{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:07:02Z","timestamp":1789132022084,"version":"build-2803163510"},"reference-count":74,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T00:00:00Z","timestamp":1753315200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T00:00:00Z","timestamp":1753315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Int J Oral Sci"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Periodontal bone defects, primarily caused by periodontitis, are highly prevalent in clinical settings and manifest as bone fenestration, dehiscence, or attachment loss, presenting a significant challenge to oral health. In regenerative medicine, harnessing developmental principles for tissue repair offers promising therapeutic potential. Of particular interest is the condensation of progenitor cells, an essential event in organogenesis that has inspired clinically effective cell aggregation approaches in dental regeneration. However, the precise cellular coordination mechanisms during condensation and regeneration remain elusive. Here, taking the tooth as a model organ, we employed single-cell RNA sequencing to dissect the cellular composition and heterogeneity of human dental follicle and dental papilla, revealing a distinct Platelet-derived growth factor receptor alpha (PDGFRA) mesenchymal stem\/stromal cell (MSC) population with remarkable odontogenic potential. Interestingly, a reciprocal paracrine interaction between PDGFRA<jats:sup>+<\/jats:sup> dental follicle stem cells (DFSCs) and CD31<jats:sup>+<\/jats:sup> Endomucin<jats:sup>+<\/jats:sup> endothelial cells (ECs) was mediated by Vascular endothelial growth factor A (VEGFA) and Platelet-derived growth factor subunit BB (PDGFBB). This crosstalk not only maintains the functionality of PDGFRA<jats:sup>+<\/jats:sup> DFSCs but also drives specialized angiogenesis. In vivo periodontal bone regeneration experiments further reveal that communication between PDGFRA<jats:sup>+<\/jats:sup> DFSC aggregates and recipient ECs is essential for effective angiogenic-osteogenic coupling and rapid tissue repair. Collectively, our results unravel the importance of MSC-EC crosstalk mediated by the VEGFA and PDGFBB-PDGFRA reciprocal signaling in orchestrating angiogenesis and osteogenesis. These findings not only establish a framework for deciphering and promoting periodontal bone regeneration in potential clinical applications but also offer insights for future therapeutic strategies in dental or broader regenerative medicine.<\/jats:p>","DOI":"10.1038\/s41368-025-00384-6","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T03:45:57Z","timestamp":1753328757000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Single-cell transcriptomics identifies PDGFRA+ progenitors orchestrating angiogenesis and periodontal tissue regeneration"],"prefix":"10.1038","volume":"17","author":[{"given":"Jianing","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junxi","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5830-8354","authenticated-orcid":false,"given":"Xiaohui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyan","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peisheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiongyi","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiexi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuru","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haokun","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengfeng","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubohan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2586-1152","authenticated-orcid":false,"given":"Yan","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxi","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7282-0935","authenticated-orcid":false,"given":"Bingdong","family":"Sui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,24]]},"reference":[{"key":"384_CR1","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1111\/adj.12950","volume":"68","author":"A Nalbanto\u011flu","year":"2023","unstructured":"Nalbanto\u011flu, A. & Yan\u0131k, D. Fenestration and dehiscence defects in maxillary anterior teeth using two classification systems. Aust. Dent. J. 68, 48\u201357 (2023).","journal-title":"Aust. Dent. J."