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      Stromal cell‐derived factor‐1/Exendin‐4 cotherapy facilitates the proliferation, migration and osteogenic differentiation of human periodontal ligament stem cells in vitro and promotes periodontal bone regeneration in vivo

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          Abstract

          Objectives

          Stromal cell‐derived factor‐1 (SDF‐1) actively directs endogenous cell homing. Exendin‐4 (EX‐4) promotes stem cell osteogenic differentiation. Studies revealed that EX‐4 strengthened SDF‐1‐mediated stem cell migration. However, the effects of SDF‐1 and EX‐4 on periodontal ligament stem cells (PDLSCs) and bone regeneration have not been investigated. In this study, we aimed to evaluate the effects of SDF‐1/EX‐4 cotherapy on PDLSCs in vitro and periodontal bone regeneration in vivo.

          Methods

          Cell‐counting kit‐8 (CCK8), transwell assay, qRT‐PCR and western blot were used to determine the effects and mechanism of SDF‐1/EX‐4 cotherapy on PDLSCs in vitro. A rat periodontal bone defect model was developed to evaluate the effects of topical application of SDF‐1 and systemic injection of EX‐4 on endogenous cell recruitment, osteoclastogenesis and bone regeneration in vivo.

          Results

          SDF‐1/EX‐4 cotherapy had additive effects on PDLSC proliferation, migration, alkaline phosphatase (ALP) activity, mineral deposition and osteogenesis‐related gene expression compared to SDF‐1 or EX‐4 in vitro. Pretreatment with ERK inhibitor U0126 blocked SDF‐1/EX‐4 cotherapy induced ERK signal activation and PDLSC proliferation. SDF‐1/EX‐4 cotherapy significantly promoted new bone formation, recruited more CXCR4 + cells and CD90 +/CD34 ‐ stromal cells to the defects, enhanced early‐stage osteoclastogenesis and osteogenesis‐related markers expression in regenerated bone compared to control, SDF‐1 or EX‐4 in vivo.

          Conclusions

          SDF‐1/EX‐4 cotherapy synergistically regulated PDLSC activities, promoted periodontal bone formation, thereby providing a new strategy for periodontal bone regeneration.

          Abstract

          Locally delivered stromal cell‐derived factor‐1 (SDF‐1) combined with systemically applied Exendin‐4 (EX‐4) synergestically recruited endogenous stem cells towards the rat periodontal defects. Further, the cotherapy enhanced the proliferation and osteogenic differentiation of the engrafted stem cells in coordination, thus significantly facilitated periodontal bone regeneration.

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          Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis.

          Yu-Chen Sun, Wen-Zhou Liu, Tao Liu … (2015)
          The generic mitogen-activated protein kinases (MAPK) signaling pathway is shared by four distinct cascades, including the extracellular signal-related kinases (ERK1/2), Jun amino-terminal kinases (JNK1/2/3), p38-MAPK and ERK5. Mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) pathway is reported to be associated with the cell proliferation, differentiation, migration, senescence and apoptosis. The literatures were searched extensively and this review was performed to review the role of MAPK/ERK signaling pathway in cell proliferation, differentiation, migration, senescence and apoptosis.
          Article 0 comments Cited 687 times – based on 0 reviews     Review now
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            Investigation of multipotent postnatal stem cells from human periodontal ligament.

            Byoung-Moo Seo, Masako Miura, Stan Gronthos … (2004)
            Periodontal diseases that lead to the destruction of periodontal tissues--including periodontal ligament (PDL), cementum, and bone--are a major cause of tooth loss in adults and are a substantial public-health burden worldwide. PDL is a specialised connective tissue that connects cementum and alveolar bone to maintain and support teeth in situ and preserve tissue homoeostasis. We investigated the notion that human PDL contains stem cells that could be used to regenerate periodontal tissue. PDL tissue was obtained from 25 surgically extracted human third molars and used to isolate PDL stem cells (PDLSCs) by single-colony selection and magnetic activated cell sorting. Immunohistochemical staining, RT-PCR, and northern and western blot analyses were used to identify putative stem-cell markers. Human PDLSCs were transplanted into immunocompromised mice (n=12) and rats (n=6) to assess capacity for tissue regeneration and periodontal repair. Findings PDLSCs expressed the mesenchymal stem-cell markers STRO-1 and CD146/MUC18. Under defined culture conditions, PDLSCs differentiated into cementoblast-like cells, adipocytes, and collagen-forming cells. When transplanted into immunocompromised rodents, PDLSCs showed the capacity to generate a cementum/PDL-like structure and contribute to periodontal tissue repair. Our findings suggest that PDL contains stem cells that have the potential to generate cementum/PDL-like tissue in vivo. Transplantation of these cells, which can be obtained from an easily accessible tissue resource and expanded ex vivo, might hold promise as a therapeutic approach for reconstruction of tissues destroyed by periodontal diseases.
            Article 0 comments Cited 420 times – based on 0 reviews     Review now
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              The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.

