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Periodontal ligament stem cells (PDLSCs) are important for the healing of defective periodontal tissue. It is increasingly understood that healing of periodontal tissue is mediated through the secretion of trophic factors, particularly exosomes. This study investigated the effects of exosomes from human PDLSCs (HPDLSCs-Exo) on human osteoblast-like cells in vitro and on the healing of rat calvarial bone defects in vivo. HPDLSCs-Exo were isolated and characterized by their particle shape, size (133 \u00b1 6.4 nm), and expression of surface markers (CD9, CD63, and CD81). In vitro results showed that HPDLSCs-Exo promoted the migration, mineralization, and expression of bone-related genes such as alkaline phosphatase (ALP), bone morphogenetic protein 2 (BMP2), osteocalcin (OCN), and osteopontin (OPN) in human osteoblast-like cells. Furthermore, in vivo results showed that more newly formed bone was observed in the HPDLSCs-Exo-treated group than in the non-treated group at the defect sites in rats. These results indicated that HPDLSCs-Exo could promote osteogenesis in vitro and in vivo, and this suggests that HPDLSCs-Exo may be an attractive treatment tool for bone healing in defective periodontal tissue.<\/jats:p>","DOI":"10.3390\/biom14111455","type":"journal-article","created":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T05:36:45Z","timestamp":1731908205000},"page":"1455","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Exosomes from Human Periodontal Ligament Stem Cells Promote Differentiation of Osteoblast-like Cells and Bone Healing in Rat Calvarial Bone"],"prefix":"10.3390","volume":"14","author":[{"given":"Mhd Safwan","family":"Albougha","sequence":"first","affiliation":[{"name":"Department of Endodontology and Operative Dentistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Sugii","sequence":"additional","affiliation":[{"name":"Department of Endodontology and Operative Dentistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orie","family":"Adachi","sequence":"additional","affiliation":[{"name":"Department of Endodontology and Operative Dentistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bara","family":"Mardini","sequence":"additional","affiliation":[{"name":"Department of Endodontology and Operative Dentistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serina","family":"Soeno","sequence":"additional","affiliation":[{"name":"Department of Endodontology and Operative Dentistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayuri","family":"Hamano","sequence":"additional","affiliation":[{"name":"Department of Endodontology and Operative Dentistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daigaku","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Endodontology, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0016-7444","authenticated-orcid":false,"given":"Shinichiro","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Endodontology, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Itoyama","sequence":"additional","affiliation":[{"name":"Department of Endodontology and Operative Dentistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junko","family":"Obata","sequence":"additional","affiliation":[{"name":"Department of Endodontology and Operative Dentistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1347-995X","authenticated-orcid":false,"given":"Hidefumi","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Endodontology and Operative Dentistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"},{"name":"Department of Endodontology, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1177\/0022034517693566","article-title":"Global, Regional, and National Prevalence, Incidence, and Disability-Adjusted Life Years for Oral Conditions for 195 Countries, 1990-2015: A Systematic Analysis for the Global Burden of Diseases, Injuries, and Risk Factors","volume":"96","author":"Kassebaum","year":"2017","journal-title":"J. Dent. Res."},{"key":"ref_2","unstructured":"GBD 2017 Disease and Injury Incidence and Prevalence Collaborators (2018). Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet, 392, 1789\u20131858."