Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema
Abstract 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 i...
| Päätekijät: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Aineistotyyppi: | Artikkeli |
| Kieli: | English |
| Julkaistu: |
Springer Nature
2024-01-01
|
| Sarja: | EMBO Molecular Medicine |
| Aiheet: | |
| Linkit: | https://doi.org/10.1038/s44321-023-00017-7 |
| _version_ | 1827326494882398208 |
|---|---|
| author | Justine Creff Asalaa Lamaa Emeline Benuzzi Elisa Balzan Francoise Pujol Tangra Draia-Nicolau Manon Nougué Lena Verdu Florent Morfoisse Eric Lacazette Philippe Valet Benoit Chaput Fabian Gross Regis Gayon Pascale Bouillé Julie Malloizel-Delaunay Alessandra Bura-Rivière Anne-Catherine Prats Barbara Garmy-Susini |
| author_facet | Justine Creff Asalaa Lamaa Emeline Benuzzi Elisa Balzan Francoise Pujol Tangra Draia-Nicolau Manon Nougué Lena Verdu Florent Morfoisse Eric Lacazette Philippe Valet Benoit Chaput Fabian Gross Regis Gayon Pascale Bouillé Julie Malloizel-Delaunay Alessandra Bura-Rivière Anne-Catherine Prats Barbara Garmy-Susini |
| author_sort | Justine Creff |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-07T14:46:24Z |
| format | Article |
| id | doaj.art-2898d3ab95934418854620e0a800a7ed |
| institution | Directory Open Access Journal |
| issn | 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T14:46:24Z |
| publishDate | 2024-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-2898d3ab95934418854620e0a800a7ed2024-03-05T19:55:58ZengSpringer NatureEMBO Molecular Medicine1757-46842024-01-0116238641510.1038/s44321-023-00017-7Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedemaJustine Creff0Asalaa Lamaa1Emeline Benuzzi2Elisa Balzan3Francoise Pujol4Tangra Draia-Nicolau5Manon Nougué6Lena Verdu7Florent Morfoisse8Eric Lacazette9Philippe Valet10Benoit Chaput11Fabian Gross12Regis Gayon13Pascale Bouillé14Julie Malloizel-Delaunay15Alessandra Bura-Rivière16Anne-Catherine Prats17Barbara Garmy-Susini18I2MC, Université de Toulouse, Inserm UMR 1297, UT3I2MC, Université de Toulouse, Inserm UMR 1297, UT3I2MC, Université de Toulouse, Inserm UMR 1297, UT3I2MC, Université de Toulouse, Inserm UMR 1297, UT3I2MC, Université de Toulouse, Inserm UMR 1297, UT3I2MC, Université de Toulouse, Inserm UMR 1297, UT3I2MC, Université de Toulouse, Inserm UMR 1297, UT3I2MC, Université de Toulouse, Inserm UMR 1297, UT3I2MC, Université de Toulouse, Inserm UMR 1297, UT3I2MC, Université de Toulouse, Inserm UMR 1297, UT3Institut RESTORE, UMR 1301-INSERM, 5070-CNRS, Université Paul Sabatier, Université de ToulouseDepartment of Plastic Surgery, University of Toulouse III Paul SabatierBiotherapy Module of Clinical Investigation Center (CIC 1436), University Hospital of ToulouseFlash TherapeuticsFlash TherapeuticsService de Médecine Vasculaire, Centre Hospitalier Universitaire de ToulouseService de Médecine Vasculaire, Centre Hospitalier Universitaire de ToulouseI2MC, Université de Toulouse, Inserm UMR 1297, UT3I2MC, Université de Toulouse, Inserm UMR 1297, UT3Abstract 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.https://doi.org/10.1038/s44321-023-00017-7lymphedemaApelinVEGF-CmRNACollector |
| spellingShingle | Justine Creff Asalaa Lamaa Emeline Benuzzi Elisa Balzan Francoise Pujol Tangra Draia-Nicolau Manon Nougué Lena Verdu Florent Morfoisse Eric Lacazette Philippe Valet Benoit Chaput Fabian Gross Regis Gayon Pascale Bouillé Julie Malloizel-Delaunay Alessandra Bura-Rivière Anne-Catherine Prats Barbara Garmy-Susini Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema EMBO Molecular Medicine lymphedema Apelin VEGF-C mRNA Collector |
| title | Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema |
| title_full | Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema |
| title_fullStr | Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema |
| title_full_unstemmed | Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema |
| title_short | Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema |
| title_sort | apelin vegf c mrna delivery as therapeutic for the treatment of secondary lymphedema |
| topic | lymphedema Apelin VEGF-C mRNA Collector |
| url | https://doi.org/10.1038/s44321-023-00017-7 |
| work_keys_str_mv | AT justinecreff apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT asalaalamaa apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT emelinebenuzzi apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT elisabalzan apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT francoisepujol apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT tangradraianicolau apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT manonnougue apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT lenaverdu apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT florentmorfoisse apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT ericlacazette apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT philippevalet apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT benoitchaput apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT fabiangross apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT regisgayon apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT pascalebouille apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT juliemalloizeldelaunay apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT alessandraburariviere apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT annecatherineprats apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema AT barbaragarmysusini apelinvegfcmrnadeliveryastherapeuticforthetreatmentofsecondarylymphedema |