Preclinical evaluation of Apelin mRNA delivery for the treatment of lymphedema
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ABSTRACT:
PROVIDER: PRJEB57752 | 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:Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema
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Project description:Evaluation of microRNAs that are downstream of apelin/APJ signaling in the pulmonary artery endothelial cells. Triplicates per group, subjected to: 1) control siRNA, 2) apelin siRNA, 3) APJ siRNA, 4) apelin + APJ siRNA
2012-12-04 | E-GEOD-42343 | biostudies-arrayexpress
Project description:Evaluation of gene transcripts that are downstream of apelin/APJ and FoxO1 signaling in HUVECs
2017-10-02 | GSE67390 | GEO
Project description:Evaluation of microRNAs that are downstream of apelin/APJ signaling in the pulmonary artery endothelial cells.
2012-12-04 | GSE42343 | 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:Evaluation of gene transcripts that are downstream of apelin/APJ signaling in HUVECs
2013-05-11 | GSE46825 | GEO
Project description:Evaluation of gene transcripts that are downstream of apelin/APJ signaling in HUVECs Duplicates per group, subjected to: 1) control siRNA, 2) MEF2A and MEF2C siRNA, 3) G alpha 13 siRNA, and 4) apelin and APJ siRNA
2013-05-11 | E-GEOD-46825 | biostudies-arrayexpress
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: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