Immunomodulatory Role of Stem Cells from Human Exfoliated Deciduous Teeth on Periodontal Regeneration.

Periodontitis is initiated by the infection of periodontal bacteria and subsequent tissue inflammation due to immunoreaction, eventually leading to periodontal apparatus loss. Stem cells from human exfoliated deciduous teeth (SHEDs) have exhibited beneficial characteristics in dental tissue regeneration. However, the immunomodulatory functions of SHEDs have not been elucidated in the context of periodontitis treatment. In this study, we investigated the potential immunomodulatory effects of SHEDs on experimental periodontitis and demonstrated that multidose delivery of SHEDs led to periodontal tissue regeneration. SHEDs and monocytes/macrophages were cocultured in transwell systems and SHEDs were found to be capable of promoting monocyte/macrophage conversion to CD206+ M2-like phenotype. Bioluminescence imaging (BLI) was employed to assess the survival and distribution of SHEDs after delivery in periodontal tissues in an induced periodontitis model, and BLI revealed that SHEDs survived for ∼7 days in periodontal tissues with little tissue diffusion. Then, multidose SHED delivery was applied to treat periodontitis at 7-day intervals. Results showed that mutidose SHEDs altered the cytokine expression profile in gingival crevicular fluid, reduced gum bleeding, increased new attachment of periodontal ligament, and decreased osteoclast differentiation. Micro-computed tomography analysis showed SHED administration significantly increased periodontal regeneration and alveolar bone volume, and decreased distance of cementoenamel junction to alveolar bone crest. Furthermore, an increase in the number of CD206+ M2 macrophages was observed in periodontal tissues following the delivery of SHEDs, which aligned well with the promoted conversion to CD206+ M2-like cells from monocytes/macrophages in vitro after stimulation by SHEDs. This study demonstrated in a rat periodontitis model that local delivery of SHEDs attributed to the induction of M2 macrophage polarization, reduction of periodontal tissue inflammation, and enhancement of periodontal regeneration.

[1]  Stan Gronthos,et al.  SHED: Stem cells from human exfoliated deciduous teeth , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[2]  H. Takayanagi.  Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems , 2007, Nature Reviews Immunology.

[3]  Alberto Mantovani,et al.  Macrophage activation and polarization. , 2008, Frontiers in bioscience : a journal and virtual library.

[4]  D. Hume,et al.  Osteal macrophages: a new twist on coupling during bone dynamics. , 2008, Bone.

[5]  L. Willatt,et al.  Shaffer LG, Slovak ML, Campbell LJ (2009): ISCN 2009 an international system for human cytogenetic nomenclature , 2009, Human Genetics.

[6]  S. Gronthos,et al.  Immunomodulatory properties of stem cells from human exfoliated deciduous teeth , 2010, Stem Cell Research & Therapy.

[7]  Wei Wang,et al.  Allogeneic Periodontal Ligament Stem Cell Therapy for Periodontitis in Swine , 2010, Stem cells.

[8]  E. Fu,et al.  Ameliorative effect of quercetin on the destruction caused by experimental periodontitis in rats. , 2010, Journal of periodontal research.

[9]  T. Robak,et al.  Chromosomal aberrations in chronic lymphocytic leukemia detected by conventional cytogenetics with DSP30 as a single agent: comparison with FISH. , 2011, Leukemia research.

[10]  Meng Xiangwei,et al.  Bone marrow mononuclear cell transplant therapy in mice with CCl4-induced acute liver failure. , 2012, The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology.

[11]  B. Brown,et al.  Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine. , 2012, Biomaterials.

[12]  S. Gronthos,et al.  Clinical utility of stem cells for periodontal regeneration. , 2012, Periodontology 2000.

[13]  Faming Chen,et al.  Stem cell-delivery therapeutics for periodontal tissue regeneration. , 2012, Biomaterials.

[14]  P-C Chang,et al.  Irradiation by light-emitting diode light as an adjunct to facilitate healing of experimental periodontitis in vivo. , 2013, Journal of periodontal research.

[15]  D. Prockop,et al.  Concise Review: Two negative feedback loops place mesenchymal stem/stromal cells at the center of early regulators of inflammation , 2013, Stem cells.

[16]  K. Tabeta,et al.  Profiling biomarkers in gingival crevicular fluid using multiplex bead immunoassay. , 2013, Archives of oral biology.

[17]  Dayron Rodríguez,et al.  Alterations in macrophages and monocytes from tumor-bearing mice: evidence of local and systemic immune impairment , 2013, Immunologic research.

