Nanocarrier-Assisted Delivery of Metformin Boosts Remodeling of Diabetic Periodontal Tissue via Cellular Exocytosis-Mediated Regulation of Endoplasmic Reticulum Homeostasis

作者全名："Zhong, Wenjie; Wang, Xinyan; Yang, Lanxin; Wang, Yue; Xiao, Qingyue; Yu, Simin; Cannon, Richard D.; Bai, Yan; Zhang, Chuangwei; Chen, Duanjing; Ji, Ping; Gao, Xiang; Song, Jinlin"

作者地址："[Zhong, Wenjie; Wang, Xinyan; Yang, Lanxin; Wang, Yue; Xiao, Qingyue; Yu, Simin; Zhang, Chuangwei; Chen, Duanjing; Ji, Ping; Gao, Xiang; Song, Jinlin] Chongqing Med Univ, Coll Stomatol, Chong Key Lab Oral Dis & Biomed Sci, Chongqing Municipal Key Lab Oral Biomed Engn Highe, Chongqing 401147, Peoples R China; [Cannon, Richard D.] Univ Otago, Sir John Walsh Res Inst, Fac Dent, Dept Oral Sci, Dunedin 9016, New Zealand; [Bai, Yan] Chongqing Med Univ, Coll Pharm, Chongqing Res Ctr Pharmaceut Engn, Chongqing Key Lab Biochem & Mol Pharmacol, Chongqing 400016, Peoples R China"

通信作者："Ji, P; Gao, X; Song, JL (通讯作者)，Chongqing Med Univ, Coll Stomatol, Chong Key Lab Oral Dis & Biomed Sci, Chongqing Municipal Key Lab Oral Biomed Engn Highe, Chongqing 401147, Peoples R China."

来源：ACS NANO

ESI学科分类：MATERIALS SCIENCE

WOS号：WOS:000876531000001

JCR分区：Q1

影响因子：17.1

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：metformin; diabetic periodontal tissue; endoplasmic reticulum homeostasis; exocytosis; exosome

摘要："Endoplasmic reticulum (ER) dysfunction is a potential contributor to the impaired repair capacity of periodontal tissue in diabetes mellitus (DM) patients. Restoring ER homeostasis is thus critical for successful regenerative therapy of diabetic periodontal tissue. Recent studies have shown that metformin can modulate DM-induced ER dysfunction, yet its mechanism remains unclear. Herein, we show that high glucose elevates the intracellular miR-129-3p level due to exocytosis-mediated release failure and subsequently perturbs ER calcium homeostasis via downregulating transmembrane and coiled-coil domain 1 (TMCO1), an ER Ca2+ leak channel, in periodontal ligament stem cells (PDLSCs). This results in the degradation of RUNX2 via the ubiquitination-dependent pathway, in turn leading to impaired PDLSCs osteogenesis. Interestingly, metformin could upregulate P2X7R-mediated exosome release and decrease intracellular miR-129-3p accumulation, which restores ER homeostasis and thereby rescues the impaired PDLSCs. To further demonstrate the in vivo effect of metformin, a nanocarrier for sustained local delivery of metformin (Met@HALL) in periodontal tissue is developed. Our results demonstrate that compared to controls, Met@HALL with enhanced cytocompatibility and pro-osteogenic activity could boost the remodeling of diabetic periodontal tissue in rats. Collectively, our findings unravel a mechanism of metformin in restoring cellular ER homeostasis, enabling the development of a nanocarrier-mediated ER targeting strategy for remodeling diabetic periodontal tissue."

基金机构："National Natural Science Foundation of China [82071093, 31700850]; Natural Science Foundation of Chongqing [cstc2020jcyjmsxmX0219]; China Postdoctoral Science Foundation [2019M663893XB]; Chongqing Postdoctoral Science Foundation [cstc2021jcyjbshX0078, X11229]; Program for Youth Innovation in Future Medicine, Chongqing Medical University [W0055]; Project of Chongqing Graduate Tutor Team [dstd201903]; Chongqing Young and Middle-Aged Medical Excellence Team"

基金资助正文："This work was supported in part by the National Natural Science Foundation of China (82071093, 31700850), the Natural Science Foundation of Chongqing (cstc2020jcyjmsxmX0219), a general financial grant from the China Postdoctoral Science Foundation (2019M663893XB), Chongqing Postdoctoral Science Foundation (cstc2021jcyjbshX0078, X11229), Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0055), Project of Chongqing Graduate Tutor Team (dstd201903), and Chongqing Young and Middle-Aged Medical Excellence Team. Cartoons demonstrating cellular mechanisms in Figure 1 and the TOC figure were created with BioRender.com."