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Liu G, Xue J, Zhou X, Gui M, Xia R, Zhang Y, Cai Y, Li S, Shi S, Mao X, Chen Z. The paradigm shifts of periodontal regeneration strategy: From reparative manipulation to developmental engineering. Bioact Mater 2025; 49:418-436. [PMID: 40165829 PMCID: PMC11957753 DOI: 10.1016/j.bioactmat.2025.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 02/07/2025] [Accepted: 03/10/2025] [Indexed: 04/02/2025] Open
Abstract
Ideal periodontal regeneration requires the integration of alveolar bone, periodontal ligament, and cementum, along with Sharpey's fibers for occlusal force resistance. However, physiological regeneration remains rare due to its intricate structure, making clinical regeneration a challenge. Periodontal ligament stem cells (PDLSCs), first isolated in 2004, hold the key to multi-directional differentiation into cementoblasts, fibroblasts, and osteoblasts. While traditional therapies like guided tissue regeneration (GTR) aim to activate PDLSCs, clinical outcomes are inconsistent, suggesting the need for additional strategies to enhance PDLSCs' functions. Advancements in molecular biotechnology have introduced the use of recombinant growth factors for tissue regeneration. However, maintaining their efficacy requires high doses, posing cost and safety issues. Multi-layered scaffolds combined with cell sheet technology offer new insights, but face production, ethical, and survival challenges. Immune regulation plays a crucial role in PDLSC-mediated regeneration. The concept of "coagulo-immunomodulation" has emerged, emphasizing the coupling of blood coagulation and immune responses for periodontal regeneration. Despite its potential, the clinical translation of immune-based strategies remains elusive. The "developmental engineering" approach, which mimics developmental events using embryonic-stage cells and microenvironments, shows promise. Our research group has made initial strides, indicating its potential as a viable solution for periodontal complex regeneration. However, further clinical trials and considerations are needed for successful clinical application. This review aims to summarize the strategic transitions in the development of periodontal regenerative materials and to propose prospective avenues for future development.
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Affiliation(s)
- Guanqi Liu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
| | - Junlong Xue
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
| | - Xuan Zhou
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
| | - Mixiao Gui
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
| | - Ruidi Xia
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
| | - Yanshu Zhang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
| | - Yihua Cai
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
| | - Shuhua Li
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
| | - Songtao Shi
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- South China Center of Craniofacial Stem Cell Research, Guangzhou, 510055, China
| | - Xueli Mao
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- South China Center of Craniofacial Stem Cell Research, Guangzhou, 510055, China
| | - Zetao Chen
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
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Ma L, Li M, Xuan G, Dai Y. METTL14-mediated m6A RNA methylation promotes the osteogenic differentiation of pPDLSCs by regulating WNT3A. Odontology 2025:10.1007/s10266-025-01097-2. [PMID: 40249476 DOI: 10.1007/s10266-025-01097-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 03/24/2025] [Indexed: 04/19/2025]
Abstract
Periodontitis is a chronic inflammatory disease that leads to the loss of periodontal supporting tissue. Furthermore, human periodontal ligament stem cells (hPDLSCs) are identified as candidate cells for the regeneration of periodontal and alveolar bone tissues. N6-Methyladenosine (m6A) performs a vital role in osteoporosis and bone metabolism. However, the role and mechanism of Methyltransferase-like 14 (METTL14) in the osteogenic differentiation of PDLSCs from periodontitis sufferers (pPDLSCs) is unclear. In this research, GSE223924 database analyzed the expression of METTL14 and Wnt Family Member 3A (WNT3A) in gingival tissue samples of 10 healthy subjects, 10 patients with periodontitis and peri-implantitis. RT-qPCR and western blot detected METTL14, COL1A1, Runx2, ALP, and WNT3A mRNA level and protein level. Osteogenic differentiation was evaluated by Alizarin Red S staining and ALP activity. MeRIP and dual-luciferase reporter assays verified interaction between METTL14 and WNT3A. GSE223924 database showed METTL14 was differentially expressed in patients with periodontitis and peri-implantitis. Furthermore, our data verified that METTL14 and WNT3A expression were decreased in pPDLSCs and were upregulated by osteogenic induction. METTL14 promoted osteogenic differentiation of pPDLSCs. METTL14 regulated WNT3A mRNA expression via m6A methylation. METTL14 facilitates osteogenic differentiation of pPDLSCs via modulating WNT3A, providing a possible target for improving alveolar bone regeneration outcomes.Highlights 1. METTL14 expression was decreased in pPDLSCs 2. METTL14 knockdown negatively regulated the osteogenic differentiation of pPDLSCs 3. WNT3A mRNA was a m6A-methylated target by METTL14.
