Oxidized Low-Density Lipoprotein drives dysfunction of the liver lymphatic system
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE157054 | GEO | 2021/08/28
REPOSITORIES: GEO
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Project description:Background and aimsAs the incidence of nonalcoholic steatohepatitis (NASH) continues to rise, understanding how normal liver functions are affected during disease is required before developing novel therapeutics which could reduce morbidity and mortality. However, very little is understood about how the transport of proteins and cells from the liver by the lymphatic vasculature is affected by inflammatory mediators or during disease.MethodsTo answer these questions, we utilized a well-validated mouse model of NASH and exposure to highly oxidized low density lipoprotein (oxLDL). In addition to single cell sequencing, multiplexed immunofluorescence and metabolomic analysis of liver lymphatic endothelial cells (LEC)s we evaluated lymphatic permeability and transport both in vitro and in vivo.ResultsConfirming similarities between human and mouse liver lymphatic vasculature in NASH, we found that the lymphatic vasculature expands as disease progresses and results in the downregulation of genes important to lymphatic identity and function. We also demonstrate, in mice with NASH, that fluorescein isothiocyanate (FITC) dextran does not accumulate in the liver draining lymph node upon intrahepatic injection, a defect that was rescued with therapeutic administration of the lymphatic growth factor, recombinant vascular endothelial growth factor C (rVEGFC). Similarly, exposure to oxLDL reduced the amount of FITC-dextran in the portal draining lymph node and through an LEC monolayer. We provide evidence that the mechanism by which oxLDL impacts lymphatic permeability is via a reduction in Prox1 expression which decreases lymphatic specific gene expression, impedes LEC metabolism and reorganizes the highly permeable lymphatic cell-cell junctions which are a defining feature of lymphatic capillaries.ConclusionsWe identify oxLDL as a major contributor to decreased lymphatic permeability in the liver, a change which is consistent with decreased protein homeostasis and increased inflammation during chronic liver disease.
| S-EPMC7803659 | biostudies-literature
Project description:Oxidized Low-Density Lipoprotein drives dysfunction of the liver lymphatic system
| PRJNA659994 | ENA
Project description:To observe the global changes in the lymphatic endothelial cells upon exposure to filarial antigens or parasites, LECs were stimulated for 24, 48, and 72hrs and the expression profiles were carried out. Human filarial parasites Brugia malayi and Wuchereria bancrofti habitat the lymphatics and cause lymphatic dilatation and lymphedema. In order to evaluate the effect of various stage specific effects on the lymphatic endothelial cells (LEC) and understand how they modulate the lymphatic dysfunction, LECs were stimulated in antigens derived from the Brugia malayi. These are preliminary time course data towards understanding how the filarial antigens induce lymphangiogenesis.
2010-05-19 | E-GEOD-15454 | biostudies-arrayexpress
Project description:Chemokines and adhesion molecules upregulated in lymphatic endothelial cells (LECs) during tissue inflammation are believed to enhance dendritic cell (DC) migration to draining lymph nodes (dLNs), but the in vivo control of this process is not well understood. By performing transcriptional profiling of LECs isolated from murine skin, we found that inflammation induced by a contact hypersensitivity (CHS) response upregulated the adhesion molecules ICAM-1 and VCAM-1 and inflammatory chemokines in LECs. Furthermore, lymphatic lineage markers like Prox-1, VEGFR3 and LYVE-1 were significantly downregulated during CHS. By contrast, skin inflammation induced by Complete FreundM-bM-^@M-^Ys adjuvant (CFA) induced a different pattern of chemokine and lymphatic marker gene expression and almost no ICAM-1 up-regulation in LECs. In FITC painting experiments, DC migration to dLNs was more strongly increased in CFA- as compared to CHS-induced inflammation. Interestingly, DC migration did not correlate with the induction of CCL21 and ICAM-1 in LECs. However, the requirement for CCR7 signaling became further pronounced during inflammation, whereas CCR7-independent signals only had a minor role in enhancing DC migration. Collectively, these findings indicate that inflammation-induced DC migration is stimulus-dependent and only moderately enhanced by LEC-induced genes other than CCL21. Mouse ear skin single-cell suspensions were prepared by a fast protocol that minimizes the RNA degradation. Fluorescence-activated cell sorting (FACS) was used to sort lymphatic endothelial cells (LEC) from CHS inflammed and control skin. 4 pairs (each with one control and one CHS inflammed sample, sorted and extracted on the same day) of LECs were chosen based on the quality of extracted and amplified material. This gave 8 samples to analyze (4 biological replicates in each condition). Each sample was sorted from 3 mice.
