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

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 between 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE201916 | GEO | 2023/01/16

REPOSITORIES: GEO

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Project description:How cells acquire their fate is a fundamental question in both developmental and regenerative biology. Multipotent progenitors undergo gradual cell fate restriction in response to temporal and positional cues from the microenvironment, the nature of which is far from being clear. In the case of the lymphatic system, venous endothelial cells are thought to give rise to lymphatic vessels, through a process of trans-differentiation. Upon expression of a set of transcription factors, venous cells acquire a lymphatic fate, and bud out to generate the lymphatic vasculature. In this work we challenge this view and show that while lymphatic endothelial cells (LECs) do arise in the Cardinal Vein (CV), they do so from a previously uncharacterized pool of multipotent angioblasts. Using lymphatic-specific transgenic zebrafish, in combination with endothelial photoconvertible reporters, and long-term live imaging, we demonstrate that these multipotent angioblasts can generate not only lymphatic, but also arterious, and venous fates. We further reveal that the underlying endoderm serves as a source of Wnt5b, which acts as a lymphatic inductive signal, promoting the angioblast-to-lymphatic transition. Moreover, Wnt5b induced lymphatic specification in human embryonic stem cells- derived vascular progenitors, suggesting that this process is evolutionary conserved. Our results uncover a novel mechanism of lymphatic vessel formation, whereby multipotent angioblasts and not venous endothelial cells give rise to the lymphatic endothelium, and provide the first characterization of their inductive niche. More broadly, our findings highlight the CV as a plastic and heterogeneous structure containing different cell populations, analogous to the hematopoietic niche in the aortic floor. Following Kaede photoconversion of dorsal or ventral halves of the PCV in Tg(fli1:gal4;uasKaede) embryos at 24 hpf, 6 embryos per group were used for FACS isolation of Kaede photconverted (red) ECs.

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

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