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Affiliation(s)
- Lan Ma
- Department of Stomatology, Shaoxing People's Hospital, Zhongxing North Road NO.568, Shaoxing, 312000, China
| | - Min Li
- Department of Stomatology, Shaoxing People's Hospital, Zhongxing North Road NO.568, Shaoxing, 312000, China
| | - Guihong Xuan
- Department of Stomatology, Shaoxing People's Hospital, Zhongxing North Road NO.568, Shaoxing, 312000, China
| | - Ying Dai
- Department of Stomatology, Shaoxing People's Hospital, Zhongxing North Road NO.568, Shaoxing, 312000, China.
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Xu M, Gan D, Zhang X, He X, Wu RX, Yin Y, Jin R, Li L, Tan Y, Chen F, Li X, Tian B. SLC30A4-AS1 Mediates the Senescence of Periodontal Ligament Stem Cells in Inflammatory Environments via the Alternative Splicing of TP53BP1. Cell Prolif 2025; 58:e13778. [PMID: 39572253 PMCID: PMC11969240 DOI: 10.1111/cpr.13778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/25/2024] [Accepted: 11/09/2024] [Indexed: 04/05/2025] Open
Abstract
Periodontal ligament stem cells (PDLSCs) are key cells that suppress periodontal damage during both the progression and recovery stages of periodontitis. Although substantial evidence has demonstrated that incubation under an inflammatory condition may accelerate senescence of PDLSCs, whether cellular senescence in response to inflammatory incubation contributes to cell dysfunction remain unexplored. In this study, we first observed inflammation-caused PDLSC senescence in periodontitis based on comparisons of matched patients, and this cellular senescence was demonstrated in healthy cells that were subjected to inflammatory conditions. We subsequently designed further experiments to investigate the possible mechanism underlying inflammation-induced PDLSC senescence with a particular focus on the role of long noncoding RNAs (lncRNAs). LncRNA microarray analysis and functional gain/loss studies revealed SLC30A4-AS1 as a regulator of inflammation-mediated PDLSC senescence. By full-length transcriptome sequencing, we found that SLC30A4-AS1 interacted with SRSF3 to affect the alternative splicing (AS) of TP53BP1 and alter the expression of TP53BP1-204. Further functional studies showed that decreased expression of TP53BP1-204 reversed PDLSC senescence, and SLC30A4-AS1 overexpression-induced PDLSC senescence was abolished by TP53BP1-204 knockdown. Our data suggest for the first time that SLC30A4-AS1 plays a key role in regulating PDLSC senescence in inflammatory environments by modulating the AS of TP53BP1.
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Affiliation(s)
- Mei Xu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Periodontology, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| | - Dian Gan
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Periodontology, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| | - Xi‐Yu Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Periodontology, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| | - Xiao‐Tao He
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Periodontology, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| | - Rui Xin Wu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Periodontology, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| | - Yuan Yin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Periodontology, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| | - Rui Jin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Periodontology, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| | - Lin Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Periodontology, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| | - Yu‐Jie Tan
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Periodontology, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| | - Fa‐Ming Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Periodontology, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| | - Xuan Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Periodontology, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| | - Bei‐Min Tian
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Periodontology, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
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Sun T, Ma D, Song Y, Hu J, Yang Z, Wang X, Zhang J. Effects of 0.01 mM strontium on human periodontal ligament stem cell osteogenic differentiation via the Wnt/ β-catenin signaling pathway. J Int Med Res 2025; 53:3000605251315024. [PMID: 39932304 DOI: 10.1177/03000605251315024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/14/2025] Open
Abstract
OBJECTIVES Strontium (Sr2+) is a crucial trace element in humans, mainly present in the bones. We investigated the effects of Sr2+ on human periodontal ligament stem cell (hPDLSC) proliferation and osteogenesis and the relevant pathways. METHODS hPDLSCs were harvested from extracted premolars and characterized by flow cytometry, then cultured and treated with various Sr2+ concentrations. Cell-counting kit-8 (CCK-8) assays were used to assess hPDLSC proliferation, with alkaline phosphatase (ALP) staining, Alizarin red S staining, and ALP activity assays used to analyze their osteogenic capacity. Quantitative reverse transcription polymerase chain reaction and western blots were used to examine the expression levels of relevant factors, such as collagen I (COL-1), ALP, and Runx family transcription factor 2 (RUNX2). Moreover, tankyrase inhibitor XAV939 treatment was used to investigate the role of Sr2+ in the canonical Wnt/β-catenin signaling pathway. RESULTS The hPDLSCs were successfully isolated and cultured in vitro. A 0.01 mM Sr2+ concentration significantly enhanced hPDLSC proliferation and osteogenic differentiation. However, XAV939-mediated inhibition of the canonical Wnt/β-catenin pathway could reverse the Sr2+-induced osteogenic effects. CONCLUSIONS Sr2+ can enhance hPDLSC proliferation and osteogenesis by stimulating canonical Wnt/β-catenin signaling, suggesting it may play a critical role in periodontal regeneration and has clinical application potential.