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1111\/jcpe.13506","article-title":"Global, regional, and national burden of severe periodontitis, 1990-2019: An analysis of the Global Burden of Disease Study 2019","volume":"48","author":"Chen","year":"2021","journal-title":"J. Clin. Periodontol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1034\/j.1600-051X.2002.290607.x","article-title":"Periodontal attachment level of extractions presumably performed for periodontal reasons","volume":"29","author":"Splieth","year":"2002","journal-title":"J. Clin. Periodontol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1111\/prd.12008","article-title":"Surgical and nonsurgical periodontal therapy. Learned and unlearned concepts","volume":"62","author":"Lang","year":"2013","journal-title":"Periodontol. 2000"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1177\/0022034513513026","article-title":"Allogeneic bone marrow mesenchymal stem cell transplantation for periodontal regeneration","volume":"93","author":"Du","year":"2014","journal-title":"J. Dent. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1177\/0022034513498258","article-title":"Mesenchymal stem cells from iPS cells facilitate periodontal regeneration","volume":"92","author":"Hynes","year":"2013","journal-title":"J. Dent. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s13287-016-0288-1","article-title":"Treatment of periodontal intrabony defects using autologous periodontal ligament stem cells: A randomized clinical trial","volume":"7","author":"Chen","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/978-1-4939-9012-2_7","article-title":"Dental Mesenchymal Stem Cells: Dental Pulp Stem Cells, Periodontal Ligament Stem Cells, Apical Papilla Stem Cells, and Primary Teeth Stem Cells-Isolation, Characterization, and Expansion for Tissue Engineering","volume":"1922","author":"Huang","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"271","DOI":"10.3727\/096368910X519292","article-title":"Efficacy of periodontal stem cell transplantation in the treatment of advanced periodontitis","volume":"20","author":"Park","year":"2011","journal-title":"Cell Transplant."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.1016\/j.biomaterials.2013.12.053","article-title":"Application of stem cells derived from the periodontal ligament or gingival tissue sources for tendon tissue regeneration","volume":"35","author":"Moshaverinia","year":"2014","journal-title":"Biomaterials"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1111\/jre.12205","article-title":"Periodontal ligament-derived cells for periodontal regeneration in animal models: A systematic review","volume":"50","author":"Bright","year":"2015","journal-title":"J. Periodontal. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1089\/scd.2019.0025","article-title":"Periodontal Ligament Stem Cells: Current Knowledge and Future Perspectives","volume":"28","author":"Trubiani","year":"2019","journal-title":"Stem Cells Dev."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Iwasaki, K., Akazawa, K., Nagata, M., Komaki, M., Honda, I., Morioka, C., Yokoyama, N., Ayame, H., Yamaki, K., and Tanaka, Y. (2019). The Fate of Transplanted Periodontal Ligament Stem Cells in Surgically Created Periodontal Defects in Rats. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010192"},{"key":"ref_15","first-page":"611","article-title":"Bone regeneration potential of stem cells derived from periodontal ligament or gingival tissue sources encapsulated in RGD-modified alginate scaffold","volume":"20","author":"Moshaverinia","year":"2014","journal-title":"Tissue Eng. Part A"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5405","DOI":"10.2147\/IJN.S36714","article-title":"Bone repair by periodontal ligament stem cellseeded nanohydroxyapatite-chitosan scaffold","volume":"7","author":"Ge","year":"2012","journal-title":"Int. J. Nanomed."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1002\/stem.1118","article-title":"Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation","volume":"30","author":"Batsis","year":"2012","journal-title":"Stem Cells"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Marolt Presen, D., Traweger, A., Gimona, M., and Redl, H. (2019). Mesenchymal Stromal Cell-Based Bone Regeneration Therapies: From Cell Transplantation and Tissue Engineering to Therapeutic Secretomes and Extracellular Vesicles. Front. Bioeng. Biotechnol., 7.","DOI":"10.3389\/fbioe.2019.00352"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Yamamoto, Y., Xiao, Z., and Ochiya, T. (2019). The Immunomodulatory Functions of Mesenchymal Stromal\/Stem Cells Mediated via Paracrine Activity. J. Clin. Med., 8.","DOI":"10.3390\/jcm8071025"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"aau6977","DOI":"10.1126\/science.aau6977","article-title":"The biology, function, and biomedical applications of exosomes","volume":"367","author":"Kalluri","year":"2020","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1146\/annurev-biochem-013118-111902","article-title":"Exosomes","volume":"88","author":"Pegtel","year":"2019","journal-title":"Annu. Rev. Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/s13287-023-03345-0","article-title":"Stem cell-derived exosomes: Emerging therapeutic opportunities for wound healing","volume":"14","author":"Zhou","year":"2023","journal-title":"Stem Cell Res. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hade, M.D., Suire, C.N., and Suo, Z. (2021). Mesenchymal Stem Cell-Derived Exosomes: Applications in Regenerative Medicine. Cells, 10.","DOI":"10.3390\/cells10081959"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Dostert, G., Mesure, B., Menu, P., and Velot, E. (2017). How Do Mesenchymal Stem Cells Influence or Are Influenced by Microenvironment through Extracellular Vesicles Communication?. Front. Cell Dev. Biol., 5.","DOI":"10.3389\/fcell.2017.00006"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.transci.2016.07.015","article-title":"Circulating extracellular vesicles: Their role in tissue repair and regeneration","volume":"55","author":"Teixeira","year":"2016","journal-title":"Transfus. Apher. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Torrecillas-Baena, B., Pulido-Escribano, V., Dorado, G., Galvez-Moreno, M.A., Camacho-Cardenosa, M., and Casado-Diaz, A. (2023). Clinical Potential of Mesenchymal Stem Cell-Derived Exosomes in Bone Regeneration. J. Clin. Med., 12.","DOI":"10.3390\/jcm12134385"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.actbio.2019.03.021","article-title":"Mesenchymal stem cell exosomes enhance periodontal ligament cell functions and promote periodontal regeneration","volume":"89","author":"Chew","year":"2019","journal-title":"Acta Biomater."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Mohammed, E., Khalil, E., and Sabry, D. (2018). Effect of Adipose-Derived Stem Cells and Their Exo as Adjunctive Therapy to Nonsurgical Periodontal Treatment: A Histologic and Histomorphometric Study in Rats. Biomolecules, 8.","DOI":"10.3390\/biom8040167"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5797","DOI":"10.1021\/acsbiomaterials.0c00882","article-title":"Small Extracellular Vesicles from Lipopolysaccharide-Preconditioned Dental Follicle Cells Promote Periodontal Regeneration in an Inflammatory Microenvironment","volume":"6","author":"Shi","year":"2020","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1089\/ten.tea.2016.0274","article-title":"Conditioned Medium from Periodontal Ligament Stem Cells Enhances Periodontal Regeneration","volume":"23","author":"Nagata","year":"2017","journal-title":"Tissue Eng. Part A"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Rajan, T.S., Giacoppo, S., Diomede, F., Ballerini, P., Paolantonio, M., Marchisio, M., Piattelli, A., Bramanti, P., Mazzon, E., and Trubiani, O. (2016). The secretome of periodontal ligament stem cells from MS patients protects against EAE. Sci. Rep., 6.","DOI":"10.1038\/srep38743"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1177\/0394632017722332","article-title":"Human periodontal ligament stem cells secretome from multiple sclerosis patients suppresses NALP3 inflammasome activation in experimental autoimmune encephalomyelitis","volume":"30","author":"Giacoppo","year":"2017","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3805","DOI":"10.2147\/IJN.S162836","article-title":"A novel role in skeletal segment regeneration of extracellular vesicles released from periodontal-ligament stem cells","volume":"13","author":"Diomede","year":"2018","journal-title":"Int. J. Nanomed."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Pizzicannella, J., Gugliandolo, A., Orsini, T., Fontana, A., Ventrella, A., Mazzon, E., Bramanti, P., Diomede, F., and Trubiani, O. (2019). Engineered Extracellular Vesicles From Human Periodontal-Ligament Stem Cells Increase VEGF\/VEGFR2 Expression During Bone Regeneration. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00512"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1002\/jcp.26086","article-title":"Wnt5a suppresses osteoblastic differentiation of human periodontal ligament stem cell-like cells via Ror2\/JNK signaling","volume":"233","author":"Hasegawa","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Adachi, O., Sugii, H., Itoyama, T., Fujino, S., Kaneko, H., Tomokiyo, A., Hamano, S., Hasegawa, D., Obata, J., and Yoshida, S. (2022). Decorin Promotes Osteoblastic Differentiation of Human Periodontal Ligament Stem Cells. Molecules, 27.","DOI":"10.3390\/molecules27238224"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.bone.2014.05.021","article-title":"Effects of Activin A on the phenotypic properties of human periodontal ligament cells","volume":"66","author":"Sugii","year":"2014","journal-title":"Bone"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Bernar, A., Gebetsberger, J.V., Bauer, M., Streif, W., and Schirmer, M. (2022). Optimization of the Alizarin Red S Assay by Enhancing Mineralization of Osteoblasts. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010723"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.joen.2009.12.024","article-title":"Mineral trioxide aggregate induces bone morphogenetic protein-2 expression and calcification in human periodontal ligament cells","volume":"36","author":"Maeda","year":"2010","journal-title":"J. Endod."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Sugii, H., Albougha, M.S., Adachi, O., Tomita, H., Tomokiyo, A., Hamano, S., Hasegawa, D., Yoshida, S., Itoyama, T., and Maeda, H. (2021). Activin A Promotes Osteoblastic Differentiation of Human Preosteoblasts through the ALK1-Smad1\/5\/9 Pathway. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413491"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1038\/nprot.2012.113","article-title":"Evaluation of bone regeneration using the rat critical size calvarial defect","volume":"7","author":"Spicer","year":"2012","journal-title":"Nat. Protoc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2896","DOI":"10.1097\/SCS.0000000000007690","article-title":"Influence of Age on Calvarial Critical Size Defect Dimensions: A Radiographic and Histological Study","volume":"32","author":"Hudieb","year":"2021","journal-title":"J. Craniofac. Surg."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1002\/jbmr.141","article-title":"Guidelines for assessment of bone microstructure in rodents using micro-computed tomography","volume":"25","author":"Bouxsein","year":"2010","journal-title":"J. Bone Miner. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1101\/pdb.prot073411","article-title":"Manual hematoxylin and eosin staining of mouse tissue sections","volume":"2014","author":"Cardiff","year":"2014","journal-title":"Cold Spring Harb. Protoc."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Sugii, H., Yoshida, S., Albougha, M.S., Hamano, S., Hasegawa, D., Itoyama, T., Obata, J., Kaneko, H., Minowa, F., and Tomokiyo, A. (2024). 4-META\/MMA-TBB resin containing nano hydroxyapatite induces the healing of periodontal tissue repair in perforations at the pulp chamber floor. Cell Biochem. Funct., 42.","DOI":"10.1002\/cbf.4058"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6917","DOI":"10.2147\/IJN.S264498","article-title":"Exosome: A Review of Its Classification, Isolation Techniques, Storage, Diagnostic and Targeted Therapy Applications","volume":"15","author":"Zhang","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1535750","DOI":"10.1080\/20013078.2018.1535750","article-title":"Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines","volume":"7","author":"Thery","year":"2018","journal-title":"J. Extracell. Vesicles"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Tan, S.H.S., Wong, J.R.Y., Sim, S.J.Y., Tjio, C.K.E., Wong, K.L., Chew, J.R.J., Hui, J.H.P., and Toh, W.S. (2020). Mesenchymal stem cell exosomes in bone regenerative strategies-a systematic review of preclinical studies. Mater. Today Bio, 7.","DOI":"10.1016\/j.mtbio.2020.100067"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/s00223-019-00656-4","article-title":"Exosomes Secreted by Young Mesenchymal Stem Cells Promote New Bone Formation During Distraction Osteogenesis in Older Rats","volume":"106","author":"Jia","year":"2020","journal-title":"Calcif. Tissue Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5450768","DOI":"10.1155\/2018\/5450768","article-title":"Detection, Characterization, and Clinical Application of Mesenchymal Stem Cells in Periodontal Ligament Tissue","volume":"2018","author":"Tomokiyo","year":"2018","journal-title":"Stem Cells Int."