Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema
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PROVIDER: PRJEB66475 | ENA |
REPOSITORIES: ENA
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Project description:Secondary lymphedema (LD) corresponds to a severe lymphatic dysfunction leading to the accumulation of fluid and fibrotic adipose tissue in a limb. Here, we identified apelin (APLN) as a powerful molecule for regenerating lymphatic function in LD. We identified the loss of APLN expression in lymphedematous arm compared to normal arm in patients. The role of APLN in LD was confirmed in APLN-knockout mice, in which LD is increased and associated with fibrosis and dermal backflow. This was reversed by intradermal injection of APLN-lentivectors. Mechanistically, APLN stimulates lymphatic endothelial cell gene expression and induces the binding of E2F8 transcription factor to the promoter of CCBE1 that controls VEGF-C processing. In addition, APLN induces Akt and eNOS pathways to stimulate lymphatic collector pumping. Our results show that APLN represents a novel partner for VEGF-C to restore lymphatic function in both initial and collecting vessels. As LD appears after cancer treatment, we validated the APLN-VEGF-C combination using a novel class of non-integrative RNA-delivery LentiFlash® vector that will be evaluated for phase I/IIa clinical trial.
2023-10-20 | E-MTAB-13381 | biostudies-arrayexpress
Project description:Preclinical evaluation of Apelin mRNA delivery for the treatment of lymphedema
| PRJEB57752 | ENA
Project description:Prostate cancer is the most common cancer in men and is often associated with distant metastasis in its later stages. Lymphangiogenesis has been identified as a critical factor in cancer metastasis, and the adipokine apelin has been implicated in cancer progression and metastasis. However, researchers have yet to elucidate the mechanisms by which apelin regulates the key lymphangiogenic factor, Vascular Endothelial Growth Factor-C (VEGF-C), to promote distant metastasis in prostate cancer. This study identified a strong positive correlation between apelin levels and prostate cancer metastasis. Apelin stimulation was shown to upregulate VEGF-C expression, promoting the formation of new lymphatic vessels. Apelin treatment was also shown to downregulate miR-196a-5p expression via the proto-oncogene tyrosine kinase c-Src (c-Src) and Signal transducer and activator of transcription 3 (STAT3) signaling pathways, which regulates VEGF-C expression and lymphangiogenesis in prostate cancer cell lines. In an orthotopic mouse model, apelin inhibition prevented lymphangiogenesis and distant metastasis. These findings suggest that targeting apelin could be a promising therapeutic approach to preventing prostate cancer metastasis and lymphangiogenesis
2024-11-09 | GSE281393 | GEO
Project description:Secondary lymphedema (LD) corresponds to a severe lymphatic dysfunction leading to the accumulation of fluid and fibrotic adipose tissue in a limb. Here, we identified apelin (APLN) as a powerful molecule for regenerating lymphatic function in LD. We identified the loss of APLN expression in the lymphedematous arm compared to the normal arm in patients. The role of APLN in LD was confirmed in APLN knockout mice, in which LD is increased and associated with fibrosis and dermal backflow. This was reversed by intradermal injection of APLN-lentivectors. Mechanistically, APLN stimulates lymphatic endothelial cell gene expression and induces the binding of E2F8 transcription factor to the promoter of CCBE1 that controls VEGF-C processing. In addition, APLN induces Akt and eNOS pathways to stimulate lymphatic collector pumping. Our results show that APLN represents a novel partner for VEGF-C to restore lymphatic function in both initial and collecting vessels. As LD appears after cancer treatment, we validated the APLN-VEGF-C combination using a novel class of nonintegrative RNA delivery LentiFlash® vector that will be evaluated for phase I/IIa clinical trial.
| S-EPMC10898257 | biostudies-literature
Project description:We isolated adipose-derived mesenchymal stem cells (ASCs) from the lymphedema adipose tissue from liposuction specimens of 10 patients with malignancy-related extremity lymphedema, and we used adipose tissue from the normal upper abdomen of the same patients as control tissue. We compared the proliferation and adipogenic differentiation capacity between the two kinds of ASCs, and we explored the transcriptomic differences between them. We found that lymphedema-associated ASCs had more rapid proliferation and a higher adipogenic differentiation capacity. CDK1 inhibitors could return the abnormal biological characteristics of these cells to normal phenotype, suggesting that CDK1 is a key driver of proliferation and adipogenic differentiation in these cells, which might expound the accumulation of adipose tissue extensively observed in secondary lymphedema, indicating the CDK1 may be a potential target for lymphedema therapy. On the other hand, our finding showed that ASCs from lymphedema adipose tissues have higher immunosuppressive effect, and the inhibition of up-regulated cytokine CHI3L1 may be clinically beneficial. In summary, explore the underlying mechanisms of fat deposition in lymphedema may provide powerful strategies for the treatment of lymphedema.
