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Here, we constructed a high-resolution cellular atlas of miniature pig tooth germs using 10\u00d7 single-cell RNA sequencing to investigate the molecular mechanisms underlying tooth mineralization. By leveraging cellular heterogeneity and dynamic gene expression trajectories in epithelial and mesenchymal populations, we identified microfibril-associated protein 5 (MFAP5) as a previously unrecognized regulator of the odontogenic program. Functional assays demonstrate that MFAP5, an extracellular matrix component, is indispensable for mesenchymal differentiation and matrix mineralization in vitro. Mechanistically, MFAP5 engages Integrin alpha-5 (ITGA5) to activate Extracellular Signal-Regulated Kinase\/Mitogen-Activated Protein Kinase (ERK\/MAPK) signaling in odontoblast-lineage cells, thereby promoting odontoblast differentiation and dentin deposition. Collectively, our single-cell\u2013resolved analyses uncovered a MFAP5\u2013ITGA5\u2013ERK\/MAPK signaling axis that operates in a cell-state\u2013specific manner during tooth germ mineralization, providing new mechanistic insights into odontogenic differentiation and a potential molecular basis for dental tissue regeneration strategies.<\/jats:p>","DOI":"10.3390\/ijms27010394","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T15:30:32Z","timestamp":1767195032000},"page":"394","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["MFAP5 Activates ITGA5 to Drive Tooth Germ Mineralization Through the MAPK\/ERK Pathway: Insights from Single-Cell Transcriptomics"],"prefix":"10.3390","volume":"27","author":[{"given":"Xu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, China"},{"name":"National Center for Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1094-2205","authenticated-orcid":false,"given":"Lanxin","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, China"},{"name":"National Center for Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8651-2100","authenticated-orcid":false,"given":"Ping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, China"},{"name":"National Center for Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, China"},{"name":"Beijing Key Laboratory of Digital Stomatology, National Health Commission Key Laboratory of Digital Technology of Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, China"},{"name":"Institute of Advanced Clinical Medicine, Peking University, No.38 Xueyuan Road, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4332-0878","authenticated-orcid":false,"given":"Yongsheng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, China"},{"name":"National Center for Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, China"},{"name":"Beijing Key Laboratory of Digital Stomatology, National Health Commission Key Laboratory of Digital Technology of Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, China"},{"name":"Institute of Advanced Clinical Medicine, Peking University, No.38 Xueyuan Road, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1152\/physrev.00030.2016","article-title":"Dental Enamel Formation and Implications for Oral Health and Disease","volume":"97","author":"Lacruz","year":"2017","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41368-022-00208-x","article-title":"Tooth Number Abnormality: From Bench to Bedside","volume":"15","author":"Zhang","year":"2023","journal-title":"Int. J. Oral Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/bs.ctdb.2018.12.013","article-title":"Regulatory Mechanisms of Jaw Bone and Tooth Development","volume":"133","author":"Yuan","year":"2019","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/bs.ctdb.2015.07.006","article-title":"Tissue Interactions Regulating Tooth Development and Renewal","volume":"115","author":"Balic","year":"2015","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1177\/0022034517720158","article-title":"The Biology Underlying Abnormalities of Tooth Number in Humans","volume":"96","author":"Juuri","year":"2017","journal-title":"J. Dent. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1111\/cpr.12051","article-title":"An Inductive Signalling Network Regulates Mammalian Tooth Morphogenesis with Implications for Tooth Regeneration","volume":"46","author":"Li","year":"2013","journal-title":"Cell Prolif."},{"key":"ref_7","first-page":"dev184754","article-title":"Molecular and Cellular Mechanisms of Tooth Development, Homeostasis and Repair","volume":"147","author":"Yu","year":"2020","journal-title":"Dev. Camb. Engl."