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Affiliation(s)
- Tongke Sun
- Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Dan Ma
- Department of Stomatology & Shandong, Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China
| | - Yang Song
- Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Jing Hu
- Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Ziqing Yang
- Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Xu Wang
- Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Jun Zhang
- Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
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Chen M, Huang B, Su X. Mesenchymal stem cell-derived extracellular vesicles in periodontal bone repair. J Mol Med (Berl) 2025; 103:137-156. [PMID: 39821702 DOI: 10.1007/s00109-025-02513-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 12/20/2024] [Accepted: 12/30/2024] [Indexed: 01/19/2025]
Abstract
Periodontitis is a chronic inflammatory disease that destroys tooth-supporting structures and poses significant public health challenges due to its high prevalence and links to systemic health conditions. Traditional treatments are effective in reducing the inflammatory response and improving the clinical symptoms of periodontitis. However, these methods are challenging to achieve an ideal treatment effect in alveolar bone repair. Mesenchymal stem cells (MSCs) represent a potential alternative for the treatment of periodontal bone defects due to their self-renewal and differentiation capabilities. Recent research indicates that MSCs exert their effects primarily through paracrine mechanisms. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) serve as pivotal mediators in intercellular communication, transferring microRNAs (miRNAs), messenger RNAs (mRNAs), proteins, and cytokines to recipient cells, thereby emulating the therapeutic effects of MSCs. In periodontitis, MSC-EVs play a pivotal role in immunomodulation and bone remodeling, thereby facilitating periodontal bone repair. As a cell-free therapy, MSC-EVs demonstrate considerable clinical potential due to their specialized membrane structure, minimal immunogenicity, low toxicity, high biocompatibility, and nanoscale size. This review indicates that MSC-EVs represent a promising approach for periodontitis treatment, with the potential to overcome the limitations of traditional therapies and offer a more effective solution for bone repair in periodontal disease. In this review, we introduce MSC-EVs, emphasizing their mechanisms and clinical applications in periodontal bone repair. It synthesizes recent advances, existing challenges, and future prospects to present up-to-date information and novel techniques for periodontal regeneration and to guide the improvement of MSC-EV therapy in clinical practice.
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Affiliation(s)
- Mengbing Chen
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases &, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Bo Huang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases &, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xiaoxia Su
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases &, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China.
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Osorio R, Rodríguez-Lozano FJ, Toledano M, Toledano-Osorio M, García-Bernal D, Murcia L, López-García S. Mitigating lipopolysaccharide-induced impairment in human dental pulp stem cells with tideglusib-doped nanoparticles: Enhancing osteogenic differentiation and mineralization. Dent Mater 2024; 40:1591-1601. [PMID: 39068091 DOI: 10.1016/j.dental.2024.07.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 07/18/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024]
Abstract
OBJECTIVE Drug-loaded non-resorbable polymeric nanoparticles (NPs) are proposed as an adjunctive treatment for pulp regenerative strategies. The present in vitro investigation aimed to evaluate the effectiveness of tideglusib-doped nanoparticles (TDg-NPs) in mitigating the adverse effects of bacterial lipopolysaccharide endotoxin (LPS) on the viability, morphology, migration, differentiation and mineralization potential of human dental pulp stem cells (hDPSCs). METHODS Cell viability, proliferation, and differentiation were assessed using a MTT assay, cell migration evaluation, cell cytoskeleton staining analysis, Alizarin Red S staining and expression of the odontogenic related genes by a real-time quantitative polymerase chain reaction (RT-qPCR) were also performed. Cells were tested both with and without stimulation with LPS at various time points. One-way ANOVA and Tukey's test were employed for statistical analysis (p < 0.05). RESULTS Adequate cell viability was encountered in all groups and at every tested time point (24, 48, 72 and 168 h), without differences among the groups (p > 0.05). The analysis of cell cytoskeleton showed nuclear alteration in cultures with undoped NPs after LPS stimulation. These cells exhibited an in blue diffuse and multifocal appearance. Some nuclei looked fragmented and condensed. hDPSCs after LPS stimulation but in the presence of TDg-NPs exhibited less nuclei changes. LPS induced down-regulation of Alkaline phosphatase, Osteonectin and Collagen1 gene markers, after 21d. LPS half-reduced the cells production of calcium deposits in all groups (p < 0.05), except in the group with TDg-NPs (decrease about 10 %). SIGNIFICANCE LPS induced lower mineral deposition and cytoskeletal disorganization in hDPSCs. These effects were counteracted by TDg-NPs, enhancing osteogenic differentiation and mineralization.
