{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:10:46Z","timestamp":1790946646335,"version":"4.1.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T00:00:00Z","timestamp":1738540800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ebm-journal.org"],"crossmark-restriction":true},"short-container-title":["Exp. Biol. Med."],"abstract":"<jats:p>Bone fractures and bone loss represent significant global health challenges, with their incidence rising due to an aging population. Despite autologous bone grafts remain the gold standard for treatment, challenges such as limited bone availability, immune reactions, and the risk of infectious disease transmission have driven the search for alternative cell-based therapies for bone regeneration. Stem cells derived from oral tissues and umbilical cord mesenchymal stem cells (MSCs) have shown potential in both preclinical and clinical studies for bone tissue regeneration. However, their limited differentiation capacity and wound healing abilities necessitate the exploration of alternative cell sources. In this study, we generated induced pluripotent stem cells (iPSCs) using a safe, nonviral and mRNA-based approach from human periodontal ligament fibroblasts (PDLF), an easily accessible cell source. These iPSCs were subsequently differentiated into MSCs, referred to as induced MSCs (iMSCs). The resulting iMSCs were homogeneous, highly proliferative, and possessed anti-inflammatory properties, suggesting their potential as a superior alternative to traditional MSCs for regenerative therapy. These iMSCs demonstrated trilineage differentiation potential, giving rise to osteocytes, chondrocytes, and adipocytes. The iMSC-derived osteocytes (iOSTs) were homogeneous, patient-specific and showed excellent attachment and growth on commercial collagen-based membranes, highlighting their suitability for bone tissue regeneration applications. Given their promising characteristics compared to traditional MSCs, PDLF-derived iMSCs are strong candidates for future clinical studies in bone regeneration and other regenerative dental therapies.<\/jats:p>","DOI":"10.3389\/ebm.2025.10342","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T04:11:11Z","timestamp":1738555871000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Induced mesenchymal stem cells generated from periodontal ligament fibroblast for regenerative therapy"],"prefix":"10.3389","volume":"250","author":[{"given":"Hemanathan","family":"Vembuli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheeja","family":"Rajasingh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Nabholz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jefferson","family":"Guenther","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian R.","family":"Morrow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret M.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marziyeh","family":"Aghazadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinoth","family":"Sigamani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnson","family":"Rajasingh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1016\/j.tibtech.2012.07.005","article-title":"Recent advances in bone tissue engineering scaffolds","volume":"30","author":"Bose","year":"2012","journal-title":"Trends Biotechnology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1007\/s00441-011-1184-8","article-title":"Treatment of long bone defects and non-unions: from research to clinical practice","volume":"347","author":"Berner","year":"2012","journal-title":"Cell Tissue Res"},{"key":"B3","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1007\/s40204-018-0100-7","article-title":"The role of stem cell therapy in regeneration of dentine-pulp complex: a systematic review","volume":"7","author":"Bakhtiar","year":"2018","journal-title":"Prog Biomater"},{"key":"B4","doi-asserted-by":"publisher","first-page":"17014","DOI":"10.1038\/boneres.2017.14","article-title":"Injectable hydrogels for cartilage and bone tissue engineering","volume":"5","author":"Liu","year":"2017","journal-title":"Bone Res"},{"key":"B5","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/1749-799x-9-18","article-title":"Bone regenerative medicine: classic options, novel strategies, and future directions","volume":"9","author":"Oryan","year":"2014","journal-title":"J orthopaedic Surg Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1634\/stemcells.2007-0484","article-title":"Human dental pulp stem cells improve left ventricular function, induce angiogenesis, and reduce infarct size in rats with acute myocardial infarction","volume":"26","author":"Gandia","year":"2008","journal-title":"Stem cells"},{"key":"B7","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s13770-014-9053-7","article-title":"Dental pulp stem cells derived conditioned medium promotes angiogenesis in hindlimb ischemia","volume":"12","author":"Shen","year":"2015","journal-title":"Tissue Eng Regenerative Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e66748","DOI":"10.1371\/journal.pone.0066748","article-title":"Intraventricular injection of human dental pulp stem cells improves hypoxic-ischemic brain damage in neonatal rats","volume":"8","author":"Fang","year":"2013","journal-title":"PLoS One"},{"key":"B9","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1172\/JCI59251","article-title":"Human dental pulp-derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms","volume":"122","author":"Sakai","year":"2012","journal-title":"The J Clin Invest"},{"key":"B10","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1177\/0022034510396879","article-title":"Differentiation of dental pulp stem cells into islet-like aggregates","volume":"90","author":"Govindasamy","year":"2011","journal-title":"J dental Res"},{"key":"B11","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1016\/j.dld.2013.02.007","article-title":"In vitro differentiation