation
| Autor: | Milena Petkova, Marle Kraft, Simon Stritt, Ines Martinez-Corral, Henrik Ortsäter, Michael Vanlandewijck, Bojana Jakic, Eulàlia Baselga, Sandra D. Castillo, Mariona Graupera, Christer Betsholtz, Taija Mäkinen |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Journal of Experimental Medicine. 220 |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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