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Affiliation(s)
- Raquel Osorio
- Faculty of Dentistry, University of Granada Colegio Máximo de Cartuja s/n, Granada 18071, Spain
| | - Francisco J Rodríguez-Lozano
- Department of Dermatology, Stomatology, Radiology and Physical Medicine, Morales Meseguer Hospital, Biomedical Research Institute (IMIB), Regional Campus of International Excellence "Campus Mare Nostrum", Faculty of Medicine, University of Murcia, Murcia 30008, Spain
| | - Manuel Toledano
- Faculty of Dentistry, University of Granada Colegio Máximo de Cartuja s/n, Granada 18071, Spain.
| | - Manuel Toledano-Osorio
- Postgraduate Program of Specialization in Periodontology, Faculty of Dentistry, University Complutense of Madrid, Madrid, Spain
| | - David García-Bernal
- Department of Biochemistry, Molecular Biology B and Immunology, Faculty of Medicine, University of Murcia, Biomedical Research Institute (IMIB), Murcia 30120, Spain
| | - Laura Murcia
- Department of Health Sciences, Catholic University San Antonio of Murcia, Murcia 30107, Spain
| | - Sergio López-García
- Department of Dermatology, Stomatology, Radiology and Physical Medicine, Morales Meseguer Hospital, Biomedical Research Institute (IMIB), Regional Campus of International Excellence "Campus Mare Nostrum", Faculty of Medicine, University of Murcia, Murcia 30008, Spain
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Li Z, Wang D, Li J, Liu H, Nie L, Li C. Bone Regeneration Facilitated by Autologous Bioscaffold Material: Liquid Phase of Concentrated Growth Factor with Dental Follicle Stem Cell Loading. ACS Biomater Sci Eng 2024; 10:3173-3187. [PMID: 38605468 DOI: 10.1021/acsbiomaterials.3c01981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/13/2024]
Abstract
The application of bioengineering techniques for achieving bone regeneration in the oral environment is an increasingly prominent field. However, the clinical use of synthetic materials carries certain risks. The liquid phase of concentrated growth factor (LPCGF), as a biologically derived material, exhibits superior biocompatibility. In this study, LPCGF was employed as a tissue engineering scaffold, hosting dental follicle cells (DFCs) to facilitate bone regeneration. Both in vivo and in vitro experimental results demonstrate that this platform significantly enhances the expression of osteogenic markers in DFCs, such as alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and type I collagen (Col1a1). Simultaneously, it reduces the expression of inflammation-related genes, particularly interleukin-6 (IL-6) and interleukin-8 (IL-8), thereby alleviating the negative impact of the inflammatory microenvironment on DFCs. Further investigation into potential mechanisms reveals that this process is regulated over time by the WNT pathway. Our research results demonstrate that LPCGF, with its favorable physical characteristics, holds great potential as a scaffold. It can effectively carry DFCs, thereby providing an optimal initial environment for bone regeneration. Furthermore, LPCGF endeavors to closely mimic the mechanisms of bone healing post-trauma to facilitate bone formation. This offers new perspectives and insights into bone regeneration engineering.
