Berberine mediates root remodeling in an immature tooth with apical periodontitis by regulating stem cells from apical papilla differentiation

Once pulp necrosis or apical periodontitis occurs on immature teeth, the weak root and open root apex are challenging to clinicians. Berberine (BBR) is a potential medicine for bone disorders, therefore, we proposed to apply BBR in root canals to enhance root repair in immature teeth. An in vivo model of immature teeth with apical periodontitis was established in rats, and root canals were filled with BBR, calcium hydroxide or sterilized saline for 3 weeks. The shape of the roots was analyzed by micro-computed tomography and histological staining. In vitro, BBR was introduced into stem cells from apical papilla (SCAPs). Osteogenic differentiation of stem cells from apical papilla was investigated by alkaline phosphatase activity, mineralization ability, and gene expression of osteogenic makers. The signaling pathway, which regulated the osteogenesis of SCAPs was evaluated by quantitative real time PCR, Western blot analysis, and immunofluorescence. In rats treated with BBR, more tissue was formed, with longer roots, thicker root walls, and smaller apex diameters. In addition, we found that BBR promoted SCAPs osteogenesis in a time-dependent and concentration-dependent manner. BBR induced the expression of β-catenin and enhanced β-catenin entering into the nucleus, to up-regulate more runt-related nuclear factor 2 downstream. BBR enhanced root repair in immature teeth with apical periodontitis by activating the canonical Wnt/β-catenin pathway in SCAPs.

[1]  Michael Kühl,et al.  Functional interaction of β-catenin with the transcription factor LEF-1 , 1996, Nature.

[2]  K. Chopra,et al.  Current knowledge and pharmacological profile of berberine: An update. , 2015, European journal of pharmacology.

[3]  Deming Xiao,et al.  Berberine promotes bone marrow-derived mesenchymal stem cells osteogenic differentiation via canonical Wnt/β-catenin signaling pathway. , 2016, Toxicology letters.

[4]  K. Johnson.  An Update. , 1984, Journal of food protection.

[5]  S. Gronthos,et al.  Mesenchymal Stem Cells Derived from Dental Tissues vs. Those from Other Sources: Their Biology and Role in Regenerative Medicine , 2009, Journal of dental research.

[6]  Sangwan Kim,et al.  Pulp-dentin regeneration: current approaches and challenges , 2019, Journal of tissue engineering.

[7]  L. Mo,et al.  Berberine Ameliorates Periodontal Bone Loss by Regulating Gut Microbiota , 2018, Journal of dental research.

[8]  Manju Sharma,et al.  Pioglitazone-induced bone loss in diabetic rats and its amelioration by berberine: A portrait of molecular crosstalk. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[9]  Je-Yong Choi,et al.  Berberine Promotes Osteoblast Differentiation by Runx2 Activation With p38 MAPK , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[10]  G. Kose,et al.  Dental Stem Cells in Bone Tissue Engineering: Current Overview and Challenges. , 2018, Advances in experimental medicine and biology.

[11]  Li-na Zhang,et al.  Berberine improves advanced glycation end products-induced osteogenic differentiation responses in human periodontal ligament stem cells through the canonical Wnt/β-catenin pathway , 2019, Molecular medicine reports.

[12]  R Grosschedl,et al.  Functional interaction of beta-catenin with the transcription factor LEF-1. , 1996, Nature.

[13]  Z. Wang,et al.  Regulatory Interplay between NFIC and TGF-β1 in Apical Papilla-derived Stem Cells , 2014, Journal of dental research.

[14]  G. Fraedrich,et al.  Juvenile recurrent respiratory papillomatosis: Still a mystery disease with difficult management , 2007, Head & neck.

[15]  H. Yoshie,et al.  Occlusion regulates tooth-root elongation during root development in rat molars. , 2011, European journal of oral sciences.

[16]  L. Levin,et al.  Prognosis and complications of immature teeth following lateral luxation: A systematic review , 2018, Dental traumatology : official publication of International Association for Dental Traumatology.

[17]  A. Diogenes,et al.  Survival of the Apical Papilla and Its Resident Stem Cells in a Case of Advanced Pulpal Necrosis and Apical Periodontitis , 2017, Journal of endodontics.

[18]  E. Mohammadi,et al.  Barriers and facilitators related to the implementation of a physiological track and trigger system: A systematic review of the qualitative evidence , 2017, International journal for quality in health care : journal of the International Society for Quality in Health Care.

[19]  C. Torneck,et al.  Revascularization: a treatment for permanent teeth with necrotic pulp and incomplete root development. , 2013, Journal of endodontics.

[20]  J. Xie,et al.  Substrate Compliance Directs the Osteogenic Lineages of Stem Cells from the Human Apical Papilla via the Processes of Mechanosensing and Mechanotransduction. , 2019, ACS applied materials & interfaces.

[21]  B. Liu,et al.  Effects of Wnt/β‐catenin signalling on proliferation and differentiation of apical papilla stem cells , 2012, Cell Proliferation.

[22]  J. Xie,et al.  FGF-7 Dictates Osteocyte Cell Processes Through Beta-Catenin Transduction , 2018, Scientific Reports.

