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Lymphatic vessel function is impaired in chronic ulcers but the role of lymphangiogenesis in wound healing has remained unclear. We found that lymphatic vessels are largely absent from chronic human wounds as evaluated in patient biopsies. Excisional wound healing studies were conducted using transgenic mice with or without an increased number of cutaneous lymphatic vessels, as well as antibody-mediated inhibition of lymphangiogenesis. We found that a lack of lymphatic vessels mediated a proinflammatory wound microenvironment and delayed wound closure, and that the VEGF-C\/VEGFR3 signaling axis is required for wound lymphangiogenesis. Treatment of diabetic mice (db\/db mice) with the F8\u2013VEGF-C fusion protein that targets the alternatively spliced extra domain A (EDA) of fibronectin, expressed in remodeling tissue, promoted wound healing, and potently induced wound lymphangiogenesis. The treatment also reduced tissue inflammation and exerted beneficial effects on the wound microenvironment, including myofibroblast density and collagen deposition. These findings indicate that activating the lymphatic vasculature might represent a new therapeutic strategy for treating chronic non-healing wounds.<\/jats:p>","DOI":"10.3390\/cells12030472","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T05:04:48Z","timestamp":1675227888000},"page":"472","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Promotion of Lymphangiogenesis by Targeted Delivery of VEGF-C Improves Diabetic Wound Healing"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5959-4948","authenticated-orcid":false,"given":"Lorenz M.","family":"Brunner","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4463-2125","authenticated-orcid":false,"given":"Yuliang","family":"He","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1237-1429","authenticated-orcid":false,"given":"Nikola","family":"Cousin","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeannette","family":"Scholl","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2030-3538","authenticated-orcid":false,"given":"Livia K.","family":"Albin","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Schmucki","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrin","family":"Supersaxo","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4364-2364","authenticated-orcid":false,"given":"Gaetana","family":"Restivo","sequence":"additional","affiliation":[{"name":"Institute for Dermatology, University Hospital of Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrg","family":"Hafner","sequence":"additional","affiliation":[{"name":"Institute for Dermatology, University Hospital of Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Neri","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland"},{"name":"Philochem AG, 8112 Otelfingen, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7397-8710","authenticated-orcid":false,"given":"Sabine","family":"Werner","sequence":"additional","affiliation":[{"name":"Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5351-5054","authenticated-orcid":false,"given":"Michael","family":"Detmar","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/nature07039","article-title":"Wound repair and regeneration","volume":"453","author":"Gurtner","year":"2008","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"265sr6","DOI":"10.1126\/scitranslmed.3009337","article-title":"Wound repair and regeneration: Mechanisms, signaling, and translation","volume":"6","author":"Eming","year":"2014","journal-title":"Sci. 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