              Daniel Drucker, Michael A. Nauck (2006)
              Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin and suppresses glucagon secretion, inhibits gastric emptying, and reduces appetite and food intake. Therapeutic approaches for enhancing incretin action include degradation-resistant GLP-1 receptor agonists (incretin mimetics), and inhibitors of dipeptidyl peptidase-4 (DPP-4) activity (incretin enhancers). Clinical trials with the incretin mimetic exenatide (two injections per day or long-acting release form once weekly) and liraglutide (one injection per day) show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (HbA1c) (1-2%), associated with weight loss (2-5 kg). The most common adverse event associated with GLP-1 receptor agonists is mild nausea, which lessens over time. Orally administered DPP-4 inhibitors, such as sitagliptin and vildagliptin, reduce HbA1c by 0.5-1.0%, with few adverse events and no weight gain. These new classes of antidiabetic agents, and incretin mimetics and enhancers, also expand beta-cell mass in preclinical studies. However, long-term clinical studies are needed to determine the benefits of targeting the incretin axis for the treatment of type 2 diabetes.
              Article 0 comments Cited 352 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Shaohua Ge:
                ORCID: https://orcid.org/0000-0003-3821-5480
                shaohuage@sdu.edu.cn
                Journal
                Journal ID (nlm-ta): Cell Prolif
                Journal ID (iso-abbrev): Cell Prolif
                Journal ID (doi): 10.1111/(ISSN)1365-2184
                Journal ID (publisher-id): CPR
                Title: Cell Proliferation
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 0960-7722
                ISSN (Electronic): 1365-2184
                Publication date (Electronic): 29 January 2021
                Publication date Collection: March 2021
                Volume: 54
                Issue: 3 ( doiID: 10.1111/cpr.v54.3 )
                Electronic Location Identifier: e12997
                Affiliations
                [ 1 ] Department of Periodontology School and Hospital of Stomatology Cheeloo College of Medicine Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration Jinan Shandong China
                [ 2 ] Department of Stomatology The Second Hospital Cheeloo College of Medicine Shandong University Jinan Shandong China
                [ 3 ] Department of Endodontics Hospital of stomatology Zunyi Medical University Zunyi Guizhou China
                Author notes
                [*] [* ] Correspondence

                Shaohua Ge, Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No. 44‐1 Wenhua Road West, Jinan, China.

                Email: shaohuage@ 123456sdu.edu.cn

                Author information
                https://orcid.org/0000-0002-5779-0395
                https://orcid.org/0000-0001-6874-3087
                https://orcid.org/0000-0002-3485-0308
                https://orcid.org/0000-0003-3821-5480
                Article
                Publisher ID: CPR12997
                DOI: 10.1111/cpr.12997
                PMC ID: 7941242
                PubMed ID: 33511708
                SO-VID: 7f82a0ca-99ff-4b93-82b9-4a4770929acb
                Copyright © © 2021 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 06 December 2020
                Date revision received : 06 January 2021
                Date accepted : 10 January 2021
                Page count
                Figures: 10, Tables: 1, Pages: 16, Words: 8115
                Funding
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 81873716
                Award ID: 81670993
                Funded by: Construction Engineering Special Fund of “Taishan Scholars” of Shandong Province
                Award ID: ts20190975
                Award ID: tsqn201909180
                Funded by: National Key R&D Program of China
                Award ID: 2017YFB0405400
                Funded by: Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, The National Key Research and Development Program of China
                Award ID: 2017YFA0104604
                Funded by: Open Foundation of Shandong Provincial Key Laboratory of Oral Tissue Regeneration
                Award ID: SDKQ201901
                Award ID: SDKQ201904
                Categories
                Subject: Original Article
                Subject: Original Articles
                Custom metadata
                source-schema-version-number 2.0
                cover-date March 2021
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.9 mode:remove_FC converted:09.03.2021

                ScienceOpen disciplines: Cell biology
                Keywords: exendin‐4,osteogenic differentiation,periodontal bone regeneration,periodontal ligament stem cell,stromal cell‐derived factor‐1
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: exendin‐4, osteogenic differentiation, periodontal bone regeneration, periodontal ligament stem cell, stromal cell‐derived factor‐1

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