into insulin-producing \u03b2-cells of stem cells isolated from human amniotic fluid and dental pulp","volume":"45","author":"Carnevale","year":"2013","journal-title":"Dig Liver Dis"},{"key":"B12","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1111\/j.1432-0436.2004.07209010.x","article-title":"Cultured human and rat tooth papilla cells induce hair follicle regeneration and fiber growth","volume":"72","author":"Reynolds","year":"2004","journal-title":"Differentiation"},{"key":"B13","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1097\/scs.0b013e318207b507","article-title":"Human deciduous teeth dental pulp cells with basic fibroblast growth factor enhance wound healing of skin defect","volume":"22","author":"Nishino","year":"2011","journal-title":"J Craniofac Surg"},{"key":"B14","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/1479-5876-6-35","article-title":"Early transplantation of human immature dental pulp stem cells from baby teeth to golden retriever muscular dystrophy (GRMD) dogs: local or systemic?","volume":"6","author":"Kerkis","year":"2008","journal-title":"J translational Med"},{"key":"B15","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1016\/j.archoralbio.2010.03.003","article-title":"5-Aza-2\u2032-deoxycytidine treatment induces skeletal myogenic differentiation of mouse dental pulp stem cells","volume":"55","author":"Nakatsuka","year":"2010","journal-title":"Arch Oral Biol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e13547","DOI":"10.1371\/journal.pone.0013547","article-title":"Clones of ectopic stem cells in the regeneration of muscle defects in vivo","volume":"5","author":"Yang","year":"2010","journal-title":"PloS one"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2493","DOI":"10.1634\/stemcells.2006-0161","article-title":"Side population cells isolated from porcine dental pulp tissue with self\u2010renewal and multipotency for dentinogenesis, chondrogenesis, adipogenesis, and neurogenesis","volume":"24","author":"Iohara","year":"2006","journal-title":"Stem cells"},{"key":"B18","doi-asserted-by":"publisher","first-page":"149","DOI":"10.3390\/osteology1030016","article-title":"Chondrogenic potential of dental-derived mesenchymal stromal cells","volume":"1","author":"Jeyaraman","year":"2021","journal-title":"Osteology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"316","DOI":"10.5966\/sctm.2012-0136","article-title":"Three years after transplants in human mandibles, histological and in-line holotomography revealed that stem cells regenerated a compact rather than a spongy bone: biological and clinical implications","volume":"2","author":"Giuliani","year":"2013","journal-title":"Stem Cells Translational Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"644","DOI":"10.4103\/0972-124x.119284","article-title":"Sinus lift tissue engineering using autologous pulp micro-grafts: a case report of bone density evaluation","volume":"17","author":"Carinci","year":"2013","journal-title":"J Indian Soc Periodontol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"e469","DOI":"10.4317\/medoral.22466","article-title":"Autologous dental pulp mesenchymal stem cells for inferior third molar post-extraction socket healing: a split-mouth randomised clinical trial","volume":"23","author":"Barbier","year":"2018","journal-title":"Medicina Oral, Patolog\u00eda Oral y Cirug\u00eda Bucal"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1111\/jcpe.13368","article-title":"Periodontal regeneration using a xenogeneic bone substitute seeded with autologous periodontal ligament\u2010derived mesenchymal stem cells: a 12\u2010month quasi\u2010randomized controlled pilot clinical trial","volume":"47","author":"S\u00e1nchez","year":"2020","journal-title":"J Clin Periodontol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.reth.2018.07.002","article-title":"Periodontal regeneration with autologous periodontal ligament-derived cell sheets\u2013a safety and efficacy study in ten patients","volume":"9","author":"Iwata","year":"2018","journal-title":"Regenerative Ther"},{"key":"B24","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1186\/s13287-020-02011-z","article-title":"What is the impact of human umbilical cord mesenchymal stem cell transplantation on clinical treatment?","volume":"11","author":"Xie","year":"2020","journal-title":"Stem Cel Res & Ther"},{"key":"B25","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.nmd.2007.11.003","article-title":"Mesenchymal stem cells from umbilical cord: do not discard the cord","volume":"18","author":"Secco","year":"2008","journal-title":"Neuromuscul Disord"},{"key":"B26","first-page":"1099","article-title":"Isolation of human mesenchymal stem cells: bone marrow versus umbilical cord blood","volume":"86","author":"Mareschi","year":"2001","journal-title":"Haematologica"},{"key":"B27","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1089\/107632701300062859","article-title":"Multilineage cells from human adipose tissue: implications for cell-based therapies","volume":"7","author":"Zuk","year":"2001","journal-title":"Tissue Eng"},{"key":"B28","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1002\/pbc.26185","article-title":"Expression and methylation status of MDR-1 gene in pediatric primary myelodysplastic syndrome","volume":"64","author":"Ferreira Rodrigues","year":"2017","journal-title":"Pediatr Blood Cancer"},{"key":"B29","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.diff.2019.12.001","article-title":"Non-viral reprogramming and induced pluripotent stem cells for cardiovascular therapy","volume":"112","author":"Panda","year":"2020","journal-title":"Differentiation"},{"key":"B30","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/978-1-62703-348-0_3","article-title":"A review of the methods for human iPSC derivation","volume":"997","author":"Malik","year":"2013","journal-title":"Methods Mol