},{"key":"384_CR2","first-page":"391","volume":"50","author":"VR Nimigean","year":"2009","unstructured":"Nimigean, V. R. et al. Alveolar bone dehiscences and fenestrations: an anatomical study and review. Rom. J. Morphol. Embryol. 50, 391\u2013397 (2009).","journal-title":"Rom. J. Morphol. Embryol."},{"key":"384_CR3","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/s41586-018-0089-z","volume":"557","author":"CM Madl","year":"2018","unstructured":"Madl, C. M., Heilshorn, S. C. & Blau, H. M. Bioengineering strategies to accelerate stem cell therapeutics. Nature 557, 335\u2013342 (2018).","journal-title":"Nature"},{"key":"384_CR4","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1016\/j.stem.2020.09.014","volume":"27","author":"S Yamanaka","year":"2020","unstructured":"Yamanaka, S. Pluripotent stem cell-based cell therapy-promise and challenges. Cell Stem Cell 27, 523\u2013531 (2020).","journal-title":"Cell Stem Cell"},{"key":"384_CR5","doi-asserted-by":"publisher","first-page":"20240027","DOI":"10.1002\/EXP.20240027","volume":"4","author":"M Li","year":"2024","unstructured":"Li, M. et al. Bioengineer mesenchymal stem cell for treatment of glioma by IL-12 mediated microenvironment reprogramming and nCD47-SLAMF7 mediated phagocytosis regulation of macrophages. Exploration4, 20240027 (2024).","journal-title":"Exploration"},{"key":"384_CR6","doi-asserted-by":"publisher","first-page":"1467","DOI":"10.1016\/j.cell.2020.11.003","volume":"183","author":"M Zhu","year":"2020","unstructured":"Zhu, M. & Zernicka-Goetz, M. Principles of self-organization of the mammalian embryo. Cell 183, 1467\u20131478 (2020).","journal-title":"Cell"},{"key":"384_CR7","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1016\/j.stem.2019.05.005","volume":"24","author":"JA Brassard","year":"2019","unstructured":"Brassard, J. A. & Lutolf, M. P. Engineering stem cell self-organization to build better organoids. Cell Stem Cell 24, 860\u2013876 (2019).","journal-title":"Cell Stem Cell"},{"key":"384_CR8","doi-asserted-by":"publisher","first-page":"1899","DOI":"10.1152\/physrev.00019.2022","volume":"103","author":"B-D Sui","year":"2023","unstructured":"Sui, B.-D. et al. Mesenchymal condensation in tooth development and regeneration: a focus on translational aspects of organogenesis. Physiol. Rev. 103, 1899\u20131964 (2023).","journal-title":"Physiol. Rev."},{"key":"384_CR9","doi-asserted-by":"publisher","DOI":"10.1002\/agt2.497","volume":"5","author":"C-X Zheng","year":"2024","unstructured":"Zheng, C.-X., Sui, B.-D. & Jin, Y. Harnessing mesenchymal aggregation for engineered organ-level regeneration: recent progress and perspective. Aggregate 5, e497 (2024).","journal-title":"Aggregate"},{"key":"384_CR10","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1038\/nmeth1012","volume":"4","author":"K Nakao","year":"2007","unstructured":"Nakao, K. et al. The development of a bioengineered organ germ method. Nat. Methods 4, 227\u2013230 (2007).","journal-title":"Nat. Methods"},{"key":"384_CR11","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1007\/7651_2018_186","volume":"2002","author":"B-D Sui","year":"2019","unstructured":"Sui, B.-D., Zhu, B., Hu, C.-H., Zhao, P. & Jin, Y. Reconstruction of regenerative stem cell niche by cell aggregate engineering. Methods Mol. Biol. 2002, 87\u201399 (2019).","journal-title":"Methods Mol. Biol."