Transcriptional profiles of venous and lymphatic endothelial cells from tie1 mutant zebrafish
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1003386 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25567703.fastq.gz | Fastqsanger.gz | |||
| SRR25567704.fastq.gz | Fastqsanger.gz | |||
| SRR25567705.fastq.gz | Fastqsanger.gz | |||
| SRR25567706.fastq.gz | Fastqsanger.gz | |||
| SRR25567707.fastq.gz | Fastqsanger.gz |
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Project description:To investigate what kind of gene expression is regulated downstream of Tie1 signaling, we performed RNA-seq analyses on venous and lymphatic endothelial cells (ECs) between homozygous tie1 mutant embryos and their wild-type and heterozygous siblings during secondary sprouting, respectively. Our analyses indicate that Tie1 signaling controls a series of gene expression involved in lymphatic development including EC migration, proliferation, and differentiation.
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Project description: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.
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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.
2015-05-21 | E-GEOD-65751 | biostudies-arrayexpress
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.
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2016-07-20 | E-GEOD-84551 | biostudies-arrayexpress
Project description:Formation and maturation of a functional blood vascular system is required for the development and maintenance of all tissues in the body. During the process of blood vessel development, primordial endothelial cells are formed and become specified toward arterial or venous fates to generate a circulatory network that provides nutrients and oxygen to, and removes metabolic waste from, all tissues. Specification of arterial and venous endothelial cells occurs in conjunction with suppression of endothelial cell cycle progression, and endothelial cell hyperproliferation is associated with potentially lethal arterial-venous malformations. However, the mechanistic role that cell cycle state plays in arterial-venous specification is unknown. Herein, studying vascular development in Cdh5-CreERT2;R26FUCCI2aR reporter mice, we find that venous and arterial endothelial cells exhibit a propensity for different cell cycle states during development and in adulthood. That is, venous endothelial cells are predominantly FUCCI-Negative, while arterial endothelial cells are enriched for the FUCCI-Red reporter. Single cell RNA sequencing analysis of developing retinal endothelial cells reveals that venous endothelial cells are enriched for the FUCCI-Negative state and BMP signaling, while arterial endothelial cells are enriched for the FUCCI-Red state and TGF-b signaling. Further transcriptional analyses and live imaging of cultured endothelial cells expressing the FUCCI reporter show that reporter-negative corresponds to an early G1 state and reporter-red corresponds to late G1 state. We find the early G1 state is essential for BMP4-induced venous gene expression, whereas late G1 state is essential for TGF-b1-induced arterial gene expression. In a mouse model of endothelial cell hyperproliferation and disrupted arterial-venous specification, pharmacological inhibition of endothelial cell cycle prevents the vascular defects. Collectively, our results show that endothelial cell cycle control plays a key role in arterial-venous network formation, and distinct cell cycle states provide distinct windows of opportunity for the molecular induction of arterial vs. venous specification.
2022-08-22 | GSE211658 | GEO
Project description:GeneChip® Mouse Gene 2.0 ST Array for C57BL/6 mouse skin dermal primary lymphatic endothelial cells (Ms LEC) and mouse lymphatic endothelial cell line SVEC4-10 GeneChip® Human Gene 2.0 ST Array for human primary lymphatic endothelial cells (Hu LEC) Total RNA from lymphatic cell line SVEC4-10 were used for GeneChip® Mouse Gene 2.0 ST Array.
2016-07-20 | GSE84551 | GEO
Project description:DHX15 is an ATP-dependent RNA helicase involved in pre-mRNA splicing. We have recently reported that DHX15 is a downstream substrate for Akt1, which plays a significant role in vascular biology. Therefore, we aimed to explore the regulatory function of DHX15 over the vasculature, and the endothelial cell biology in different contexts: development, metabolism, ischemia and tumor growth. Methods: Deficient DHX15 mice and zebrafish were generated using transcription activator-like effector nuclease (TALEN) and Crispr/cas9 gene edition. Lymphatic functionality was evaluated by lymphangiography and magnetic resonance imaging. Mouse-induced tumor and metastasis model were generated by injection of syngeneic LLC1 tumor cells. DHX15 gene silencing in mouse liver endothelial cells (LEC) was performed by the lentiviral transduction of shRNA (Dharmacon). The changes in the transcriptome and the proteome resulting from the shRNA transduction were investigated by RNAseq and mass spectrometry, respectively. Results: Homozygous DHX15 gene deficiency was lethal in mouse and zebrafish embryos. DHX15-/- zebrafish also showed an undeveloped parachordal line, which leads to the formation of lymphatic structures in the trunk during the development. DHX15+/- mice and zebrafish were viable, although DHX15+/- gene deficiency triggered lower vascular network density and impaired lymphatic function postnatally in mice. Whole transcriptome and proteome analysis of DHX15 silenced LEC revealed differential expression of enzymes involved in the glycolysis and the gluconeogenesis pathways. The functional validation of these results demonstrated an uncoupling of the glycolysis with the oxidation of pyruvate into the mitochondria and lower activity of the Complex I in the mitochondrial membrane, resulting in lower cellular ATP production. Noteworthy, heterozygous DHX15 deficiency partially inhibited primary tumor growth and reduced lung metastasis after injection of syngeneic LLC1 tumor cells, compared to wild-type mice
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