{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T09:58:01Z","timestamp":1776419881581,"version":"3.51.2"},"reference-count":68,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T00:00:00Z","timestamp":1693180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["Nos. 81973767 and 82274239"],"award-info":[{"award-number":["Nos. 81973767 and 82274239"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hangzhou Science and Technology Development Program","award":["Grant No. 20180533B38"],"award-info":[{"award-number":["Grant No. 20180533B38"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,10,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Diabetic foot ulcer (DFU) is a main diabetic complication with unmet treatment needs. This study applied human umbilical cord-derived mesenchymal stem cells-hyaluronic acid (hucMSCs-HA) gel to treat DFU in a noninvasive external way and investigated its paracrine action and mechanism. In this study, after analyzing the physical and biological properties of HA gel, hucMSCs-HA gel was applied in 2 in vivo models (types I and II DFU), and a molecular mechanism was investigated. To evaluate the paracrine action of hucMSCs, hucMSCs-conditional medium (MSC-CM) was collected to treat 1 in vivo model (type I DFU) and 2 in vitro models (high glucose (HG)-injured human umbilical vein endothelial cells (HUVECs) and human skin fibroblasts (HSFs)). The results indicated that HA gel with a porous microstructure underwent over 90% degradation and swelled to the maximum value within 48 h. In vivo, hucMSCs-HA gel accelerated wound healing of DFU rats by improving re-epithelialization, collagen deposition, and angiogenesis, in which a paracrine action of hucMSCs was confirmed and the phosphorylation of p38, ERK1\/2, JNK, and Akt was increased. In vitro, MSC-CM improved cell viability, wound healing, migration, tube formation, cell senescence, and abnormal expressions (TNF-\u03b1, IL-1\u03b2, IL-6, ET-1, p16 genes, and PCNA protein) of HUVECs, also improved cell viability, wound healing, antioxidant stress, and abnormal expressions (COL1, COL3, COL4, SOD1, SOD2 genes, and PCNA protein) of HSFs. Summarily, noninvasive external application of hucMSCs-HA gel shows great perspective against DFU and exerts wound healing effects through the MAPK and Akt pathways-mediated paracrine mechanism.<\/jats:p>","DOI":"10.1093\/stcltm\/szad050","type":"journal-article","created":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T19:08:27Z","timestamp":1693249707000},"page":"689-706","source":"Crossref","is-referenced-by-count":24,"title":["External Application of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Hyaluronic Acid Gel Repairs Foot Wounds of Types I and II Diabetic Rats Through Paracrine Action Mode"],"prefix":"10.1093","volume":"12","author":[{"given":"Jingan","family":"Chen","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences, Zhejiang Chinese Medical University , Hangzhou , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Zhejiang Chinese Medical University , Hangzhou , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cell Resource Bank and Integrated Cell Preparation Center of Xiaoshan District, Hangzhou Regional Cell Preparation Center (Shangyu Biotechnology Co., Ltd) , Hangzhou , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuping","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Zhejiang Chinese Medical University , Hangzhou , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haowei","family":"Liang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Zhejiang Chinese Medical University , Hangzhou , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Li","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, Zhejiang Chinese Medical University , Hangzhou , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Yan","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, Zhejiang Chinese Medical University , Hangzhou , People\u2019s Republic of China"},{"name":"Cell Resource Bank and Integrated Cell Preparation Center of Xiaoshan District, Hangzhou Regional Cell Preparation Center (Shangyu Biotechnology Co., Ltd) , Hangzhou , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Zhou","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, Zhejiang Chinese Medical University , Hangzhou , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4926-0527","authenticated-orcid":false,"given":"Letian","family":"Shan","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, Zhejiang Chinese Medical University , Hangzhou , People\u2019s Republic of China"},{"name":"Cell Resource Bank and Integrated Cell Preparation Center of Xiaoshan District, Hangzhou Regional Cell Preparation Center (Shangyu Biotechnology Co., Ltd) , Hangzhou , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0108-8254","authenticated-orcid":false,"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Zhejiang Chinese Medical University , Hangzhou , People\u2019s Republic of China"},{"name":"Jinhua Academy, Zhejiang Chinese Medical University , Hangzhou , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,8,28]]},"reference":[{"key":"2023100513381049800_CIT0001","first-page":"109119","article-title":"IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045","volume-title":"Diabetes Res Clin Pract","author":"Sun","year":"2022"},{"key":"2023100513381049800_CIT0002","first-page":"588","article-title":"Prevalence and risk evaluation of diabetic complications of the foot among adults with type 1 and type 2 diabetes in a large Canadian population (PEDAL Study)","volume-title":"Can J Diabetes","author":"Aronson","year":"2021"},{"key":"2023100513381049800_CIT0003","first-page":"e14725","article-title":"Incidence, hospitalization and mortality and their changes over time in people with a first ever diabetic foot ulcer","volume-title":"Diabet 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