},{"key":"384_CR12","doi-asserted-by":"publisher","first-page":"eaaf3227","DOI":"10.1126\/scitranslmed.aaf3227","volume":"10","author":"K Xuan","year":"2018","unstructured":"Xuan, K. et al. Deciduous autologous tooth stem cells regenerate dental pulp after implantation into injured teeth. Sci. Transl. Med. 10, eaaf3227 (2018).","journal-title":"Sci. Transl. Med."},{"key":"384_CR13","doi-asserted-by":"publisher","first-page":"121223","DOI":"10.1016\/j.biomaterials.2021.121223","volume":"279","author":"H Guo","year":"2021","unstructured":"Guo, H. et al. Odontogenesis-related developmental microenvironment facilitates deciduous dental pulp stem cell aggregates to revitalize an avulsed tooth. Biomaterials 279, 121223 (2021).","journal-title":"Biomaterials"},{"key":"384_CR14","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1007\/s12015-011-9229-7","volume":"7","author":"M Pevsner-Fischer","year":"2011","unstructured":"Pevsner-Fischer, M., Levin, S. & Zipori, D. The origins of mesenchymal stromal cell heterogeneity. Stem Cell Rev. Rep. 7, 560\u2013568 (2011).","journal-title":"Stem Cell Rev. Rep."},{"key":"384_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18512-7","volume":"11","author":"J Krivanek","year":"2020","unstructured":"Krivanek, J. et al. Dental cell type atlas reveals stem and differentiated cell types in mouse and human teeth. Nat. Commun. 11, 4816 (2020).","journal-title":"Nat. Commun."},{"key":"384_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32490-y","volume":"13","author":"J Jing","year":"2022","unstructured":"Jing, J. et al. Spatiotemporal single-cell regulatory atlas reveals neural crest lineage diversification and cellular function during tooth morphogenesis. Nat. Commun. 13, 4803 (2022).","journal-title":"Nat. Commun."},{"key":"384_CR17","doi-asserted-by":"publisher","first-page":"eaay1514","DOI":"10.1126\/sciadv.aay1514","volume":"6","author":"H Chen","year":"2020","unstructured":"Chen, H. et al. Regeneration of pulpo-dentinal-like complex by a group of unique multipotent CD24a+ stem cells. Sci. Adv. 6, eaay1514 (2020).","journal-title":"Sci. Adv."},{"key":"384_CR18","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s13287-016-0288-1","volume":"7","author":"F-M Chen","year":"2016","unstructured":"Chen, F.-M. et al. Treatment of periodontal intrabony defects using autologous periodontal ligament stem cells: a randomized clinical trial. Stem Cell Res. Ther. 7, 33 (2016).","journal-title":"Stem Cell Res. Ther."},{"key":"384_CR19","volume":"4","author":"M Bao","year":"2022","unstructured":"Bao, M. Self-organization principles in stem-cell-derived synthetic embryo models. Innovation 4, 100366 (2022).","journal-title":"Innovation"},{"key":"384_CR20","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1016\/j.stem.2015.03.004","volume":"16","author":"T Takebe","year":"2015","unstructured":"Takebe, T. et al. Vascularized and complex organ buds from diverse tissues via mesenchymal cell-driven condensation. Cell Stem Cell 16, 556\u2013565 (2015).","journal-title":"Cell Stem Cell"},{"key":"384_CR21","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1111\/joa.12950","volume":"234","author":"O Shadad","year":"2019","unstructured":"Shadad, O., Chaulagain, R., Luukko, K. & Kettunen, P. Establishment of tooth blood supply and innervation is developmentally regulated and takes place through differential patterning processes. J. Anat. 234, 465\u2013479 (2019).","journal-title":"J. Anat."},{"key":"384_CR22","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1177\/154405910808701216","volume":"87","author":"A Nait Lechguer","year":"2008","unstructured":"Nait Lechguer, A., Kuchler-Bopp, S., Hu, B., Ha\u00efkel, Y. & Lesot, H. Vascularization of engineered teeth. J. Dent. Res. 87, 1138\u20131143 (2008).","journal-title":"J. Dent. Res."},{"key":"384_CR23","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/s41422-022-00615-z","volume":"32","author":"S Hou","year":"2022","unstructured":"Hou, S. et al. Heterogeneity in endothelial cells and widespread venous arterialization during early vascular development in mammals. Cell Res. 32, 333\u2013348 (2022).","journal-title":"Cell Res."