},{"key":"ref_8","first-page":"374","article-title":"Cellular and Molecular Mechanisms of Tooth Root Development","volume":"144","author":"Li","year":"2017","journal-title":"Dev. Camb. Engl."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"a008425","DOI":"10.1101\/cshperspect.a008425","article-title":"Signaling Networks Regulating Tooth Organogenesis and Regeneration, and the Specification of Dental Mesenchymal and Epithelial Cell Lineages","volume":"4","author":"Jussila","year":"2012","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1007\/s12015-023-10551-z","article-title":"Emerging Roles of YAP\/TAZ in Tooth and Surrounding: From Development to Regeneration","volume":"19","author":"Yang","year":"2023","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e1800140","DOI":"10.1002\/bies.201800140","article-title":"Tissue Mechanical Forces and Evolutionary Developmental Changes Act Through Space and Time to Shape Tooth Morphology and Function","volume":"40","author":"Calamari","year":"2018","journal-title":"BioEssays"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1177\/00220345241257866","article-title":"PIEZO1 Promotes Odontoblast-Mediated Reactionary Dentinogenesis via SEMA3A","volume":"103","author":"Huang","year":"2024","journal-title":"J. Dent. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1074\/jbc.M114.599274","article-title":"P38\u03b1 MAPK Is Required for Tooth Morphogenesis and Enamel Secretion","volume":"290","author":"Greenblatt","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Yong, J., Groeger, S., Meyle, J., and Ruf, S. (2022). MAPK and \u03b2-Catenin Signaling: Implication and Interplay in Orthodontic Tooth Movement. Front. Biosci. Landmark Ed., 27.","DOI":"10.31083\/j.fbl2702054"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9610025","DOI":"10.26599\/OSHM.2025.9610025","article-title":"ECM Stiffness-Mediated Regulation of Glucose Metabolism in MSCs Osteogenic Differentiation: Mechanisms, Intersections, and Implications","volume":"1","author":"Yan","year":"2025","journal-title":"Oral Sci. Homeost. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1177\/00220345211052982","article-title":"Extracellular Matrix in Human Craniofacial Development","volume":"101","author":"Yamada","year":"2022","journal-title":"J. Dent. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.addr.2015.11.001","article-title":"Extracellular Matrix Structure","volume":"97","author":"Theocharis","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.matbio.2015.05.003","article-title":"The Microfibril-Associated Glycoproteins (MAGPs) and the Microfibrillar Niche","volume":"47","author":"Mecham","year":"2015","journal-title":"Matrix Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100121","DOI":"10.1016\/j.labinv.2023.100121","article-title":"Microfibril-Associated Glycoprotein-2 Promoted Fracture Healing via Integrin Av\u03b23\/PTK2\/AKT Signaling","volume":"103","author":"Chen","year":"2023","journal-title":"Lab. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1186\/s10020-021-00413-0","article-title":"Microfibrillar-Associated Protein 5 Regulates Osteogenic Differentiation by Modulating the Wnt\/\u03b2-Catenin and AMPK Signaling Pathways","volume":"27","author":"Li","year":"2021","journal-title":"Mol. Med. Camb. Mass"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.matbio.2018.04.005","article-title":"Genetics of the Extracellular Matrix in Aortic Aneurysmal Diseases","volume":"71\u201372","author":"Lin","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/j.ajhg.2014.10.018","article-title":"MFAP5 Loss-of-Function Mutations Underscore the Involvement of Matrix Alteration in the Pathogenesis of Familial Thoracic Aortic Aneurysms and Dissections","volume":"95","author":"Barbier","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1007\/s12094-019-02156-1","article-title":"Stromal Fibroblast-Derived MFAP5 Promotes the Invasion and Migration of Breast Cancer Cells via Notch1\/Slug Signaling","volume":"22","author":"Chen","year":"2020","journal-title":"Clin. Transl. