{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T14:05:10Z","timestamp":1783605910022,"version":"3.55.0"},"reference-count":37,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82270848"],"award-info":[{"award-number":["82270848"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2025,9,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The activation of islet stellate cells (ISCs) plays an important role in islet fibrosis, which leads to impaired islet function. While our previous work showed that the expression of the\n                    <jats:italic>Pdpn<\/jats:italic>\n                    gene was significantly increased in activated ISCs, it remains unknown whether\n                    <jats:italic>Pdpn<\/jats:italic>\n                    is responsible for islet fibrosis. This study was aimed at elucidating its function on islet fibrosis, along with the exploration of the underlying mechanisms. Then, diabetic mice were used for in\u00a0vivo studies, while primary ISCs were used for in\u00a0vitro experiments. Podoplanin (PDPN) expression was manipulated using gene knockdown and overexpression techniques. Beta\u2010cell function was assessed by insulin secretion and glucose tolerance tests. Islet fibrosis was evaluated by quantifying extracellular matrix deposition and ISCs activation markers using histological staining and immunohistochemistry, respectively. The effects of advanced glycation end products (AGEs) and TGF\u2010\u03b21 on PDPN expression and the corresponding mechanisms of ISCs activation were investigated. Finally, it was found that knocking down PDPN in diabetic mice led to reduced ISCs activation and islet fibrosis, accompanied by improved insulin expression and lower fasting blood glucose. AGEs were found to induce PDPN expression in ISCs. The overexpression of PDPN triggers the activation of ISCs via cell deformation and TGF\u2010\u03b21 secretion. Interestingly, TGF\u2010\u03b21 in turn activates the TGF\u2010\u03b21\/SMAD2\/3 pathway by binding to TGF\u2010\u03b2RI, inducing the expression of PDPN and the activation of ISCs. In summary, PDPN regulates the activation of ISCs through a mechanism involving cell deformation and a PDPN\u2010TGF\u2010\u03b21 autocrine feedback loop, thereby significantly contributing to islet fibrosis in diabetes.\n                  <\/jats:p>","DOI":"10.1096\/fj.202500760r","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T12:30:32Z","timestamp":1756902632000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Podoplanin\u2010\n                    <scp>TGF<\/scp>\n                    \u2010\u03b21 Autocrine Loop: Pivotal Regulator of Islet Stellate Cell Activation via Cell Deformation, Orchestrating Islet Fibrosis in Diabetes"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2111-9601","authenticated-orcid":false,"given":"Xiaohang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine Southeast University  Nanjing China"},{"name":"Institute of Translational Medicine, Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Medical College Yangzhou University  Yangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengming","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhensheng","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2597-3856","authenticated-orcid":false,"given":"Shanhu","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of General Practice, Zhongda Hospital; Institute of Diabetes, School of Medicine Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7814-5723","authenticated-orcid":false,"given":"Jinbang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0833-5601","authenticated-orcid":false,"given":"Vladmir","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zilin","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijie","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical College Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2007.1610"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.2337\/db05-1526"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.10-156075"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2003.12.180"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2011.4079"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.02.082"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.4161\/isl.28701"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/6924593"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2015.11.002"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202201879R"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/7361684"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6163"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2019.04.012"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.37861"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-90-481-3271-3_21"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.695467"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13814"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2013.1887"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2014.03.027"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019001388"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20030707"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1503807"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.3109\/03009734.2015.1032453"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI88881"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.106988"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222111716"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/289751"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2011.04614.x"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00595-017-1559-x"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-12-168"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00344.2015"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13225719"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0405747102"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-85416-x"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23041961"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27157"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1308887110"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202500760R","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.202500760R","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202500760R","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T08:30:58Z","timestamp":1772958658000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202500760R"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,3]]},"references-count":37,"journal-issue":{"issue":"17","published-print":{"date-parts":[[2025,9,15]]}},"alternative-id":["10.1096\/fj.202500760R"],"URL":"https:\/\/doi.org\/10.1096\/fj.202500760r","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,3]]},"assertion":[{"value":"2025-03-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70970"}}