},{"key":"384_CR24","doi-asserted-by":"publisher","first-page":"1154","DOI":"10.1016\/j.scib.2022.03.012","volume":"67","author":"Y Wang","year":"2022","unstructured":"Wang, Y. et al. Single cell atlas of developing mouse dental germs reveals populations of CD24+ and Plac8+ odontogenic cells. Sci. Bull. 67, 1154\u20131169 (2022).","journal-title":"Sci. Bull."},{"key":"384_CR25","doi-asserted-by":"publisher","first-page":"e79","DOI":"10.1371\/journal.pone.0000079","volume":"1","author":"W Sonoyama","year":"2006","unstructured":"Sonoyama, W. et al. Mesenchymal stem cell-mediated functional tooth regeneration in swine. PLoS ONE 1, e79 (2006).","journal-title":"PLoS ONE"},{"key":"384_CR26","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.matbio.2004.12.004","volume":"24","author":"C Morsczeck","year":"2005","unstructured":"Morsczeck, C. et al. Isolation of precursor cells (PCs) from human dental follicle of wisdom teeth. Matrix Biol. 24, 155\u2013165 (2005).","journal-title":"Matrix Biol."},{"key":"384_CR27","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.stemcr.2020.06.007","volume":"15","author":"J Chen","year":"2020","unstructured":"Chen, J. et al. Gli1+ cells couple with type H vessels and are required for type H vessel formation. Stem Cell Rep. 15, 110\u2013124 (2020).","journal-title":"Stem Cell Rep."},{"key":"384_CR28","doi-asserted-by":"publisher","first-page":"e2300019","DOI":"10.1002\/adhm.202300019","volume":"12","author":"L Liu","year":"2023","unstructured":"Liu, L. et al. Mesenchymal stem cell aggregation-released extracellular vesicles induce CD31+ EMCN+ vessels in skin regeneration and improve diabetic wound healing. Adv. Healthc. Mater. 12, e2300019 (2023).","journal-title":"Adv. Healthc. Mater."},{"key":"384_CR29","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1002\/dvdy.406","volume":"251","author":"VC Bastos","year":"2022","unstructured":"Bastos, V. C., Gomez, R. S. & Gomes, C. C. Revisiting the human dental follicle: From tooth development to its association with unerupted or impacted teeth and pathological changes. Dev. Dyn. 251, 408\u2013423 (2022).","journal-title":"Dev. Dyn."},{"key":"384_CR30","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1111\/jre.12477","volume":"52","author":"T de Jong","year":"2017","unstructured":"de Jong, T., Bakker, A. D., Everts, V. & Smit, T. H. The intricate anatomy of the periodontal ligament and its development: lessons for periodontal regeneration. J. Periodontal Res. 52, 965\u2013974 (2017).","journal-title":"J. Periodontal Res."},{"key":"384_CR31","doi-asserted-by":"publisher","first-page":"2483","DOI":"10.1084\/jem.20091046","volume":"206","author":"S Morikawa","year":"2009","unstructured":"Morikawa, S. et al. Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow. J. Exp. Med. 206, 2483\u20132496 (2009).","journal-title":"J. Exp. Med."},{"key":"384_CR32","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1016\/j.stem.2024.04.011","volume":"31","author":"T Guo","year":"2024","unstructured":"Guo, T. et al. Vascular architecture regulates mesenchymal stromal cell heterogeneity via P53-PDGF signaling in the mouse incisor. Cell Stem Cell 31, 904\u2013920.e6 (2024).","journal-title":"Cell Stem Cell"},{"key":"384_CR33","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1038\/nature13145","volume":"507","author":"AP Kusumbe","year":"2014","unstructured":"Kusumbe, A. P., Ramasamy, S. K. & Adams, R. H. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 507, 323\u2013328 (2014).","journal-title":"Nature"},{"key":"384_CR34","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/nature13146","volume":"507","author":"SK Ramasamy","year":"2014","unstructured":"Ramasamy, S. K., Kusumbe, A. P., Wang, L. & Adams, R. H. