Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation
Petkova, Milena (Uppsala University, Sweden)
Kraft, Marle (Uppsala University, Sweden)
Stritt, Simon (Uppsala University, Sweden)
Martinez-Corral, Ines (Uppsala University, Sweden)
Ortsäter, Henrik (Uppsala University, Sweden)
Vanlandewijck, Michael (Uppsala University, Sweden)
Jakic, Bojana (Uppsala University, Sweden)
Baselga Torres, Eulàlia (Hospital Sant Joan de Déu (Manresa))
Castillo, Sandra D. (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Graupera, Mariona (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Betsholtz, Christer (Uppsala University, Sweden)
Mäkinen, Taija (Uppsala University, Sweden)

Date:	2023
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 prolymphangiogenic macrophages to promote progressive lymphatic overgrowth. Mouse model of Pik3ca-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 Pik3ca mice. Expression of pro-inflammatory genes, including monocyte/ macrophage chemokine Ccl2, inPik3ca-iLECs was associated with recruitment of VEGF-C-producing macrophages. Macrophage depletion, CCL2 blockade, or anti-inflammatory COX-2 inhibition limited Pik3ca-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.
Grants:	European Commission. Horizon 2020 646849 European Commission. Horizon 2020 814316 "la Caixa" Foundation HR18-00120 European Commission. Horizon 2020 749731
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	The journal of experimental medicine, Vol. 220 Núm. 4 (april 2023) , ISSN 1540-9538

DOI: 10.1084/jem.20220741
PMID: 36688917

29 p, 10.2 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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Articles > Published articles