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Immune-interacting ...
Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation
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- Petkova, Milena (author)
- Uppsala universitet,Vaskulärbiologi
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- Kraft, Marle (author)
- Uppsala universitet,Vaskulärbiologi
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- Stritt, Simon (author)
- Uppsala universitet,Vaskulärbiologi
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- Martinez-Corral, Ines (author)
- Uppsala universitet,Vaskulärbiologi
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- Ortsäter, Henrik (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Vanlandewijck, Michael, 1982- (author)
- Uppsala universitet,Karolinska Institutet,Vaskulärbiologi,Karolinska Inst, Dept Med Huddinge, Campus Flemingsberg, Neo, Sweden.
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- Jakic, Bojana (author)
- Uppsala universitet,Vaskulärbiologi
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- Baselga, E (author)
- Hosp St Joan Deu, Dept Dermatol, Barcelona, Spain.
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- Castillo, SD (author)
- Josep Carreras Leukaemia Res Inst IJC, Endothelial Pathobiol & Microenvironm Grp, Barcelona, Spain.
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- Graupera, M (author)
- Josep Carreras Leukaemia Res Inst IJC, Endothelial Pathobiol & Microenvironm Grp, Barcelona, Spain.;Inst Salud Carlos III, CIBERONC, Madrid, Spain.;ICREA, Barcelona, Spain.
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- Betsholtz, Christer (author)
- Uppsala universitet,Vaskulärbiologi,Karolinska Inst, Dept Med Huddinge, Campus Flemingsberg, Neo, Sweden.
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- Mäkinen, Taija (author)
- Uppsala universitet,Vaskulärbiologi
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(creator_code:org_t)
- 2023-01-23
- 2023
- English.
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In: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 220:4
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Petkova, Milena
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Kraft, Marle
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Stritt, Simon
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Martinez-Corral, ...
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Ortsäter, Henrik
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Vanlandewijck, M ...
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show more...
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Jakic, Bojana
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Baselga, E
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Castillo, SD
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Graupera, M
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Betsholtz, Chris ...
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Mäkinen, Taija
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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The Journal of e ...
- By the university
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Karolinska Institutet
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Uppsala University