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature 507, 376\u2013380 (2014).","journal-title":"Nature"},{"key":"384_CR35","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.addr.2020.11.012","volume":"169","author":"I Papantoniou","year":"2021","unstructured":"Papantoniou, I. et al. Turning Nature\u2019s own processes into design strategies for living bone implant biomanufacturing: a decade of Developmental Engineering. Adv. Drug Deliv. Rev. 169, 22\u201339 (2021).","journal-title":"Adv. Drug Deliv. Rev."},{"key":"384_CR36","doi-asserted-by":"publisher","first-page":"eaav7756","DOI":"10.1126\/scitranslmed.aav7756","volume":"11","author":"AM McDermott","year":"2019","unstructured":"McDermott, A. M. et al. Recapitulating bone development through engineered mesenchymal condensations and mechanical cues for tissue regeneration. Sci. Transl. Med. 11, eaav7756 (2019).","journal-title":"Sci. Transl. Med."},{"key":"384_CR37","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1186\/s13578-021-00691-5","volume":"11","author":"Y Shi","year":"2021","unstructured":"Shi, Y. et al. A single-cell interactome of human tooth germ from growing third molar elucidates signaling networks regulating dental development. Cell Biosci. 11, 178 (2021).","journal-title":"Cell Biosci."},{"key":"384_CR38","doi-asserted-by":"publisher","first-page":"111737","DOI":"10.1016\/j.celrep.2022.111737","volume":"41","author":"H Hu","year":"2022","unstructured":"Hu, H. et al. Dental niche cells directly contribute to tooth reconstitution and morphogenesis. Cell Rep. 41, 111737 (2022).","journal-title":"Cell Rep."},{"key":"384_CR39","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/nrg1380","volume":"5","author":"A Tucker","year":"2004","unstructured":"Tucker, A. & Sharpe, P. The cutting-edge of mammalian development; how the embryo makes teeth. Nat. Rev. Genet. 5, 499\u2013508 (2004).","journal-title":"Nat. Rev. Genet."},{"key":"384_CR40","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1038\/s41368-023-00258-9","volume":"15","author":"P Rao","year":"2023","unstructured":"Rao, P., Jing, J., Fan, Y. & Zhou, C. Spatiotemporal cellular dynamics and molecular regulation of tooth root ontogeny. Int. J. Oral. Sci. 15, 50 (2023).","journal-title":"Int. J. Oral. Sci."},{"key":"384_CR41","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1016\/j.biomaterials.2011.09.068","volume":"33","author":"W Guo","year":"2012","unstructured":"Guo, W. et al. Dental follicle cells and treated dentin matrix scaffold for tissue engineering the tooth root. Biomaterials 33, 1291\u20131302 (2012).","journal-title":"Biomaterials"},{"key":"384_CR42","doi-asserted-by":"publisher","first-page":"102405","DOI":"10.1016\/j.isci.2021.102405","volume":"24","author":"P Pagella","year":"2021","unstructured":"Pagella, P., de Vargas Roditi, L., Stadlinger, B., Moor, A. E. & Mitsiadis, T. A. A single-cell atlas of human teeth. iScience 24, 102405 (2021).","journal-title":"iScience"},{"key":"384_CR43","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1089\/ten.tea.2009.0518","volume":"16","author":"GT-J Huang","year":"2010","unstructured":"Huang, G. T.-J. et al. Stem\/Progenitor cell-mediated de novo regeneration of dental pulp with newly deposited continuous layer of dentin in an in vivo model. Tissue Eng. Part A 16, 605\u2013615 (2010).","journal-title":"Tissue Eng. Part A"},{"key":"384_CR44","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1046\/j.1440-169X.1997.t01-5-00009.x","volume":"39","author":"H Kataoka","year":"1997","unstructured":"Kataoka, H. et al. Expressions of PDGF receptor alpha, c-Kit and Flk1 genes clustering in mouse chromosome 5 define distinct subsets of nascent mesodermal cells. Dev. Growth Differ. 39, 729\u2013740 (1997).","journal-title":"Dev. Growth Differ."