[18]  Michael Glogauer,et al.  Macrophage subsets and osteoimmunology: tuning of the immunological recognition and effector systems that maintain alveolar bone. , 2013, Periodontology 2000.

[19]  W. Fibbe,et al.  Mesenchymal stromal cells: sensors and switchers of inflammation. , 2013, Cell stem cell.

[20]  S. Colucci,et al.  Periodontal Disease: Linking the Primary Inflammation to Bone Loss , 2013, Clinical & developmental immunology.

[21]  Han-Sung Jung,et al.  In vitro and in vivo characteristics of stem cells from human exfoliated deciduous teeth obtained by enzymatic disaggregation and outgrowth. , 2014, Archives of oral biology.

[22]  S. Gronthos,et al.  Stem cells, tissue engineering and periodontal regeneration. , 2014, Australian dental journal.

[23]  Jiang Zhu-lin.  Study of TNF-α,IL-1β and LPS Levels in the Gingival Crevicular Fluid of a Rat Model of Diabetes Mellitus and Periodontitis , 2014 .

[24]  Valérie Planat-Benard,et al.  Concise Review: Mesenchymal Stromal Cells Used for Periodontal Regeneration: A Systematic Review , 2014, Stem cells translational medicine.

[25]  Z. Shan,et al.  Allogeneic Bone Marrow Mesenchymal Stem Cell Transplantation for Periodontal Regeneration , 2014, Journal of dental research.

[26]  Masayuki Yamato,et al.  Cell sheet engineering and its application for periodontal regeneration , 2015, Journal of tissue engineering and regenerative medicine.

[27]  I. Chapple,et al.  Peripheral blood neutrophil cytokine hyper-reactivity in chronic periodontitis , 2015, Innate immunity.

[28]  Ang Li,et al.  Repair of human periodontal bone defects by autologous grafting stem cells derived from inflammatory dental pulp tissues , 2016, Stem Cell Research & Therapy.

[29]  H. Goto,et al.  Multifaceted Therapeutic Benefits of Factors Derived From Dental Pulp Stem Cells for Mouse Liver Fibrosis , 2016, Stem cells translational medicine.

[30]  A. D. de Vos,et al.  Mitochondrial Dysfunction Prevents Repolarization of Inflammatory Macrophages. , 2016, Cell reports.

[31]  R. T. Sasaki,et al.  Stem Cells from Human Exfoliated Deciduous Teeth: A Growing Literature , 2016, Cells Tissues Organs.

[32]  Selin Yıldırım,et al.  The Comparison of the Immunologic Properties of Stem Cells Isolated from Human Exfoliated Deciduous Teeth, Dental Pulp, and Dental Follicles , 2015, Stem cells international.

[33]  F. Han,et al.  Isolation, characterization and multi-lineage differentiation of stem cells from human exfoliated deciduous teeth , 2016, Molecular medicine reports.

[34]  Shijie Jin,et al.  Conditioned Medium from the Stem Cells of Human Exfoliated Deciduous Teeth Ameliorates Experimental Autoimmune Encephalomyelitis , 2016, The Journal of Immunology.

[35]  T. Morelli,et al.  Gingival crevicular fluid as a source of biomarkers for periodontitis. , 2016, Periodontology 2000.

[36]  Chengtie Wu,et al.  Osteoimmunomodulation for the development of advanced bone biomaterials , 2016 .

[37]  G. Natoli,et al.  Opposing macrophage polarization programs show extensive epigenomic and transcriptional cross talks , 2017, Nature Immunology.

[38]  W. Giannobile,et al.  Local wound healing biomarkers for real‐time assessment of periodontal regeneration: pilot study , 2017, Journal of periodontal research.

[39]  Y. Hirooka,et al.  Secreted Ectodomain of SIGLEC-9 and MCP-1 Synergistically Improve Acute Liver Failure in Rats by Altering Macrophage Polarity , 2017, Scientific Reports.

[40]  L. Fields,et al.  IL-4 as a Repurposed Biological Drug for Myocardial Infarction through Augmentation of Reparative Cardiac Macrophages: Proof-of-Concept Data in Mice , 2017, Scientific Reports.

[41]  N. Câmara,et al.  Stem cells from human-exfoliated deciduous teeth reduce tissue-infiltrating inflammatory cells improving clinical signs in experimental autoimmune encephalomyelitis. , 2017, Biologicals : journal of the International Association of Biological Standardization.