Biol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"8904","DOI":"10.1111\/jcmm.16851","article-title":"Comparative analysis of human induced pluripotent stem cell-derived mesenchymal stem cells and umbilical cord mesenchymal stem cells","volume":"25","author":"Rajasingh","year":"2021","journal-title":"J Cell Mol Med"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e0134093","DOI":"10.1371\/journal.pone.0134093","article-title":"Generation of functional cardiomyocytes from efficiently generated human iPSCs and a novel method of measuring contractility","volume":"10","author":"Rajasingh","year":"2015","journal-title":"PLoS One"},{"key":"B33","doi-asserted-by":"publisher","first-page":"112508","DOI":"10.1016\/j.yexcr.2021.112508","article-title":"Noonan syndrome patient-specific induced cardiomyocyte model carrying SOS1 gene variant c.1654A>G","volume":"400","author":"Gurusamy","year":"2021","journal-title":"Exp Cell Res"},{"key":"B34","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/nprot.2007.30","article-title":"In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro","volume":"2","author":"Liang","year":"2007","journal-title":"Nat Protoc"},{"key":"B35","doi-asserted-by":"publisher","first-page":"552","DOI":"10.4252\/wjsc.v6.i5.552","article-title":"Secretion of immunoregulatory cytokines by mesenchymal stem cells","volume":"6","author":"Kyurkchiev","year":"2014","journal-title":"World J Stem Cells"},{"key":"B36","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.job.2024.02.006","article-title":"Stem cells in regenerative dentistry: current understanding and future directions","volume":"66","author":"Shah","year":"2024","journal-title":"J Oral Biosciences"},{"key":"B37","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1177\/15353702211052927","article-title":"Modern approaches on stem cells and scaffolding technology for osteogenic differentiation and regeneration","volume":"247","author":"Kirankumar","year":"2022","journal-title":"Exp Biol Med (Maywood)"},{"key":"B38","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1111\/j.1600-0765.2011.01358.x","article-title":"Induced pluripotent stem cell lines derived from human gingival fibroblasts and periodontal ligament fibroblasts","volume":"46","author":"Wada","year":"2011","journal-title":"J Periodontal Res"},{"key":"B39","doi-asserted-by":"publisher","first-page":"11746","DOI":"10.3390\/ijms222111746","article-title":"Stem cells and their derivatives-implications for alveolar bone regeneration: a comprehensive review","volume":"22","author":"Holl\u00fd","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B40","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1161\/circresaha.111.243147","article-title":"Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease","volume":"109","author":"Williams","year":"2011","journal-title":"Circ Res"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.1111\/jcmm.12839","article-title":"hiPSC-derived iMSCs: NextGen MSCs as an advanced therapeutically active cell resource for regenerative medicine","volume":"20","author":"Sabapathy","year":"2016","journal-title":"J Cell Mol Med"},{"key":"B42","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/j.tips.2020.06.009","article-title":"Mesenchymal stem cell immunomodulation: mechanisms and therapeutic potential","volume":"41","author":"Song","year":"2020","journal-title":"Trends Pharmacological Sciences"},{"key":"B43","doi-asserted-by":"publisher","first-page":"284","DOI":"10.2174\/1874467208666150928153511","article-title":"Stem cell therapy and immunological rejection in animal models","volume":"9","author":"Jin","year":"2016","journal-title":"Curr Mol Pharmacol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"e5846","DOI":"10.1371\/journal.pone.0005846","article-title":"Aging and replicative senescence have related effects on human stem and progenitor cells","volume":"4","author":"Wagner","year":"2009","journal-title":"PLoS One"},{"key":"B45","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1111\/j.1365-2796.2007.01844.x","article-title":"Immunomodulation by mesenchymal stem cells and clinical experience","volume":"262","author":"Le Blanc","year":"2007","journal-title":"J Intern Med"},{"key":"B46","doi-asserted-by":"publisher","first-page":"881","DOI":"10.3390\/ijms24010881","article-title":"iPSC-derived MSCs are a distinct entity of MSCs with higher therapeutic potential than their donor-matched parental MSCs","volume":"24","author":"Lee","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B47","doi-asserted-by":"publisher","first-page":"055035","DOI":"10.1088\/1748-605x\/ad6ac4","article-title":"Tissue scaffolds mimicking hierarchical bone morphology as biomaterials for oral maxillofacial surgery with augmentation: structure, properties, and performance evaluation forin vitrotesting","volume":"19","author":"Thonglam","year":"2024","journal-title":"Biomed Mater"},{"key":"B48","doi-asserted-by":"publisher","first-page":"105182","DOI":"10.1016\/j.archoralbio.2021.105182","article-title":"Dental tissue-derived stem cell sheet biotechnology for periodontal tissue regeneration: a systematic review","volume":"129","author":"Magalh\u00e3es","year":"2021","journal-title":"Arch Oral Biol"}],"container-title":["Experimental Biology and Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.ebm-journal.org\/articles\/10.3389\/ebm.2025.10342\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T04:11:25Z","timestamp":1738555885000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ebm-journal.org\/articles\/10.3389\/ebm.2025.10342\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,3]]},"references-count":48,"alternative-id":["10.3389\/ebm.2025.10342"],"URL":"https:\/\/doi.org\/10.3389\/ebm.2025.10342","relation":{},"ISSN":["1535-3699"],"issn-type":[{"value":"1535-3699","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,3]]},"article-number":"10342"}}