},{"key":"384_CR45","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1038\/s41556-022-00955-3","volume":"24","author":"V Chandrakanthan","year":"2022","unstructured":"Chandrakanthan, V. et al. Mesoderm-derived PDGFRA+ cells regulate the emergence of hematopoietic stem cells in the dorsal aorta. Nat. Cell Biol. 24, 1211\u20131225 (2022).","journal-title":"Nat. Cell Biol."},{"key":"384_CR46","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1016\/j.stem.2021.01.007","volume":"28","author":"X Han","year":"2021","unstructured":"Han, X. et al. A suite of new Dre recombinase drivers markedly expands the ability to perform intersectional genetic targeting. Cell Stem Cell 28, 1160\u20131176.e7 (2021).","journal-title":"Cell Stem Cell"},{"key":"384_CR47","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/j.stemcr.2024.02.001","volume":"19","author":"Y Liao","year":"2024","unstructured":"Liao, Y. et al. MSX1+PDGFRAlow limb mesenchyme-like cells as an efficient stem cell source for human cartilage regeneration. Stem Cell Rep. 19, 399\u2013413 (2024).","journal-title":"Stem Cell Rep."},{"key":"384_CR48","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1002\/dvdy.20197","volume":"232","author":"X Xu","year":"2005","unstructured":"Xu, X., Bringas, P., Soriano, P. & Chai, Y. PDGFR-alpha signaling is critical for tooth cusp and palate morphogenesis. Dev. Dyn. 232, 75\u201384 (2005).","journal-title":"Dev. Dyn."},{"key":"384_CR49","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1002\/(SICI)1097-0177(199812)213:4<500::AID-AJA14>3.0.CO;2-A","volume":"213","author":"Y Chai","year":"1998","unstructured":"Chai, Y., Bringas, P., Mogharei, A., Shuler, C. F. & Slavkin, H. C. PDGF-A and PDGFR-alpha regulate tooth formation via autocrine mechanism during mandibular morphogenesis in vitro. Dev. Dyn. 213, 500\u2013511 (1998).","journal-title":"Dev. Dyn."},{"key":"384_CR50","doi-asserted-by":"publisher","first-page":"640","DOI":"10.3389\/fcell.2020.00640","volume":"8","author":"E Svandova","year":"2020","unstructured":"Svandova, E., Peterkova, R., Matalova, E. & Lesot, H. Formation and developmental specification of the odontogenic and osteogenic mesenchymes. Front. Cell Dev. Biol. 8, 640 (2020).","journal-title":"Front. Cell Dev. Biol."},{"key":"384_CR51","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1016\/j.devcel.2011.07.006","volume":"21","author":"T Mammoto","year":"2011","unstructured":"Mammoto, T. et al. Mechanochemical control of mesenchymal condensation and embryonic tooth organ formation. Dev. Cell 21, 758\u2013769 (2011).","journal-title":"Dev. Cell"},{"key":"384_CR52","doi-asserted-by":"publisher","first-page":"120765","DOI":"10.1016\/j.biomaterials.2021.120765","volume":"272","author":"T-W Hsu","year":"2021","unstructured":"Hsu, T.-W. et al. Transplantation of 3D MSC\/HUVEC spheroids with neuroprotective and proangiogenic potentials ameliorates ischemic stroke brain injury. Biomaterials 272, 120765 (2021).","journal-title":"Biomaterials"},{"key":"384_CR53","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/s41551-020-00674-w","volume":"5","author":"J Lee","year":"2021","unstructured":"Lee, J. et al. Mechanobiological conditioning of mesenchymal stem cells for enhanced vascular regeneration. Nat. Biomed. Eng. 5, 89\u2013102 (2021).","journal-title":"Nat. Biomed. Eng."},{"key":"384_CR54","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1161\/CIRCRESAHA.121.319590","volume":"129","author":"X Liang","year":"2021","unstructured":"Liang, X. et al. LARP7 suppresses endothelial-to-mesenchymal transition by coupling with TRIM28. Circ. Res. 129, 843\u2013856 (2021).","journal-title":"Circ. Res."},{"key":"384_CR55","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44312-w","volume":"14","author":"J Cao","year":"2023","unstructured":"Cao, J. et al. Reassessing endothelial-to-mesenchymal transition in mouse bone marrow: insights from lineage tracing models. Nat. Commun. 14, 8461 (2023).","journal-title":"Nat. Commun."