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.stem.2020.11.002","article-title":"Differentiated Daughter Cells Regulate Stem Cell Proliferation and Fate through Intra-tissue Tension","volume":"28","author":"Ning","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"116933","DOI":"10.1016\/j.bone.2023.116933","article-title":"Osteoblast-derived exosomes promote osteogenic differentiation of osteosarcoma cells via URG4\/Wnt signaling pathway","volume":"178","author":"Leng","year":"2024","journal-title":"Bone"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1359\/jbmr.1999.14.1.47","article-title":"Differential cell surface expression of the STRO-1 and alkaline phosphatase antigens on discrete developmental stages in primary cultures of human bone cells","volume":"14","author":"Gronthos","year":"1999","journal-title":"J. Bone Miner. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"144855","DOI":"10.1016\/j.gene.2020.144855","article-title":"Alkaline phosphatase: Structure, expression and its function in bone mineralization","volume":"754","author":"Vimalraj","year":"2020","journal-title":"Gene"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41421-024-00689-6","article-title":"Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis","volume":"10","author":"Zhu","year":"2024","journal-title":"Cell Discov."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/s41580-020-00279-w","article-title":"Mechanisms of bone development and repair","volume":"21","author":"Salhotra","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Bandyopadhyay, A., Tsuji, K., Cox, K., Harfe, B.D., Rosen, V., and Tabin, C.J. (2006). Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet., 2.","DOI":"10.1371\/journal.pgen.0020216"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1038\/ng1916","article-title":"BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing","volume":"38","author":"Tsuji","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"9417914","DOI":"10.1155\/2019\/9417914","article-title":"The Role of Exosomes in Bone Remodeling: Implications for Bone Physiology and Disease","volume":"2019","author":"Masaoutis","year":"2019","journal-title":"Dis. Markers"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/odi.13202","article-title":"Exosomes derived from maxillary BMSCs enhanced the osteogenesis in iliac BMSCs","volume":"26","author":"Li","year":"2020","journal-title":"Oral Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e12669","DOI":"10.1111\/cpr.12669","article-title":"Exosomes derived from miR-375-overexpressing human adipose mesenchymal stem cells promote bone regeneration","volume":"52","author":"Chen","year":"2019","journal-title":"Cell Prolif."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.7150\/ijbs.16150","article-title":"Exosomes from Human Synovial-Derived Mesenchymal Stem Cells Prevent Glucocorticoid-Induced Osteonecrosis of the Femoral Head in the Rat","volume":"12","author":"Guo","year":"2016","journal-title":"Int. J. Biol. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e12570","DOI":"10.1111\/cpr.12570","article-title":"Exosomes from human umbilical cord mesenchymal stem cells enhance fracture healing through HIF-1alpha-mediated promotion of angiogenesis in a rat model of stabilized fracture","volume":"52","author":"Zhang","year":"2019","journal-title":"Cell Prolif."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/j.1601-6343.2005.00331.x","article-title":"The efficacy of mesenchymal stem cells to regenerate and repair dental structures","volume":"8","author":"Shi","year":"2005","journal-title":"Orthod. Craniof. Res."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Hertel, F.C., Silva, A.S.D., Sabino, A.P., Valente, F.L., and Reis, E.C.C. (2022). Preconditioning Methods to Improve Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Bone Regeneration-A Systematic Review. Biology, 11.","DOI":"10.3390\/biology11050733"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1002\/1873-3468.12024","article-title":"Exosomes derived from mineralizing osteoblasts promote ST2 cell osteogenic differentiation by alteration of microRNA expression","volume":"590","author":"Cui","year":"2016","journal-title":"FEBS Lett."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3716","DOI":"10.1021\/acsabm.1c00311","article-title":"Exosome-Functionalized Ceramic Bone Substitute Promotes Critical-Sized Bone Defect Repair in Rats","volume":"4","author":"Teotia","year":"2021","journal-title":"ACS Appl. 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