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Affiliation(s)
- Zhentao Li
- Stomatological Hospital of Chongqing Medical University, No. 426 Songshi North Road, Yubei District, Chongqing 401147, China
| | - Di Wang
- Stomatological Hospital of Chongqing Medical University, No. 426 Songshi North Road, Yubei District, Chongqing 401147, China
| | - Jie Li
- College of Stomatology, Chongqing Medical University, No. 426 Songshi North Road, Yubei District, Chongqing 401147, China
| | - Hao Liu
- Stomatological Hospital of Chongqing Medical University, No. 426 Songshi North Road, Yubei District, Chongqing 401147, China
| | - Li Nie
- Stomatological Hospital of Chongqing Medical University, No. 426 Songshi North Road, Yubei District, Chongqing 401147, China
| | - Conghua Li
- Stomatological Hospital of Chongqing Medical University, No. 426 Songshi North Road, Yubei District, Chongqing 401147, China
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Wang X, Zong X, Ye M, Jin C, Xu T, Yang J, Gao C, Wang X, Yan H. Lysine Distinctively Manipulates Myogenic Regulatory Factors and Wnt/Ca 2+ Pathway in Slow and Fast Muscles, and Their Satellite Cells of Postnatal Piglets. Cells 2024; 13:650. [PMID: 38607088 PMCID: PMC11011516 DOI: 10.3390/cells13070650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 03/22/2024] [Accepted: 04/05/2024] [Indexed: 04/13/2024] Open
Abstract
Muscle regeneration, representing an essential homeostatic process, relies mainly on the myogenic progress of resident satellite cells, and it is modulated by multiple physical and nutritional factors. Here, we investigated how myogenic differentiation-related factors and pathways respond to the first limiting amino acid lysine (Lys) in the fast and slow muscles, and their satellite cells (SCs), of swine. Thirty 28-day-old weaned piglets with similar body weights were subjected to three diet regimens: control group (d 0-28: 1.31% Lys, n = 12), Lys-deficient group (d 0-28: 0.83% Lys, n = 12), and Lys rescue group (d 0-14: 0.83% Lys; d 15-28: 1.31% Lys, n = 6). Pigs on d 15 and 29 were selectively slaughtered for muscular parameters evaluation. Satellite cells isolated from fast (semimembranosus) and slow (semitendinosus) muscles were also selected to investigate differentiation ability variations. We found Lys deficiency significantly hindered muscle development in both fast and slow muscles via the distinct manipulation of myogenic regulatory factors and the Wnt/Ca2+ pathway. In the SC model, Lys deficiency suppressed the Wnt/Ca2+ pathways and myosin heavy chain, myogenin, and myogenic regulatory factor 4 in slow muscle SCs but stimulated them in fast muscle SCs. When sufficient Lys was attained, the fast muscle-derived SCs Wnt/Ca2+ pathway (protein kinase C, calcineurin, calcium/calmodulin-dependent protein kinase II, and nuclear factor of activated T cells 1) was repressed, while the Wnt/Ca2+ pathway of its counterpart was stimulated to further the myogenic differentiation. Lys potentially manipulates the differentiation of porcine slow and fast muscle myofibers via the Wnt/Ca2+ pathway in opposite trends.
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Affiliation(s)
- Xiaofan Wang
- College of Animal Science, South China Agricultural University, State Key Laboratory of Swine and Poultry Breeding Industry, National Engineering Research Center for Breeding Swine Industry, Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou 510642, China; (X.W.); (X.Z.); (M.Y.); (C.J.); (T.X.); (C.G.); (X.W.)
| | - Xiaoyin Zong
- College of Animal Science, South China Agricultural University, State Key Laboratory of Swine and Poultry Breeding Industry, National Engineering Research Center for Breeding Swine Industry, Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou 510642, China; (X.W.); (X.Z.); (M.Y.); (C.J.); (T.X.); (C.G.); (X.W.)
| | - Mao Ye
- College of Animal Science, South China Agricultural University, State Key Laboratory of Swine and Poultry Breeding Industry, National Engineering Research Center for Breeding Swine Industry, Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou 510642, China; (X.W.); (X.Z.); (M.Y.); (C.J.); (T.X.); (C.G.); (X.W.)
| | - Chenglong Jin
- College of Animal Science, South China Agricultural University, State Key Laboratory of Swine and Poultry Breeding Industry, National Engineering Research Center for Breeding Swine Industry, Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou 510642, China; (X.W.); (X.Z.); (M.Y.); (C.J.); (T.X.); (C.G.); (X.W.)
- Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Key Laboratory of Animal Nutrition and Feed Science (South China) of Ministry of Agriculture, State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Public Laboratory of Animal Breeding and Nutrition, Guangdong Key Laboratory of Animal Breeding and Nutrition, Guangzhou 510640, China
| | - Tao Xu
- College of Animal Science, South China Agricultural University, State Key Laboratory of Swine and Poultry Breeding Industry, National Engineering Research Center for Breeding Swine Industry, Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou 510642, China; (X.W.); (X.Z.); (M.Y.); (C.J.); (T.X.); (C.G.); (X.W.)
| | - Jinzeng Yang
- Department of Human Nutrition, Food and Animal Sciences, University of Hawaii at Manoa, Honolulu, HI 96822, USA;
| | - Chunqi Gao
- College of Animal Science, South China Agricultural University, State Key Laboratory of Swine and Poultry Breeding Industry, National Engineering Research Center for Breeding Swine Industry, Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou 510642, China; (X.W.); (X.Z.); (M.Y.); (C.J.); (T.X.); (C.G.); (X.W.)
| | - Xiuqi Wang
- College of Animal Science, South China Agricultural University, State Key Laboratory of Swine and Poultry Breeding Industry, National Engineering Research Center for Breeding Swine Industry, Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou 510642, China; (X.W.); (X.Z.); (M.Y.); (C.J.); (T.X.); (C.G.); (X.W.)
| | - Huichao Yan
- College of Animal Science, South China Agricultural University, State Key Laboratory of Swine and Poultry Breeding Industry, National Engineering Research Center for Breeding Swine Industry, Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou 510642, China; (X.W.); (X.Z.); (M.Y.); (C.J.); (T.X.); (C.G.); (X.W.)
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Zhang X, Liu J, Gao J, Sun W, Chen X, Wang X, Qin W, Jin Z. N6-methyladenosine promotes osteogenic differentiation of PDLSCs from periodontitis patients. Oral Dis 2024; 30:1322-1336. [PMID: 36516331 DOI: 10.1111/odi.14467] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 12/01/2022] [Accepted: 12/12/2022] [Indexed: 12/15/2022]
Abstract
OBJECTIVES This study aimed to investigate the mechanism of N6-methyladenosine (m6A) in the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) from periodontitis patients. METHODS Differentially m6A-methylated lncRNA/mRNA profiles were detected by a m6A epitranscriptomic microarray. Bioinformatics analysis was performed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis. The transfection efficiency of the lentivirus was detected. The osteogenic activity of PDLSCs from periodontitis patients (PPDLSCs) was assessed. RESULTS The microarray results showed that 275 lncRNAs and 1292 mRNAs were significantly differentially methylated between PPDLSCs and PDLSCs from healthy people. Among those lncRNAs, lncRNA4114 (transcript_ID: ENST00000444114) showed both reduced m6A methylation levels and expression levels in PPDLSCs. Further bioinformatics analysis predicted that the differentially methylated mRNAs were mainly involved in cell interaction, stem cell pluripotency, and osteogenic differentiation signals. Then, overexpression of methyltransferase like 3 (METTL3) promoted the osteogenic differentiation of PPDLSCs, while knocking down METTL3 showed an inhibitory effect. Furthermore, METTL3 overexpression promotes the stability of lncRNA4114 to upregulate the expression level. Moreover, lncRNA4114 overexpression promoted the osteogenic differentiation of PPDLSCs. CONCLUSION METTL3 promotes the osteogenic differentiation of PPDLSCs by regulating the stability of lncRNA4114.
