{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:51:40Z","timestamp":1791525100371,"version":"4.3.4"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The extracellular matrix (ECM) within the pancreatic microenvironment plays an integral role in the pathogenesis of diabetes. However, how matrix stiffness regulates islet \u03b2-cell function through mechanosensitive ion channels remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A three-dimensional biomimetic islet culture system with graded matrix stiffness was established using hyaluronic acid methacrylate (HAMA) hydrogels with different crosslinking times. MIN6 insulin-secreting cells were encapsulated in soft and stiff HAMA matrices, and cell viability, Piezo1 expression, intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      levels, \u03b2-cell function-related gene expression, and glucose-stimulated insulin secretion (GSIS) were evaluated. Pharmacological modulation of mechanosensitive ion channels and Piezo1 knockdown were used to investigate the potential role of Piezo1 in stiffness-dependent \u03b2-cell responses. RNA sequencing and pathway enrichment analyses were performed to identify signaling pathways associated with matrix stiffness. In addition, stiff or soft matrix-encapsulated MIN6 cells were transplanted into diabetic mice to evaluate in vivo glucose regulation and biocompatibility.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Stiffer HAMA hydrogels significantly increased Piezo1 expression in MIN6 cells and were associated with elevated intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      levels. Compared with the soft matrix, the stiff matrix significantly increased the expression of \u03b2-cell function-related genes, including Insulin, Pdx1, Mafa, and Nkx6-1, and enhanced insulin secretion under both basal and glucose-stimulated conditions. Pharmacological activation of Piezo1 in the soft matrix partially mimicked the effects of the stiff matrix, whereas inhibition of mechanosensitive ion channels reduced insulin-associated signals and \u03b2-cell function-related gene expression. RNA-seq and pathway enrichment analyses identified HIF-related signaling and metabolic pathways as potential molecular responses to matrix stiffness. However, the present data did not establish a direct mechanistic relationship between HIF signaling and Piezo1. In diabetic mice, transplantation of stiff matrix-encapsulated MIN6 cells was associated with improved blood glucose control during the observation period and showed good in vivo biocompatibility.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings indicate that matrix stiffness can modulate \u03b2-cell function and glucose-responsive insulin secretion within a three-dimensional microenvironment. Overall, this study provides evidence that biomechanical properties of the three-dimensional ECM may influence \u03b2-cell function and highlights matrix mechanics as a potential regulatory component of the islet microenvironment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fchem.2026.1981529","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:30:03Z","timestamp":1791523803000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The stiffness of three-dimensional biomimetic matrices regulates insulin secretion via the Piezo1 mechanosensitive ion channel"],"prefix":"10.3389","volume":"14","author":[{"given":"Xi","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University","place":["Nantong, China"]},{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University","place":["Nantong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University","place":["Nantong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University","place":["Nantong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xue","sequence":"additional","affiliation":[{"name":"Research Center of Molecular Medicine, Nantong Health Vocational College","place":["Nantong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University","place":["Nantong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University","place":["Nantong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongzhi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University","place":["Nantong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1038\/nature08933","article-title":"Genetics, pathogenesis and clinical interventions in type 1 diabetes","volume":"464","author":"Bluestone","year":"2010","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2277","DOI":"10.1039\/d2bm01410f","article-title":"Cellular metabolism: a link connecting cellular behaviour with the physiochemical properties of biomaterials for bone tissue engineering","volume":"11","author":"Chaudhary","year":"2023","journal-title":"Biomater. Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"100391","DOI":"10.1016\/j.mtbio.2022.100391","article-title":"Mechanosensation mediates volume adaptation of cardiac cells and spheroids in 3D","volume":"16","author":"Chin","year":"2022","journal-title":"Mater Today Bio"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1016\/j.cell.2016.05.082","article-title":"Modeling development and disease with organoids","volume":"165","author":"Clevers","year":"2016","journal-title":"Cell."},{"key":"B5","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1126\/science.1193270","article-title":"Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels","volume":"330","author":"Coste","year":"2010","journal-title":"Science"},{"key":"B6","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.semcancer.2010.04.004","article-title":"Physico-mechanical aspects of extracellular matrix influences on tumorigenic behaviors","volume":"20","author":"Cukierman","year":"2010","journal-title":"Semin. Cancer Biol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1186\/s12967-022-03768-y","article-title":"Biological role of matrix stiffness in tumor growth and treatment","volume":"20","author":"Deng","year":"2022","journal-title":"J. Transl. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1038\/s41392-023-01501-9","article-title":"Cellular mechanotransduction in health and diseases: from molecular mechanism to therapeutic targets","volume":"8","author":"Di","year":"2023","journal-title":"Signal Transduct. Target Ther."},{"key":"B9","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1007\/s13105-023-00960-6","article-title":"Metabolic dependency of non-small cell lung cancer cells affected by three-dimensional scaffold and its stiffness","volume":"79","author":"Fu","year":"2023","journal-title":"J. Physiol. Biochem."},{"key":"B10","doi-asserted-by":"publisher","first-page":"631991","DOI":"10.3389\/fonc.2021.631991","article-title":"Extracellular matrix stiffness: new areas affecting cell metabolism","volume":"11","author":"Ge","year":"2021","journal-title":"Front. Oncol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"5347","DOI":"10.1021\/acsbiomaterials.3c00487","article-title":"Biomimetic microenvironmental stiffness boosts stemness of pancreatic ductal adenocarcinoma via augmented autophagy","volume":"9","author":"Gong","year":"2023","journal-title":"ACS Biomater. Sci. Eng."},{"key":"B12","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1016\/j.jhep.2022.03.029","article-title":"Mechanotransduction-induced glycolysis epigenetically regulates a CXCL1-dominant angiocrine signaling program in liver sinusoidal endothelial cells in vitro and in vivo","volume":"77","author":"Greuter","year":"2022","journal-title":"J. Hepatol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"12200","DOI":"10.3390\/ijms222212200","article-title":"3D cell culture systems: tumor application, advantages, and disadvantages","volume":"22","author":"Habanjar","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"188418","DOI":"10.1016\/j.bbcan.2020.188418","article-title":"Mechanically stressed cancer microenvironment: role in pancreatic cancer progression","volume":"1874","author":"Hadden","year":"2020","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e76262","DOI":"10.7554\/elife.76262","article-title":"Local activation of focal adhesion kinase orchestrates the positioning of presynaptic scaffold proteins and Ca2+ signalling to control glucose-dependent insulin secretion","volume":"11","author":"Hallahan","year":"2022","journal-title":"eLife"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e2301137","DOI":"10.1002\/adhm.202301137","article-title":"Fibrin stiffness regulates phenotypic plasticity of metastatic breast cancer cells","volume":"12","author":"Heilala","year":"2023","journal-title":"Adv. Healthc. Mater"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1862","DOI":"10.1111\/bph.16050","article-title":"Piezo1 channel activation stimulates ATP production through enhancing mitochondrial respiration and glycolysis in vascular endothelial cells","volume":"180","author":"Jiang","year":"2023","journal-title":"Br. J. Pharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1016\/j.jare.2025.10.041","article-title":"Matrix stiffness drives squamous cell carcinoma progression via a Piezo1-mediated mechanotransduction feedback loop","volume":"85","author":"Jiang","year":"2025","journal-title":"J. Adv. Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"120936","DOI":"10.1016\/j.lfs.2022.120936","article-title":"Fluid shear stress facilitates prostate cancer metastasis through Piezo1-Src-YAP axis","volume":"308","author":"Kim","year":"2022","journal-title":"Life Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1928","DOI":"10.2337\/diab.46.12.1928","article-title":"Augmentation of insulin release by glucose in the absence of extracellular Ca2+: new insights into stimulus-secretion coupling","volume":"46","author":"Komatsu","year":"1997","journal-title":"Diabetes"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1990","DOI":"10.1002\/jbm.a.37191","article-title":"Evaluation of the effect of 3D porous Chitosan-alginate scaffold stiffness on breast cancer proliferation and migration","volume":"109","author":"Le","year":"2021","journal-title":"J. Biomed. Mater Res. A"},{"key":"B22","doi-asserted-by":"publisher","first-page":"976482","DOI":"10.3389\/fimmu.2022.976482","article-title":"Ion channel Piezo1 activation promotes aerobic glycolysis in macrophages","volume":"13","author":"Leng","year":"2022","journal-title":"Front. Immunol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1038\/s41586-019-1499-2","article-title":"Force-induced conformational changes in PIEZO1","volume":"573","author":"Lin","year":"2019","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","first-page":"490","DOI":"10.3390\/cancers12020490","article-title":"Stiffer matrix accelerates migration of hepatocellular carcinoma cells through enhanced aerobic glycolysis Via the MAPK-YAP signaling","volume":"12","author":"Liu","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1007\/s00125-017-4524-8","article-title":"Extracellular matrix molecules and their potential contribution to the function of transplanted pancreatic islets","volume":"61","author":"Llacua","year":"2018","journal-title":"Diabetologia"},{"key":"B26","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.jot.2024.11.004","article-title":"Harnessing the potential of hyaluronic acid methacrylate (HAMA) hydrogel for clinical applications in orthopaedic diseases","volume":"50","author":"Lu","year":"2025","journal-title":"J. Orthop. Transl."},{"key":"B27","doi-asserted-by":"publisher","first-page":"787485","DOI":"10.3389\/fcell.2021.787485","article-title":"Targeting tumor-stromal interactions in pancreatic cancer: impact of collagens and mechanical traits","volume":"9","author":"Maneshi","year":"2021","journal-title":"Front. Cell. Dev. Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1186\/s12943-021-01428-1","article-title":"Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives","volume":"20","author":"Mao","year":"2021","journal-title":"Mol. Cancer"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1518","DOI":"10.3390\/biom11101518","article-title":"Hyaluronic acid: a key ingredient in the therapy of inflammation","volume":"11","author":"Marinho","year":"2021","journal-title":"Biomolecules"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz0868","article-title":"Physical traits of cancer","volume":"370","author":"Nia","year":"2020","journal-title":"Science"},{"key":"B31","doi-asserted-by":"publisher","first-page":"7358","DOI":"10.1039\/d3bm00598d","article-title":"Matrix stiffness triggers chemoresistance through elevated autophagy in pancreatic ductal adenocarcinoma","volume":"11","author":"Pan","year":"2023","journal-title":"Biomater. Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"S44","DOI":"10.1016\/j.cgh.2009.07.039","article-title":"Desmoplasia of pancreatic ductal adenocarcinoma","volume":"7","author":"Pandol","year":"2009","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"121185","DOI":"10.1016\/j.biomaterials.2021.121185","article-title":"ECM stiffness-tuned exosomes drive breast cancer motility through thrombospondin-1","volume":"279","author":"Patwardhan","year":"2021","journal-title":"Biomaterials"},{"key":"B34","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.ceca.2019.03.007","article-title":"Mechanosensitive ion channels push cancer progression","volume":"80","author":"Peth\u0151","year":"2019","journal-title":"Cell. Calcium"},{"key":"B35","doi-asserted-by":"publisher","first-page":"165625","DOI":"10.1016\/j.bbadis.2019.165625","article-title":"Matrix stiffness modulates ILK-mediated YAP activation to control the drug resistance of breast cancer cells","volume":"1866","author":"Qin","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"B36","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1007\/s13577-022-00853-8","article-title":"Piezo protein determines stem cell fate by transmitting mechanical signals","volume":"36","author":"Qiu","year":"2023","journal-title":"Hum. Cell."