Transcription factor FOXP2 is a flow‐induced regulator of collecting lymphatic vessels

Hernández-Vásquez, Magda Nohemí; Ulvmar, Maria H.; González-Loyola, Alejandra; Kritikos, Ioannis; Sun, Ying; He, Liqun; Halin, Cornelia; Petrova, Tatiana V.; Mäkinen, Taija

doi:10.15252/embj.2020107192

Cited by 16 publications

(9 citation statements)

References 66 publications

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“…In contrast, all these genes have been reported to be consistently upregulated in murine dermal collecting LECs. 13 Correspondingly, distinct gene enrichment analyses revealed that although Icam1 hi LECs were mainly associated with leukocyte migration, Foxp2 hi LECs were mainly related to the regulation of apoptosis or oxidative stress pathways (Figure 3D). Meanwhile, a Spearman correlation analysis with LEC subsets isolated from normal aortas ( Lyve1 hi / Ccl21a hi initial LECs and Lyve1 low / Ccl21a low collecting LECs; Figure S2E and S2F) showed lesser comparability within the collecting LECs of grafted aortas, reflecting their greater heterogeneity after transplantation (Figure 3E).…”

Section: Resultsmentioning

confidence: 90%

The Effect of Lymphangiogenesis in Transplant Arteriosclerosis

et al. 2023

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BACKGROUND: Transplant arteriosclerosis is a major complication in long-term survivors of heart transplantation. Increased lymph flow from donor heart to host lymph nodes has been reported to play a role in transplant arteriosclerosis, but how lymphangiogenesis affects this process is unknown. METHODS: Vascular allografts were transplanted among various combinations of mice, including wild-type, Lyve1 -CreER T2 ;R26-tdTomato, CAG-Cre-tdTomato, severe combined immune deficiency, Ccr2 KO , Foxn1 KO , and lghm / lghd KO mice. Whole-mount staining and 3-dimensional reconstruction identified lymphatic vessels within the grafted arteries. Lineage tracing strategies delineated the cellular origin of lymphatic endothelial cells. Adeno-associated viral vectors and a selective inhibitor were used to regulate lymphangiogenesis. RESULTS: Lymphangiogenesis within allograft vessels began at the anastomotic sites and extended from preexisting lymphatic vessels in the host. Tertiary lymphatic organs were identified in transplanted arteries at the anastomotic site and lymphatic vessels expressing CCL21 (chemokine [C-C motif] ligand 21) were associated with these immune structures. Fibroblasts in the vascular allografts released VEGF-C (vascular endothelial growth factor C), which stimulated lymphangiogenesis into the grafts. Inhibition of VEGF-C signaling inhibited lymphangiogenesis, neointima formation, and adventitial fibrosis of vascular allografts. These studies identified VEGF-C released from fibroblasts as a signal stimulating lymphangiogenesis extending from the host into the vascular allografts. CONCLUSIONS: Formation of lymphatic vessels plays a key role in the immune response to vascular transplantation. The inhibition of lymphangiogenesis may be a novel approach to prevent transplant arteriosclerosis.

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Section: Resultsmentioning

confidence: 90%

The Effect of Lymphangiogenesis in Transplant Arteriosclerosis

et al. 2023

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“…5 C ). Based on the expression of known LEC subtype markers, the clusters were annotated as valve LECs ( Cldn11 + ; Takeda et al, 2019 ), collecting vessel LECs ( Foxp2 + ; Hernández Vásquez et al, 2021 ), and capillary LECs ( Lyve1 high ; Fig. 5 C ).…”

Section: Resultsmentioning

confidence: 99%

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

Petkova

Kraft

Stritt

et al. 2023

Journal of Experimental Medicine

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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.

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“…Each cluster included an equal contribution of cells from the 3 control samples ( Figure 5D ). Based on the expression of known LEC subtype markers, the clusters were annotated as valve LECs ( Cldn11 + ) (30), collecting vessel LECs ( Foxp2 + ) (31), and capillary LECs ( Lyve1 high ) ( Figure 5, B-D ). Trajectory analysis based on gene expression data suggested phenotypic progression from collecting vessel to capillary LECs ( Figure 5, C-E ), which mirrors anatomical positioning of so called pre-collecting vessels that share molecular and functional features of the two vessel types (32).…”

Section: Resultsmentioning

confidence: 99%

Immunoregulatory subtype of dermal lymphatic endothelial cells at capillary terminals drives lymphatic malformations

Petkova

Kraft

Stritt

et al. 2022

Preprint

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Vascular malformations are congenital, chronically debilitating diseases. Somatic oncogenic mutations in PIK3CA, encoding p110α-PI3K, specifically cause venous and lymphatic malformations (LM), yet the basis of vessel type-restricted disease manifestation is unknown. Here we report endothelial subtype-specific responses to the common causative Pik3caH1047R mutation, and reveal a new immunoregulatory subtype of dermal lymphatic capillary endothelial cells (iLECs) as a driver of LM pathology. Mouse model of Pik3caH1047R-driven vascular malformations showed that cell proliferation was a common early response of venous and lymphatic ECs to oncogenic Pik3ca, but sustained selectively in LECs of advanced lesions. Lymphatic overgrowth was associated with increased pro-inflammatory cytokine levels and pro-lymphangiogenic myeloid cell infiltrate. Single-cell transcriptomics revealed a new LEC subtype at capillary terminals, characterized by the expression of immunoregulatory genes. Selective expansion and activation of iLECs in the Pik3caH1047R mice was evidenced by proliferation and upregulation of pro-inflammatory genes. Importantly, macrophage depletion or anti-inflammatory COX-2 inhibition limited Pik3caH1047R-driven lymphangiogenesis. This provides a therapeutic target for LM and suggests a paracrine crosstalk in which LEC-autonomous oncogenic Pik3ca signaling induces immune activation that in turn sustains pathological lymphangiogenesis. Identification of iLECs indicates that peripheral lymphatic vessels not only respond to inflammation but also actively orchestrate the immune response.

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Transcription factor FOXP2 is a flow‐induced regulator of collecting lymphatic vessels

Cited by 16 publications

References 66 publications

The Effect of Lymphangiogenesis in Transplant Arteriosclerosis

The Effect of Lymphangiogenesis in Transplant Arteriosclerosis

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

Immunoregulatory subtype of dermal lymphatic endothelial cells at capillary terminals drives lymphatic malformations

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