A single-cell atlas of normal and KRASG12D-malformed lymphatic vessels
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PROVIDER: PRJNA1139099 | ENA |
REPOSITORIES: ENA
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Project description:Somatic activating mutations in KRAS can cause complex lymphatic anomalies (CLAs). However, the specific cellular and molecular processes that drive KRAS-mediated CLAs have yet to be fully elucidated. Here, we use single-cell RNA sequencing to construct an atlas of normal and KrasG12D-malformed lymphatic vessels. We show that adult wild-type mice have six subtypes of lymphatic endothelial cells (LECs) in their lungs (Ptx3, capillary, collecting, valve, mixed, and proliferating). To determine when the LEC subtypes are specified during development, we integrated our data with data from four stages of development. We show that proliferating and Ptx3 LECs are prevalent during early lymphatic development and that collecting and valve LECs emerge later in development. Additionally, we demonstrate that the proportion of Ptx3 LECs decreases as the lymphatic network matures but remains high in KrasG12D mice. We also show that KrasG12D mice have fewer collecting and valve LECs than wild-type mice. Last, we demonstrate that immature lymphatic vessels in young mice are more sensitive to the pathologic effects of KrasG12D than mature lymphatic vessels in older mice. Together, our results expand the current model for the development of the lymphatic system and suggest that KRAS mutations impair the maturation of lymphatic vessels.
2025-01-23 | GSE272843 | GEO
Project description:The muscle cells within the wall of collecting lymphatic vessels exhibit tonic and autonomous phasic contractions, which drive active lymph transport to maintain tissue-fluid homeostasis and support immune surveillance. Damage to the lymphatic muscle cells (LMC) disrupts lymphatic function and is related to various diseases. Despite their importance, knowledge of the transcriptional signatures in LMC and how they relate to lymphatic function in normal and diseases contexts is largely missing. In this study, we have generated to date the most comprehensive transcriptional single-cell atlas—including LMC—of collecting lymphatic vessels in mouse dermis at various ages.
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Project description:Single-cell Transcriptional Atlas of Murine Collecting Lymphatic Vessels
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Project description:Complex lymphatic anomalies (CLAs) are sporadically occurring diseases caused by the maldevelopment of lymphatic vessels. We and others recently reported that somatic activating mutations in KRAS can cause CLAs. However, the mechanisms by which activating KRAS mutations cause CLAs are poorly understood. Here we show that KRASG12D expression in lymphatic endothelial cells (LECs) during embryonic development impairs the formation of lymphovenous valves and causes the enlargement of lymphatic vessels. We demonstrate that KRASG12D expression in primary human LECs induces cell spindling, proliferation, and migration. It also increases AKT and ERK1/2 phosphorylation and decreases the expression of genes that regulate lymphatic vessel maturation. We show that MEK1/2 inhibition with the FDA-approved drug trametinib suppresses KRASG12D-induced morphological changes, proliferation, and migration. Trametinib also decreases ERK1/2 phosphorylation and increases the expression of genes that regulate the maturation of lymphatic vessels. We also show that trametinib and Cre-mediated expression of a dominant-negative form of MEK1 (Map2k1K97M) suppresses KRASG12D-induced lymphatic vessel hyperplasia in embryos. Last, we demonstrate that conditional knockout of wild-type Kras in LECs does not affect the formation or function of lymphatic vessels. Together, our data indicate that KRAS/MAPK signaling must be tightly regulated during embryonic development for the proper development of lymphatic vessels and further support the testing of MEK1/2 inhibitors for treating CLAs.
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Project description:Lymphogenous metastasis is an important event in the progression of many human cancers, and is associated with expression of vascular endothelial growth factor-D (VEGF-D). Changes to the lymphatic vasculature can occur during metastasis, and may aid metastatic spread. We investigated the effect of tumour derived VEGFD on the endothelium of the collecting lymphatic vessels draining primary tumors. We used microarrays to detail the changes in gene expression in the collecting lymphatic endothelium of mice with 293EBNA xenografts compared to 293EBNA xenografts overexpressing VEGFD.
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Project description:The lineage and developmental trajectory of a cell are key determinant s of cellular identity. In the vascular system, endothelial cells (ECs) of blood and lymphatic vessels (LVs) differentiate and diversify to cater the different physiological demands of each organ . While LVs are known to originate from multiple origins , lymphatic ECs (LECs) themselves are not known to generate other cell - types . Here, we u s e recurrent imaging and lineage - tracing of ECs in zebrafish anal fins (AF) from early development through adulthood , to uncover an unexpected mechanism of specialized blood vessel formation through transdifferentiation of LECs . Moreover, we demonstrate distinct functional implications for deriving AF vessels from either LECs or blood ECs, uncovering a link between cell ontogeny and functionality. We further use scRNA - seq to characterize the different cellular populations and transition states involved in the transdifferentiation process . Finally, we show that akin to its normal development, the vasculature is re - derived from lymphatics during AF regeneration, demonstr ating that LECs in adult fish retain both potency and plasticity for generating blood ECs . Overall, our work highlights a new innate mechanism of blood vess el formation through LEC trans differentiation, and provides in vivo evidence for a link between cell ontogeny and functionality in ECs
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Project description:Real-time quantitative PCR analysis of human collecting lymphatic vessels
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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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