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1016\/j.addr.2007.08.007","article-title":"Cell responses to the mechanochemical microenvironment--implications for regenerative medicine and drug delivery","volume":"59","author":"Rehfeldt","year":"2007","journal-title":"Adv. Drug Deliv. Rev."},{"key":"B38","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1016\/j.ccr.2011.05.008","article-title":"Actomyosin-mediated cellular tension drives increased tissue stiffness and \u03b2-catenin activation to induce epidermal hyperplasia and tumor growth","volume":"19","author":"Samuel","year":"2011","journal-title":"Cancer Cell."},{"key":"B39","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/nature25453","article-title":"Structure of the mechanically activated ion channel Piezo1","volume":"554","author":"Saotome","year":"2018","journal-title":"Nature"},{"key":"B40","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/s41580-023-00583-1","article-title":"Cell-extracellular matrix mechanotransduction in 3D","volume":"24","author":"Saraswathibhatla","year":"2023","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/1475-2840-5-3","article-title":"Type-2 diabetes-induced changes in vascular extracellular matrix gene expression: relation to vessel size","volume":"5","author":"Song","year":"2006","journal-title":"Cardiovasc Diabetol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"e12905","DOI":"10.1371\/journal.pone.0012905","article-title":"Matrix rigidity regulates cancer cell growth and cellular phenotype","volume":"5","author":"Tilghman","year":"2010","journal-title":"PLoS One"},{"key":"B43","doi-asserted-by":"publisher","first-page":"5269","DOI":"10.1002\/cphy.c230005","article-title":"Mechanosensing in metabolism","volume":"14","author":"Tranter","year":"2023","journal-title":"Compr. Physiol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"e2301506","DOI":"10.1002\/adhm.202301506","article-title":"3D volumetric mechanosensation of MCF7 breast cancer spheroids in a linear stiffness gradient GelAGE","volume":"12","author":"Vahala","year":"2023","journal-title":"Adv. Healthc. Mater"},{"key":"B45","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.tibs.2016.09.004","article-title":"Touch, tension, and transduction - the function and regulation of piezo ion channels","volume":"42","author":"Wu","year":"2017","journal-title":"Trends Biochem. Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1038\/s41419-023-06249-2","article-title":"Pyruvate dehydrogenase kinase 1 protects against neuronal injury and memory loss in mouse models of diabetes","volume":"14","author":"Yao","year":"2023","journal-title":"Cell. Death and Dis."},{"key":"B47","doi-asserted-by":"publisher","first-page":"4237","DOI":"10.1038\/s41467-022-31103-y","article-title":"A critical role of the mechanosensor PIEZO1 in glucose-induced insulin secretion in pancreatic \u03b2-cells","volume":"13","author":"Ye","year":"2022","journal-title":"Nat. Commun."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1016\/j.cmet.2021.04.002","article-title":"Mechanoresponsive metabolism in cancer cell migration and metastasis","volume":"33","author":"Zanotelli","year":"2021","journal-title":"Cell. Metab."},{"key":"B49","doi-asserted-by":"publisher","first-page":"188583","DOI":"10.1016\/j.bbcan.2021.188583","article-title":"Matrix stiffness and its influence on pancreatic diseases","volume":"1876","author":"Zhang","year":"2021","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"B50","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1186\/s12933-024-02238-7","article-title":"Ion channel Piezo1 activation aggravates the endothelial dysfunction under a high glucose environment","volume":"23","author":"Zhang","year":"2024","journal-title":"Cardiovasc Diabetol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1016\/j.addr.2010.11.001","article-title":"Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis","volume":"63","author":"Zhao","year":"2011","journal-title":"Adv. Drug Deliv. Rev."}],"container-title":["Frontiers in Chemistry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2026.1981529\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:30:05Z","timestamp":1791523805000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2026.1981529\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,9]]},"references-count":51,"alternative-id":["10.3389\/fchem.2026.1981529"],"URL":"https:\/\/doi.org\/10.3389\/fchem.2026.1981529","relation":{},"ISSN":["2296-2646"],"issn-type":[{"value":"2296-2646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,9]]},"article-number":"1981529"}}