2019-06-19 | GSE132936 | GEO
Project description:Secondary lymphedema (LD) corresponds to a severe lymphatic dysfunction leading to the accumulation of fluid and fibrotic adipose tissue in a limb. Here, we identified apelin (APLN) as a powerful molecule for regenerating lymphatic function in LD. We identified the loss of APLN expression in lymphedematous arm compared to normal arm in patients. The role of APLN in LD was confirmed in APLN-knockout mice, in which LD is increased and associated with fibrosis and dermal backflow. This was reversed by intradermal injection of APLN-lentivectors. Mechanistically, APLN stimulates lymphatic endothelial cell gene expression and induces the binding of E2F8 transcription factor to the promoter of CCBE1 that controls VEGF-C processing. In addition, APLN induces Akt and eNOS pathways to stimulate lymphatic collector pumping. Our results show that APLN represents a novel partner for VEGF-C to restore lymphatic function in both initial and collecting vessels. As LD appears after cancer treatment, we validated the APLN-VEGF-C combination using a novel class of non-integrative RNA-delivery LentiFlash® vector that will be evaluated for phase I/IIa clinical trial.
| S-SCDT-10_1038-S44321-023-00017-7 | biostudies-other
Project description:Angiogenesis-inhibitor (AI) drugs targeting vascular endothelial growth factor (VEGF) signalling to the endothelial cell (EC) are used to treat various cancers types. However, primary or secondary resistance to therapy is common. Clinical and pre-clinical studies suggest that other alternative pro-angiogenic factors are up-regulated after VEGF-pathway inhibition. Therefore, identification alternative pro-angiogenic pathway(s) is critical for the development of more effective anti-angiogenic therapy. Here we study the role of apelin as a pro-angiogenic G-protein coupled receptor (GPCR) ligand in tumor growth and angiogenesis. We applied single-cell RNA-sequencing to Mouse Lewis lung carcinoma (LLC1) or B16F10 mouse melanoma cell lines (1 X 106) implanted subcutaneously into the flanks of 12 weeks old Apln-/y or littermate control mice in combination with sunitinib or control (vehicle) treatment. We found apelin loss reduced angiogenic sprouting and tip cell marker gene expression in comparison to the sunitinib-alone treated mice and prevented EC tip cell differentiation.
2023-04-06 | E-MTAB-11663 | biostudies-arrayexpress
Project description:First, transcriptome analysis of purified CD31+ endothelial cells (ECs) from VEGF-treated sprouting embryoid bodies showed angiogenesis as the top affected category when Apelin is not present. In addition, loss of Apelin resulted in the modulation of pathways in ECs related to vasculogenesis, cell adhesion and response to hypoxia. Ingenuity Pathway Analysis (IPA) further identified VEGFR pathway as the main upstream regulator affected in endothelial cells, closely followed by the TGFβ1 and TNF pathways, all reduced in the absence of Apelin. The most inhibited genes from the VEGFR pathway in the absence of Apelin are angiogenesis-related genes. Second, transcriptome analysis of CD31+/CD105+ ECs sorted from Apelin wild-type and Apln-depleted tumors found a significant decrease in processes associated with endothelial cell proliferation and angiogenesis in ECs sorted out of Apelin-depleted tumors using IPA. Further, IPA predicted a decrease in the adhesion of granulocytes and upstream regulator analysis showed that proteins of the TGF-superfamily, Inhibin-βA and TGF-β1, as well as C/EBP-alpha, β-Catenin, ErbB2 and EGFR are predicted to be inhibited upstream regulators in ECs isolated from Apelin-depleted tumors.
2019-05-27 | GSE100293 | GEO
Project description:Mouse surgical model of acute lymphedema induction. We performed three sets of microarrays with three replicates each for a total of 9 arrays. Each array was run using pooled RNA from three animals. The three conditions were Normal tail skin (no intervention), Lymphedema tail skin(due to surgical lymphatic vessel blockage), and Surgical Sham control tail skin(surgical incision with no lymphatic vessel blockage). 15ug of test and reference (e17.5 mouse whole embryo) RNA was used for labeling. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set
2006-03-04 | GSE4333 | GEO
Project description:Transcriptome Analysis and Functional Identification of Adipose-Derived Mesenchymal Stem Cells in Secondary Lymphedema
| PRJNA549491 | ENA