[23]  Jidapa Silujjai,et al.  Treatment Outcomes of Apexification or Revascularization in Nonvital Immature Permanent Teeth: A Retrospective Study , 2017, Journal of endodontics.

[24]  F. Wang,et al.  Berberine Promotes Osteogenic Differentiation of Human Dental Pulp Stem Cells Through Activating EGFR-MAPK-Runx2 Pathways , 2019, Pathology & Oncology Research.

[25]  M. Torabinejad,et al.  A clinical and histological report of a tooth with an open apex treated with regenerative endodontics using platelet-rich plasma. , 2012, Journal of endodontics.

[26]  E. Bair,et al.  Effect of Residual Bacteria on the Outcome of Pulp Regeneration In Vivo , 2017, Journal of dental research.

[27]  S. Millar,et al.  Wnt/β-catenin Signaling in Oral Tissue Development and Disease , 2010, Journal of dental research.

[28]  A. Tsiftsoglou,et al.  Comparative analysis of in vitro osteo/odontogenic differentiation potential of human dental pulp stem cells (DPSCs) and stem cells from the apical papilla (SCAP). , 2011, Archives of oral biology.

[29]  D. Kolodrubetz,et al.  Effect of Bacterial Biofilm on the Osteogenic Differentiation of Stem Cells of Apical Papilla , 2017, Journal of endodontics.

[30]  Sicen Wang,et al.  The promotion function of Berberine for osteogenic differentiation of human periodontal ligament stem cells via ERK-FOS pathway mediated by EGFR , 2018, Scientific Reports.

[31]  Zhijun Luo,et al.  Metformin and berberine, two versatile drugs in treatment of common metabolic diseases , 2015, Oncotarget.

[32]  J. Dai,et al.  Overexpression of Dlx2 enhances osteogenic differentiation of BMSCs and MC3T3-E1 cells via direct upregulation of Osteocalcin and Alp , 2019, International Journal of Oral Science.

[33]  T. He,et al.  Canonical Wnt signaling acts synergistically on BMP9-induced osteo/odontoblastic differentiation of stem cells of dental apical papilla (SCAPs). , 2015, Biomaterials.

[34]  A. Iglesias-Linares,et al.  Revascularization of immature permanent teeth with apical periodontitis. , 2014, International endodontic journal.

[35]  R. Nusse,et al.  Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities , 2017, Cell.

[36]  Pengfei Zhou,et al.  Pro-Inflammatory Cytokine TNF-α Attenuates BMP9-Induced Osteo/ Odontoblastic Differentiation of the Stem Cells of Dental Apical Papilla (SCAPs) , 2017, Cellular Physiology and Biochemistry.

[37]  Yu-yu Liu,et al.  Preventive effects of berberine on glucocorticoid-induced osteoporosis in rats. , 2010, Planta medica.

[38]  Wei Hu,et al.  Possible therapeutic potential of berberine in the treatment of STZ plus HFD-induced diabetic osteoporosis. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[39]  L. Bonewald,et al.  The role of the wnt/β-catenin signaling pathway in formation and maintenance of bone and teeth. , 2016, The international journal of biochemistry & cell biology.

[40]  Lei Ke,et al.  A Novel Artificial Anal Sphincter System in an in Vitro and in Vivo Experiment , 2014, The International journal of artificial organs.

[41]  Zhiwei Dong,et al.  Dental stem cell and dental tissue regeneration , 2018, Frontiers of Medicine.

[42]  Louis M. Lin,et al.  An Evidence‐based Review of the Efficacy of Treatment Approaches for Immature Permanent Teeth with Pulp Necrosis , 2017, Journal of endodontics.

[43]  G. Stein,et al.  Lymphocyte enhancer‐binding factor 1 (Lef1) inhibits terminal differentiation of osteoblasts , 2006, Journal of cellular biochemistry.

[44]  Chao Lu,et al.  Retrospective study , 2016, Medicine.

[45]  R. Tuan,et al.  Stem/progenitor cell-mediated de novo regeneration of dental pulp with newly deposited continuous layer of dentin in an in vivo model. , 2010, Tissue engineering. Part A.

[46]  S. Harlamb.  Management of incompletely developed teeth requiring root canal treatment. , 2016, Australian dental journal.

[47]  Hsiao-Pei Tu,et al.  Berberine's effect on periodontal tissue degradation by matrix metalloproteinases: an in vitro and in vivo experiment. , 2013, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[48]  J. Wang,et al.  Signaling Pathways Critical for Tooth Root Formation , 2017, Journal of dental research.

[49]  H. Hosseinzadeh,et al.  Berberine and barberry (Berberis vulgaris): A clinical review , 2019, Phytotherapy research : PTR.

[50]  C. Liu,et al.  Long-term exposure to pro-inflammatory cytokines inhibits the osteogenic/dentinogenic differentiation of stem cells from the apical papilla. , 2016, International Endodontic Journal.

[51]  S. Ima-Nirwana,et al.  Berberine and musculoskeletal disorders: The therapeutic potential and underlying molecular mechanisms. , 2020, Phytomedicine : international journal of phytotherapy and phytopharmacology.