2011-05-19 | E-GEOD-26229 | biostudies-arrayexpress
Project description:Background: The inflammatory response to acute kidney injury (AKI) likely dictates future renal health. Lymphatic vessels are responsible for maintaining tissue homeostasis through transport and immunomodulatory roles. Due to the relative sparsity of lymphatic endothelial cells (LECs) in the kidney, past sequencing efforts have not characterized these cells and their response to AKI. Methods: Here we characterized murine renal LEC subpopulations by single-cell RNA sequencing and investigated their changes in cisplatin AKI 72 hours post injury. Data was processed using the Seurat package. We validated our findings by qPCR in LECs isolated from both cisplatin-injured and ischemia reperfusion injury, by immunofluorescence, and confirmation in in vitro human LECs. Results: We have identified renal LECs and their lymphatic vascular roles that have yet to be characterized in previous studies. We report unique gene changes mapped across control and cisplatin injured conditions. Following AKI, renal LECs alter genes involved in endothelial cell apoptosis and vasculogenic processes as well as immunoregulatory signaling and metabolism. Differences between injury models were also identified with renal LECs further demonstrating changed gene expression between cisplatin and ischemia reperfusion injury models, indicating the renal LEC response is both specific to where they lie in the lymphatic vasculature and the renal injury type. Conclusions: In this study, we uncover lymphatic vessel structural features of captured populations and injury-induced genetic changes. We further determine LEC gene expression is altered between injury models. How LECs respond to AKI may therefore be key in regulating future kidney disease progression.
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Project description:Kaposi sarcoma is the most common cancer in AIDS patients and is typified by red skin lesions. The disease is caused by the KSHV virus (HHV8) and is recognizable by its distinctive red skin lesions. The lesions are KSHV infected spindle cells, most commonly the lymphatic endothelial and blood vessel endothelial cells (LEC and BEC), plus surrounding stroma. The effects of KSHV infection of LECs were assayed using Affymetrix hgu133plus2 chips at 6 and 72 hours post infection. There were n=4 each of lymphatic endothelial cells (LEC) following 6 hours of culture, LEC following 6 hours post KSHV infection, LEC following 72 hours of culture, and LEC following 72 hours post KSHV infection.
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Project description:Extracorporeal shockwave treatment was shown to improve orthopaedic diseases, wound healing and to stimulate lymphangiogenesis in vivo. The aim of this study was to investigate in vitro shockwave treatment (IVSWT) effects on lymphatic endothelial cell (LEC) behavior and lymphangiogenesis. We analyzed migration, proliferation, vascular tube forming capability and marker expression changes of LECs after IVSWT compared with HUVECs. Finally, transcriptome- and miRNA analyses were conducted to gain deeper insight into the IVSWT-induced molecular mechanisms in LECs. The results indicate that IVSWT-mediated proliferation changes of LECs are highly energy flux density-dependent and LEC 2D as well as 3D migration was enhanced through IVSWT. IVSWT suppressed HUVEC 3D migration but enhanced vasculogenesis. Furthermore, we identified podoplaninhigh and podoplaninlow cell subpopulations, whose ratios changed upon IVSWT treatment. Transcriptome- and miRNA analyses on these populations showed differences in genes specific for signaling and vascular tissue. Our findings help to understand the cellular and molecular mechanisms underlying shockwave-induced lymphangiogenesis in vivo. Immortalized lymphatic endothelial cells were flow-sorted in two populations according to their differences in FSC and SSC values and subjected to Affymetrix analysis in triplicate samples
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Project description:Tissue lymphatic vessels network plays critical roles in immune surveillance and tissue homeostasis in response to pathogen invasion, but how lymphatic system per se is remolded during infection is less understood. Here, we observed that influenza infection induces a significant increase of lymphatic vessel numbers in the lung, accompanied with extensive proliferation of lymphatic endothelial cells (LECs). Single-cell RNA sequencing illustrated the heterogeneity of LECs, identifying a novel PD-L1+ subpopulation that is present during viral infection but not at steady state. Specific deletion of Pd-l1 in LECs elevated the expansion of lymphatic vessel numbers during viral infection. Together these findings elucidate a dramatic expansion of lung lymphatic network in response to viral infection, and reveal a PD-L1+ LEC subpopulation that potentially modulates lymphatic vessel remolding.
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Project description:Herein, we report viral interferon regulatory factor 3 (vIRF3) as a pro-angiogenic factor together with HDAC5 that coordinates with LEC transcriptome, thus resulting in hyper-sprouting formation and ultimately leading to abnormal lymphangiogenesis. Overexpression of vIRF3 in LECs but not blood endothelial cells (BECs) exhibited a unique KSHV-associated angiogenic effect, evidenced by elongated spindle shape, sprouting, and tube formation. Furthermore, using vIRF3 knockout recombinant KSHV, we confirmed that vIRF3 is a critical factor of KSHV-mediated lymphangiogenesis in primary LECs.
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Project description:Extracorporeal shockwave treatment was shown to improve orthopaedic diseases, wound healing and to stimulate lymphangiogenesis in vivo. The aim of this study was to investigate in vitro shockwave treatment (IVSWT) effects on lymphatic endothelial cell (LEC) behavior and lymphangiogenesis. We analyzed migration, proliferation, vascular tube forming capability and marker expression changes of LECs after IVSWT compared with HUVECs. Finally, transcriptome- and miRNA analyses were conducted to gain deeper insight into the IVSWT-induced molecular mechanisms in LECs. The results indicate that IVSWT-mediated proliferation changes of LECs are highly energy flux density-dependent and LEC 2D as well as 3D migration was enhanced through IVSWT. IVSWT suppressed HUVEC 3D migration but enhanced vasculogenesis. Furthermore, we identified podoplaninhigh and podoplaninlow cell subpopulations, whose ratios changed upon IVSWT treatment. Transcriptome- and miRNA analyses on these populations showed differences in genes specific for signaling and vascular tissue. Our findings help to understand the cellular and molecular mechanisms underlying shockwave-induced lymphangiogenesis in vivo.
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