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.matbio.2018.02.022","article-title":"Contribution of Metabolic Disease to Bone Fragility in MAGP1-Deficient Mice","volume":"67","author":"Turecamo","year":"2018","journal-title":"Matrix Biol. J. Int. Soc. Matrix Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"23858","DOI":"10.1074\/jbc.M110.113019","article-title":"Microfibril-Associated Glycoprotein-1, an Extracellular Matrix Regulator of Bone Remodeling","volume":"285","author":"Craft","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Walji, T.A., Turecamo, S.E., Sanchez, A.C., Anthony, B.A., Abou-Ezzi, G., Scheller, E.L., Link, D.C., Mecham, R.P., and Craft, C.S. (2016). Marrow Adipose Tissue Expansion Coincides with Insulin Resistance in MAGP1-Deficient Mice. Front. Endocrinol., 7.","DOI":"10.3389\/fendo.2016.00087"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1089\/ten.tea.2009.0735","article-title":"Parameters in Three-Dimensional Osteospheroids of Telomerized Human Mesenchymal (Stromal) Stem Cells Grown on Osteoconductive Scaffolds That Predict in Vivo Bone-Forming Potential","volume":"16","author":"Burns","year":"2010","journal-title":"Tissue Eng. Part A"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1002\/jcp.29893","article-title":"Molecular Structure and Function of Microfibrillar-Associated Proteins in Skeletal and Metabolic Disorders and Cancers","volume":"236","author":"Zhu","year":"2021","journal-title":"J. Cell. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e31183","DOI":"10.1002\/jcp.31183","article-title":"MAGP2 Promotes Osteogenic Differentiation during Fracture Healing through Its Crosstalk with the \u03b2-Catenin Pathway","volume":"239","author":"Chen","year":"2024","journal-title":"J. Cell. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e13287","DOI":"10.1111\/cpr.13287","article-title":"Single-Cell RNA Sequencing in Oral Science: Current Awareness and Perspectives","volume":"55","author":"Wu","year":"2022","journal-title":"Cell Prolif."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s00018-022-04183-8","article-title":"Organoids from Human Tooth Showing Epithelial Stemness Phenotype and Differentiation Potential","volume":"79","author":"Hemeryck","year":"2022","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4803","DOI":"10.1038\/s41467-022-32490-y","article-title":"Spatiotemporal Single-Cell Regulatory Atlas Reveals Neural Crest Lineage Diversification and Cellular Function during Tooth Morphogenesis","volume":"13","author":"Jing","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1111\/odi.12126","article-title":"Morphology and Chronology of Diphyodont Dentition in Miniature Pigs, Sus Scrofa","volume":"20","author":"Wang","year":"2014","journal-title":"Oral Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1111\/j.1601-0825.2006.01337.x","article-title":"The Miniature Pig: A Useful Large Animal Model for Dental and Orofacial Research","volume":"13","author":"Wang","year":"2007","journal-title":"Oral Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e102374","DOI":"10.15252\/embj.2019102374","article-title":"Biomechanical Stress Regulates Mammalian Tooth Replacement via the Integrin \u03921-RUNX2-Wnt Pathway","volume":"39","author":"Wu","year":"2020","journal-title":"EMBO J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"dev186023","DOI":"10.1242\/dev.186023","article-title":"Pitx2-Sox2-Lef1 Interactions Specify Progenitor Oral\/Dental Epithelial Cell Signaling Centers","volume":"147","author":"Yu","year":"2020","journal-title":"Development"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"111737","DOI":"10.1016\/j.celrep.2022.111737","article-title":"Dental Niche Cells Directly Contribute to Tooth Reconstitution and Morphogenesis","volume":"41","author":"Hu","year":"2022","journal-title":"Cell Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4816","DOI":"10.1038\/s41467-020-18512-7","article-title":"Dental Cell Type Atlas Reveals Stem and Differentiated Cell Types in Mouse and Human Teeth","volume":"11","author":"Krivanek","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Andersson, K., Dahll\u00f6f, G., Lindahl, K., Kindmark, A., Grigelioniene, G., \u00c5str\u00f6m, E., and Malmgren, B. (2017). Mutations in COL1A1 and COL1A2 and Dental Aberrations in Children and Adolescents with Osteogenesis Imperfecta\u2014A Retrospective Cohort Study. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176466"},{"key":"ref_40","first-page":"4691","article-title":"Edar\/Eda Interactions Regulate Enamel Knot Formation in Tooth Morphogenesis","volume":"127","author":"Tucker","year":"2000","journal-title":"Dev. Camb. Engl."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1126\/science.1116848","article-title":"Regulation of Mammalian Tooth Cusp Patterning by Ectodin","volume":"309","author":"Kassai","year":"2005","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1177\/0022034519835194","article-title":"Wnt Production in Dental Epithelium Is Crucial for Tooth Differentiation","volume":"98","author":"Xiong","year":"2019","journal-title":"J. Dent. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1177\/0022034519869307","article-title":"Molar Bud-to-Cap Transition Is Proliferation Independent","volume":"98","author":"Yamada","year":"2019","journal-title":"J. Dent. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1080\/03008200290000529","article-title":"Cell-Cell and Cell-Matrix Interactions during Initial Enamel Organ Histomorphogenesis in the Mouse","volume":"43","author":"Lesot","year":"2002","journal-title":"Connect. Tissue Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.ydbio.2004.10.021","article-title":"LEF1 Is a Critical Epithelial Survival Factor during Tooth Morphogenesis","volume":"278","author":"Sasaki","year":"2005","journal-title":"Dev. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3173","DOI":"10.1101\/gad.1035602","article-title":"FGF4, a Direct Target of LEF1 and Wnt Signaling, Can Rescue the Arrest of Tooth Organogenesis in Lef1\u2212\/\u2212 Mice","volume":"16","author":"Kratochwil","year":"2002","journal-title":"Genes Dev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"9665706","DOI":"10.1155\/sci\/9665706","article-title":"Spatio-Temporal Regulation of IGFs in Enamel Development: Molecular Mechanisms From Ameloblast Polarity to Mineralization Homeostasis","volume":"2025","author":"Zeng","year":"2025","journal-title":"Stem Cells Int."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1387\/ijdb.150192ao","article-title":"Expression of Sox Genes in Tooth Development","volume":"59","author":"Kawasaki","year":"2015","journal-title":"Int. J. Dev. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Chiba, Y., Tian, T., Yoshizaki, K., Wang, X., Yamada, A., and Fukumoto, S. (2025). Keratin 15 Regulates Cell Proliferation in Outer Enamel Epithelium. J. Dent. Res., Epub ahead of print.","DOI":"10.1177\/00220345251368346"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2749","DOI":"10.1007\/s00018-017-2526-9","article-title":"S100A6 Protein: Functional Roles","volume":"74","author":"Donato","year":"2017","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e23608","DOI":"10.1096\/fj.202302412RR","article-title":"S100a6 Knockdown Promotes the Differentiation of Dental Epithelial Cells toward the Epidermal Lineage Instead of the Odontogenic Lineage","volume":"38","author":"Otake","year":"2024","journal-title":"FASEB J."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Miao, X., Niibe, K., Zhang, M., Liu, Z., Nattasit, P., Ohori-Morita, Y., Nakamura, T., Jiang, X., and Egusa, H. (2021). Stage-Specific Role of Amelx Activation in Stepwise Ameloblast Induction from Mouse Induced Pluripotent Stem Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22137195"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.matbio.2010.03.001","article-title":"Ameloblast Differentiation in the Human Developing Tooth: Effects of Extracellular Matrices","volume":"29","author":"He","year":"2010","journal-title":"Matrix Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e2403627","DOI":"10.1002\/advs.202403627","article-title":"Spatiotemporal Molecular Architecture of Lineage Allocation and Cellular Organization in Tooth Morphogenesis","volume":"11","author":"Jiang","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1016\/j.stemcr.2023.03.011","article-title":"Organoids from Mouse Molar and Incisor as New Tools to Study Tooth-Specific Biology and Development","volume":"18","author":"Hermans","year":"2023","journal-title":"Stem Cell Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/s41368-021-00135-3","article-title":"Analyses of Oligodontia Phenotypes and Genetic Etiologies","volume":"13","author":"Zhou","year":"2021","journal-title":"Int. J. Oral Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1006\/dbio.2002.0734","article-title":"Lunatic Fringe, FGF, and BMP Regulate the Notch Pathway during Epithelial Morphogenesis of Teeth","volume":"248","author":"Mustonen","year":"2002","journal-title":"Dev. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s13287-025-04190-z","article-title":"Decoding SFRP2 Progenitors in Sustaining Tooth Growth at Single-Cell Resolution","volume":"16","author":"Zhao","year":"2025","journal-title":"Stem Cell Res. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/j.joen.2016.01.024","article-title":"Comparative Gene Expression Analysis of the Coronal Pulp and Apical Pulp Complex in Human Immature Teeth","volume":"42","author":"Kim","year":"2016","journal-title":"J. Endod."