},{"key":"384_CR56","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.7150\/thno.65694","volume":"12","author":"Y Chen","year":"2022","unstructured":"Chen, Y. et al. Single-cell RNA landscape of the osteoimmunology microenvironment in periodontitis. Theranostics 12, 1074\u20131096 (2022).","journal-title":"Theranostics"},{"key":"384_CR57","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1111\/prd.12250","volume":"79","author":"J Nu\u00f1ez","year":"2019","unstructured":"Nu\u00f1ez, J., Vignoletti, F., Caffesse, R. G. & Sanz, M. Cellular therapy in periodontal regeneration. Periodontology 2000 79, 107\u2013116 (2019).","journal-title":"Periodontology 2000"},{"key":"384_CR58","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1111\/prd.12457","volume":"90","author":"F Pamuk","year":"2022","unstructured":"Pamuk, F. & Kantarci, A. Inflammation as a link between periodontal disease and obesity. Periodontol. 2000 90, 186\u2013196 (2022).","journal-title":"Periodontol. 2000"},{"key":"384_CR59","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.38","volume":"3","author":"DF Kinane","year":"2017","unstructured":"Kinane, D. F., Stathopoulou, P. G. & Papapanou, P. N. Periodontal diseases. Nat. Rev. Dis. Prim. 3, 17038 (2017).","journal-title":"Nat. Rev. Dis. Prim."},{"key":"384_CR60","doi-asserted-by":"publisher","first-page":"20210043","DOI":"10.1002\/EXP.20210043","volume":"3","author":"Y Peng","year":"2023","unstructured":"Peng, Y. et al. Bioinspired gradient scaffolds for osteochondral tissue engineering. Exploration3, 20210043 (2023).","journal-title":"Exploration"},{"key":"384_CR61","doi-asserted-by":"publisher","first-page":"20","DOI":"10.22203\/eCM.v042a02","volume":"42","author":"J Chu","year":"2021","unstructured":"Chu, J. et al. Dental follicle cell differentiation towards periodontal ligament-like tissue in a self-assembly three-dimensional organoid model. Eur. Cell Mater. 42, 20\u201333 (2021).","journal-title":"Eur. Cell Mater."},{"key":"384_CR62","doi-asserted-by":"publisher","first-page":"6708","DOI":"10.1016\/j.biomaterials.2009.08.034","volume":"30","author":"W Guo","year":"2009","unstructured":"Guo, W. et al. The use of dentin matrix scaffold and dental follicle cells for dentin regeneration. Biomaterials 30, 6708\u20136723 (2009).","journal-title":"Biomaterials"},{"key":"384_CR63","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13074","volume":"54","author":"M Wu","year":"2021","unstructured":"Wu, M. et al. SHED aggregate exosomes shuttled miR-26a promote angiogenesis in pulp regeneration via TGF-\u03b2\/SMAD2\/3 signalling. Cell Prolif. 54, e13074 (2021).","journal-title":"Cell Prolif."},{"key":"384_CR64","doi-asserted-by":"publisher","first-page":"2400260","DOI":"10.1002\/smll.202400260","volume":"20","author":"X Huang","year":"2024","unstructured":"Huang, X. et al. Odontogenesis-empowered extracellular vesicles safeguard donor-recipient stem cell interplay to support tooth regeneration. Small 20, 2400260 (2024).","journal-title":"Small"},{"key":"384_CR65","doi-asserted-by":"publisher","first-page":"3193","DOI":"10.1016\/j.ymthe.2022.05.006","volume":"30","author":"Z Li","year":"2022","unstructured":"Li, Z. et al. Apoptotic vesicles activate autophagy in recipient cells to induce angiogenesis and dental pulp regeneration. Mol. Ther. 30, 3193\u20133208 (2022).","journal-title":"Mol. Ther."},{"key":"384_CR66","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202306721","volume":"20","author":"S Pan","year":"2024","unstructured":"Pan, S. et al. Multifunctional injectable hydrogel microparticles loaded with miR-29a abundant BMSCs derived exosomes enhanced bone regeneration by regulating osteogenesis and angiogenesis. Small 20, e2306721 (2024).","journal-title":"Small"},{"key":"384_CR67","doi-asserted-by":"publisher","first-page":"1821","DOI":"10.7150\/ijbs.57681","volume":"17","author":"F Wang","year":"2021","unstructured":"Wang, F. et al. Accelerated bone regeneration by astragaloside IV through stimulating the coupling of osteogenesis and angiogenesis. Int. J. Biol. Sci. 17, 1821\u20131836 (2021).","journal-title":"Int. J. Biol. Sci."