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Affiliation(s)
- Xiaochen Zhang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Jia Liu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Jie Gao
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Weifu Sun
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Xin Chen
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Xian Wang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Wen Qin
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Zuolin Jin
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, China
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10
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Zhang X, Lin H, Zheng DL, Lu YG, Zou Y, Su B. Exploring the Role of Wnt Ligands in Osteogenic Differentiation of Human Periodontal Ligament Stem Cells. Clin Oral Investig 2023; 28:64. [PMID: 38158464 DOI: 10.1007/s00784-023-05449-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 12/17/2023] [Indexed: 01/03/2024]
Abstract
OBJECTIVES This study aimed to investigate the functions of 19 types of Wnt ligands during the process of osteogenic differentiation in human periodontal ligament stem cells (hPDLSCs), with particular attention to WNT3A and WNT4. MATERIALS AND METHODS The expression levels of 19 types of Wnt ligands were examined using real-time quantitative polymerase chain reaction (real-time qPCR) during hPDLSCs osteogenic differentiation at 7, 10, and 14 days. Knockdown of WNT3A and WNT4 expression was achieved using adenovirus vectors, and conditioned medium derived from WNT3A and WNT4 overexpression plasmids was employed to investigate their roles in hPDLSCs osteogenesis. Osteogenic-specific genes were analyzed using real-time qPCR. Alkaline phosphatase (ALP) and alizarin red S activities and staining were employed to assess hPDLSCs' osteogenic differentiation ability. RESULTS During hPDLSCs osteogenic differentiation, the expression of 19 types of Wnt ligands varied, with WNT3A and WNT4 showing significant upregulation. Inhibiting WNT3A and WNT4 expression hindered hPDLSCs' osteogenic capacity. Conditioned medium of WNT3A promoted early osteogenic differentiation, while WNT4 facilitated late osteogenesis slightly. CONCLUSION Wnt ligands, particularly WNT3A and WNT4, play an important role in hPDLSCs' osteogenic differentiation, highlighting their potential as promoters of osteogenesis. CLINICAL RELEVANCE Given the challenging nature of alveolar bone regeneration, therapeutic strategies that target WNT3A and WNT4 signaling pathways offer promising opportunities. Additionally, innovative gene therapy approaches aimed at regulating of WNT3A and WNT4 expression hold potential for improving alveolar bone regeneration outcomes.
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Affiliation(s)
- Xiao Zhang
- Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatological Key Laboratory of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, 350001, China
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, 350001, China
| | - Hanrui Lin
- Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatological Key Laboratory of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, 350001, China
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, 350001, China
| | - Da-Li Zheng
- Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatological Key Laboratory of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, 350001, China
| | - You-Guang Lu
- Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatological Key Laboratory of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, 350001, China
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, 350001, China
| | - Yuchun Zou
- Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatological Key Laboratory of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, 350001, China.
- Department of Orthodontics, Fujian Key Laboratory of Oral Diseases, School of Stomatology, Fujian Medical University, Fuzhou, 350001, China.
| | - Bohua Su
- Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatological Key Laboratory of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, 350001, China.
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, 350001, China.
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Xiao J, Gong X, Fu Z, Song X, Ma Q, Miao J, Cai R, Yan Z, Wang S, Li Q, Chen Y, Yang L, Bian X, Chen Y. The influence of inflammation on the characteristics of adipose-derived mesenchymal stem cells (ADMSCs) and tissue repair capability in a hepatic injury mouse model. Stem Cell Res Ther 2023; 14:334. [PMID: 37981679 PMCID: PMC10659042 DOI: 10.1186/s13287-023-03532-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 10/10/2023] [Indexed: 11/21/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are adult stem cells with self-renewal and multi-directional differentiation potential and possess the functions of immunomodulation, regulation of cell growth, and repair of damage. Over recent years, MSCs have been found to regulate the secretion of inflammatory factors and to exert regulatory effects on various lymphocytes in inflammatory states, and on the subsequent repair of tissue damage caused by inflammation. In the present study, we analyzed the effects of tissue inflammation on the characteristics of MSCs. METHODS Human fat derived from the infrapatellar fat pad (IPFP) of knees with differing degrees of inflammation was extracted from specimens derived from total knee arthroplasties. HE and immunohistochemical staining was performed to directly observe the evidence and degree of inflammation in human infrapatellar fat pad tissue in order to classify MSCs cells, by their origin, into highly inflamed and lowly inflamed groups, and to study the effect of tissue inflammation on cell acquisition rates via cellular counting data. Flow cytometry assays were performed to investigate the effect of tissue inflammation on MSC surface marker expression. Trilineage differentiation, including osteogenesis, adipogenesis, and chondrogenesis, was performed to assess the effect of tissue inflammation on the ability of MSCs to undergo directed differentiation. The effect of tissue inflammation on the ability of MSCs to proliferate was investigated via clone formation studies. RNA-sequencing was performed to evaluate the transcriptomes of MSCs derived from different areas of inflammation. The effect of tissue inflammation on tissue repair capacity and safety of MSCs was investigated via a murine model of acute liver injury. RESULTS The results of cell count data indicate that a high degree of tissue inflammation significantly decreases the acquisition rate of MSCs, and the proportion of CD34+ and CD146+ cells. The results of our trilineage differentiation assay show that a higher degree of inflammation decreases osteogenic differentiation and enhances adipogenic and chondrogenic differentiation of MSCs. However, these differences were not statistically significant. Clone formation assays indicate that the degree of tissue inflammation at the MSC source does not significantly affect the proliferative capacity of MSCs. The transcriptomes of MSCs remain relatively stable in fat pad tissues derived from both highly and lowly inflamed samples. The results of acute liver injury investigations in mice indicate that MSCs of high and low inflammatory tissue origin have no significant difference in their tissue repair capability. CONCLUSIONS High tissue inflammation at the source of MSCs reduces the acquisition rate of MSCs and the percentage of CD34+ and CD146+ cells acquisition. However, source tissue inflammation may not significantly affect trilineage differentiation potential and proliferative capacity of MSCs. Also, MSCs obtained from differing source degrees of inflammation retain stable and similar transcriptomic profile and are both safe and efficacious for tissue repair/regeneration without detectable differences.