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1002\/dvdy.20285","article-title":"Dynamic Expression of Wnt Signaling-Related Dickkopf1, -2, and -3 mRNAs in the Developing Mouse Tooth","volume":"233","author":"Fjeld","year":"2005","journal-title":"Dev. Dyn."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1152\/physrev.00019.2022","article-title":"Mesenchymal Condensation in Tooth Development and Regeneration: A Focus on Translational Aspects of Organogenesis","volume":"103","author":"Sui","year":"2023","journal-title":"Physiol. Rev."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.archoralbio.2009.12.002","article-title":"Expression of Wnt5a in Tooth Germs and the Related Signal Transduction Analysis","volume":"55","author":"Peng","year":"2010","journal-title":"Arch. Oral Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nmeth.4150","article-title":"Single-Cell mRNA Quantification and Differential Analysis with Census","volume":"14","author":"Qiu","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41368-024-00277-0","article-title":"PRX1-Positive Mesenchymal Stem Cells Drive Molar Morphogenesis","volume":"16","author":"Xu","year":"2024","journal-title":"Int. J. Oral Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1002\/jbmr.3716","article-title":"Klf4 Promotes Dentinogenesis and Odontoblastic Differentiation via Modulation of TGF-\u03b2 Signaling Pathway and Interaction With Histone Acetylation","volume":"34","author":"Tao","year":"2019","journal-title":"J. Bone Miner. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1016\/j.joen.2011.03.030","article-title":"KLF4 Promotes the Odontoblastic Differentiation of Human Dental Pulp Cells","volume":"37","author":"Lin","year":"2011","journal-title":"J. Endod."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3795","DOI":"10.1242\/dev.126.17.3795","article-title":"Craniofacial, Vestibular and Bone Defects in Mice Lacking the Distal-Less-Related Gene Dlx5","volume":"126","author":"Acampora","year":"1999","journal-title":"Development"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.archoralbio.2017.01.011","article-title":"DLX3 Mutation Negatively Regulates Odontogenic Differentiation of Human Dental Pulp Cells","volume":"77","author":"Zeng","year":"2017","journal-title":"Arch. Oral Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.yexcr.2018.11.027","article-title":"Distal-Less Homeobox 5 Promotes the Osteo-\/Dentinogenic Differentiation Potential of Stem Cells from Apical Papilla by Activating Histone Demethylase KDM4B through a Positive Feedback Mechanism","volume":"374","author":"Yang","year":"2019","journal-title":"Exp. Cell Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nrm3904","article-title":"Remodelling the Extracellular Matrix in Development and Disease","volume":"15","author":"Bonnans","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.yexcr.2016.01.011","article-title":"MAGP2 Controls Notch via Interactions with RGD Binding Integrins: Identification of a Novel ECM-Integrin-Notch Signaling Axis","volume":"341","author":"Deford","year":"2016","journal-title":"Exp. Cell Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1146\/annurev.cellbio.12.1.697","article-title":"RGD and Other Recognition Sequences for Integrins","volume":"12","author":"Ruoslahti","year":"1996","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1002\/stem.2917","article-title":"Concise Review: Cellular and Molecular Mechanisms Regulation of Tooth Initiation","volume":"37","author":"Balic","year":"2019","journal-title":"Stem Cells"},{"key":"ref_74","first-page":"dev200539","article-title":"Understanding the Development of Oral Epithelial Organs through Single Cell Transcriptomic Analysis","volume":"149","author":"Ye","year":"2022","journal-title":"Dev. Camb. Engl."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Hermans, F., Bueds, C., Hemeryck, L., Lambrichts, I., Bronckaers, A., and Vankelecom, H. (2022). Establishment of Inclusive Single-Cell Transcriptome Atlases from Mouse and Human Tooth as Powerful Resource for Dental Research. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.1021459"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Chiba, Y., Saito, K., Martin, D., Boger, E.T., Rhodes, C., Yoshizaki, K., Nakamura, T., Yamada, A., Morell, R.J., and Yamada, Y. (2020). Single-Cell RNA-Sequencing From Mouse Incisor Reveals Dental Epithelial Cell-Type Specific Genes. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00841"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Zheng, Y., Lu, T., Zhang, L., Gan, Z., Li, A., He, C., He, F., He, S., Zhang, J., and Xiong, F. (2024). Single-Cell RNA-Seq Analysis of Rat Molars Reveals Cell Identity and Driver Genes Associated with Dental Mesenchymal Cell Differentiation. BMC Biol., 22.","DOI":"10.1186\/s12915-024-01996-w"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1186\/s13578-021-00691-5","article-title":"A Single-Cell Interactome of Human Tooth Germ from Growing Third Molar Elucidates Signaling Networks Regulating Dental Development","volume":"11","author":"Shi","year":"2021","journal-title":"Cell Biosci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1016\/j.scib.2022.03.012","article-title":"Single Cell Atlas of Developing Mouse Dental Germs Reveals Populations of CD24+ and Plac8+ Odontogenic Cells","volume":"67","author":"Wang","year":"2022","journal-title":"Sci. Bull."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1177\/00220345231205283","article-title":"Single-Cell Transcriptomic Analysis of Dental Pulp and Periodontal Ligament Stem Cells","volume":"103","author":"Yang","year":"2024","journal-title":"J. Dent. Res."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Ren, H., Wen, Q., Zhao, Q., Wang, N., and Zhao, Y. (2022). Atlas of Human Dental Pulp Cells at Multiple Spatial and Temporal Levels Based on Single-Cell Sequencing Analysis. Front. Physiol., 13, Erratum in Front. Physiol.\u00a02023, 14, 1331650.","DOI":"10.3389\/fphys.2022.993478"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"5016","DOI":"10.1038\/s41467-024-49037-y","article-title":"Single-Cell and Spatially Resolved Interactomics of Tooth-Associated Keratinocytes in Periodontitis","volume":"15","author":"Easter","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41368-025-00384-6","article-title":"Single-Cell Transcriptomics Identifies PDGFRA+ Progenitors Orchestrating Angiogenesis and Periodontal Tissue Regeneration","volume":"17","author":"Liu","year":"2025","journal-title":"Int. J. Oral Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1016\/j.devcel.2023.07.013","article-title":"Single-Cell Census of Human Tooth Development Enables Generation of Human Enamel","volume":"58","author":"Alghadeer","year":"2023","journal-title":"Dev. Cell"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"9610032","DOI":"10.26599\/OSHM.2025.9610032","article-title":"Comparative Transcriptomic Analysis of Human Maxillary and Mandibular Tooth Germs Reveals Discrepancies in Gene Expression Patterns","volume":"1","author":"Zhao","year":"2025","journal-title":"Oral Sci. Homeost. Med."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Mogoll\u00f3n, I., and Ahtiainen, L. (2020). Live Tissue Imaging Sheds Light on Cell Level Events During Ectodermal Organ Development. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.00818"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/wdev.63","article-title":"From Molecules to Mastication: The Development and Evolution of Teeth","volume":"2","author":"Jheon","year":"2013","journal-title":"Wiley Interdiscip. Rev. Dev. Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"11429","DOI":"10.1016\/S0021-9258(18)67403-4","article-title":"The Major Antigen of Elastin-Associated Microfibrils Is a 31-kDa Glycoprotein","volume":"261","author":"Gibson","year":"1986","journal-title":"J. Biol. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.matbio.2018.03.006","article-title":"Microfibril-Associated Glycoproteins MAGP-1 and MAGP-2 in Disease","volume":"71\u201372","author":"Craft","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"8728","DOI":"10.1038\/s41598-023-35558-x","article-title":"Microfibril-Associated Protein 5 and the Regulation of Skin Scar Formation","volume":"13","author":"Han","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1177\/0022034510363373","article-title":"Wnt\/Beta-Catenin Signaling in Oral Tissue Development and Disease","volume":"89","author":"Liu","year":"2010","journal-title":"J. Dent. Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1177\/0022034517719886","article-title":"Hippo Pathway: An Emerging Regulator of Craniofacial and Dental Development","volume":"96","author":"Wang","year":"2017","journal-title":"J. Dent. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"26187","DOI":"10.1038\/s41598-024-76069-7","article-title":"DPP an Extracellular Matrix Molecule Induces Wnt5a Mediated Signaling to Promote the Differentiation of Adult Stem Cells into Odontogenic Lineage","volume":"14","author":"Chen","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"29462","DOI":"10.1074\/jbc.M110.194746","article-title":"Dentin Matrix Protein 1 (DMP1) Signals via Cell Surface Integrin","volume":"286","author":"Wu","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/nrc2345","article-title":"Small Integrin-Binding Ligand N-Linked Glycoproteins (SIBLINGs): Multifunctional Proteins in Cancer","volume":"8","author":"Castronovo","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"43","DOI":"10.22203\/eCM.v042a04","article-title":"Dentine Sialophosphoprotein Signal in Dentineogenesis and Dentine Regeneration","volume":"42","author":"Liu","year":"2021","journal-title":"Eur. Cells Mater."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1530\/JOE-12-0143","article-title":"The Importance of the SIBLING Family of Proteins on Skeletal Mineralisation and Bone Remodelling","volume":"214","author":"Staines","year":"2012","journal-title":"J. Endocrinol."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Pan, H., Yang, Y., Xu, H., Jin, A., Huang, X., Gao, X., Sun, S., Liu, Y., Liu, J., and Lu, T. (2023). The Odontoblastic Differentiation of Dental Mesenchymal Stem Cells: Molecular Regulation Mechanism and Related Genetic Syndromes. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1174579"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s13287-019-1148-6","article-title":"MagT1 Regulated the Odontogenic Differentiation of BMMSCs Induced byTGC-CM via ERK Signaling Pathway","volume":"10","author":"Zheng","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1186\/s13287-019-1493-5","article-title":"Magnesium-Enriched Microenvironment Promotes Odontogenic Differentiation in Human Dental Pulp Stem Cells by Activating ERK\/BMP2\/Smads Signaling","volume":"10","author":"Kong","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/nrd1177","article-title":"P38 MAP Kinases: Key Signalling Molecules as Therapeutic Targets for Inflammatory Diseases","volume":"2","author":"Kumar","year":"2003","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Sonoyama, W., Liu, Y., Fang, D., Yamaza, T., Seo, B.-M., Zhang, C., Liu, H., Gronthos, S., Wang, C.-Y., and Wang, S. (2006). Mesenchymal Stem Cell-Mediated Functional Tooth Regeneration in Swine. PLoS ONE, 1.","DOI":"10.1371\/journal.pone.0000079"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1002\/term.321","article-title":"Porcine Tooth Germ Cell Conditioned Medium Can Induce Odontogenic Differentiation of Human Dental Pulp Stem Cells","volume":"5","author":"Wang","year":"2011","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1089\/ten.tea.2018.0243","article-title":"Whole-Tooth Regeneration by Allogeneic Cell Reassociation in Pig Jawbone","volume":"25","author":"Wu","year":"2019","journal-title":"Tissue Eng. Part A"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e10243","DOI":"10.1002\/advs.202410243","article-title":"EGR1 Promotes Craniofacial Bone Regeneration via Activation of ALPL+PDGFD+ Periosteal Stem Cells","volume":"12","author":"Li","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"7970","DOI":"10.1096\/fj.201902659R","article-title":"CAFs-Derived MFAP5 Promotes Bladder Cancer Malignant Behavior through NOTCH2\/HEY1 Signaling","volume":"34","author":"Zhou","year":"2020","journal-title":"FASEB J."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"14143","DOI":"10.3390\/ijms160614143","article-title":"Local Controlled Release of Polyphenol Conjugated with Gelatin Facilitates Bone Formation","volume":"16","author":"Honda","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1186\/s13287-017-0637-8","article-title":"Protein Deubiquitinase USP7 Is Required for Osteogenic Differentiation of Human Adipose-Derived Stem Cells","volume":"8","author":"Tang","year":"2017","journal-title":"Stem Cell Res. Ther."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s11658-019-0191-8","article-title":"Cellular Hypoxia Promotes Osteogenic Differentiation of Mesenchymal Stem Cells and Bone Defect Healing via STAT3 Signaling","volume":"24","author":"Yu","year":"2019","journal-title":"Cell. Mol. Biol. Lett."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/394\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T05:29:17Z","timestamp":1767245357000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/394"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,30]]},"references-count":109,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27010394"],"URL":"https:\/\/doi.org\/10.3390\/ijms27010394","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,30]]}}}