},{"key":"384_CR68","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1038\/s41584-021-00682-3","volume":"17","author":"J Tuckermann","year":"2021","unstructured":"Tuckermann, J. & Adams, R. H. Crosstalk between endothelial cells and bone in development, homeostasis and inflammatory disease. Nat. Rev. Rheumatol. 17, 608\u2013620 (2021).","journal-title":"Nat. Rev. Rheumatol."},{"key":"384_CR69","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.5966\/sctm.2015-0062","volume":"4","author":"E Henry","year":"2015","unstructured":"Henry, E. et al. Adult lung spheroid cells contain progenitor cells and mediate regeneration in rodents with bleomycin-induced pulmonary fibrosis. Stem Cells Transl. Med. 4, 1265\u20131274 (2015).","journal-title":"Stem Cells Transl. Med."},{"key":"384_CR70","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1186\/s12931-017-0611-0","volume":"18","author":"P-UC Dinh","year":"2017","unstructured":"Dinh, P.-U. C. et al. Derivation of therapeutic lung spheroid cells from minimally invasive transbronchial pulmonary biopsies. Respir. Res. 18, 132 (2017).","journal-title":"Respir. Res."},{"key":"384_CR71","volume":"5","author":"X Han","year":"2024","unstructured":"Han, X. et al. Landscape of human organoids: ideal model in clinics and research. Innovation5, 100620 (2024).","journal-title":"Innovation"},{"key":"384_CR72","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.12830","volume":"53","author":"X Qiu","year":"2020","unstructured":"Qiu, X. et al. Exosomes released from educated mesenchymal stem cells accelerate cutaneous wound healing via promoting angiogenesis. Cell Prolif. 53, e12830 (2020).","journal-title":"Cell Prolif."},{"key":"384_CR73","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1016\/j.gpb.2021.08.001","volume":"19","author":"T Chen","year":"2021","unstructured":"Chen, T. et al. The genome sequence archive family: toward explosive data growth and diverse data types. Genom. Proteom. Bioinform. 19, 578\u2013583 (2021).","journal-title":"Genom. Proteom. Bioinform."},{"key":"384_CR74","doi-asserted-by":"publisher","first-page":"D27","DOI":"10.1093\/nar\/gkab951","volume":"50","author":"CNCB-NGDC Members and Partners","year":"2022","unstructured":"CNCB-NGDC Members and Partners Database Resources of the National Genomics Data Center, China National Center for Bioinformation in 2022. Nucleic Acids Res. 50, D27\u2013D38 (2022).","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Oral Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41368-025-00384-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41368-025-00384-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41368-025-00384-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,7]],"date-time":"2025-09-07T23:11:42Z","timestamp":1757286702000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41368-025-00384-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,24]]},"references-count":74,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["384"],"URL":"https:\/\/doi.org\/10.1038\/s41368-025-00384-6","relation":{},"ISSN":["2049-3169"],"issn-type":[{"value":"2049-3169","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,24]]},"assertion":[{"value":"17 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 May 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 June 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 July 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study was approved by the Ethics Committee of The Fourth Military Medical University (Approval No. IRB-REV-2022187).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"56"}}