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Affiliation(s)
- Jingfang Xiao
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Xiaoyuan Gong
- Center for Joint Surgery, Southwest Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Zhenlan Fu
- Center for Joint Surgery, Southwest Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Xiongbo Song
- Center for Joint Surgery, Southwest Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Qinghua Ma
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Jingya Miao
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Ruili Cai
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Zexuan Yan
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Shuai Wang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Qian Li
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Yaokai Chen
- Biobank and Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, People's Republic of China
| | - Liu Yang
- Center for Joint Surgery, Southwest Hospital, Army Medical University, Chongqing, People's Republic of China.
| | - Xiuwu Bian
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University, Chongqing, People's Republic of China.
| | - Yemiao Chen
- Biobank and Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, People's Republic of China.
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12
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Kim HY, Shim JH, Heo CY. A Rare Skeletal Disorder, Fibrous Dysplasia: A Review of Its Pathogenesis and Therapeutic Prospects. Int J Mol Sci 2023; 24:15591. [PMID: 37958575 PMCID: PMC10650015 DOI: 10.3390/ijms242115591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 10/16/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Fibrous dysplasia (FD) is a rare, non-hereditary skeletal disorder characterized by its chronic course of non-neoplastic fibrous tissue buildup in place of healthy bone. A myriad of factors have been associated with its onset and progression. Perturbation of cell-cell signaling networks and response outputs leading to disrupted building blocks, incoherent multi-level organization, and loss of rigid structural motifs in mineralized tissues are factors that have been identified to participate in FD induction. In more recent years, novel insights into the unique biology of FD are transforming our understandings of its pathology, natural discourse of the disease, and treatment prospects. Herein, we built upon existing knowledge with recent findings to review clinical, etiologic, and histological features of FD and discussed known and potential mechanisms underlying FD manifestations. Subsequently, we ended on a note of optimism by highlighting emerging therapeutic approaches aimed at either halting or ameliorating disease progression.
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Affiliation(s)
- Ha-Young Kim
- Interdisciplinary Program in Bioengineering, Seoul National University, Seoul 08826, Republic of Korea;
- Department of Plastic and Reconstructive Surgery, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea
| | - Jung-Hee Shim
- Department of Plastic and Reconstructive Surgery, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea;
- Department of Research Administration Team, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea
| | - Chan-Yeong Heo
- Interdisciplinary Program in Bioengineering, Seoul National University, Seoul 08826, Republic of Korea;
- Department of Plastic and Reconstructive Surgery, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea
- Department of Plastic and Reconstructive Surgery, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea;
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Wei X, Liu Q, Liu L, Tian W, Wu Y, Guo S. Periostin plays a key role in maintaining the osteogenic abilities of dental follicle stem cells in the inflammatory microenvironment. Arch Oral Biol 2023; 153:105737. [PMID: 37320885 DOI: 10.1016/j.archoralbio.2023.105737] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/30/2023] [Accepted: 05/31/2023] [Indexed: 06/17/2023]
Abstract
OBJECTIVE This study aimed to explore the effect of periostin in the osteogenic abilities of dental follicle stem cells (DFSCs) and DFSC sheets in the inflammatory microenvironment. DESIGN DFSCs were isolated from dental follicles and identified. A lentiviral vector was used to knock down periostin in DFSCs. 250 ng/ml lipopolysaccharide from Porphyromonas gingivalis (P.g-LPS) was used to construct the inflammatory microenvironment. Osteogenic differentiation was evaluated by alizarin red staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot. The formation of extracellular matrix was assessed by qRT-PCR and immunofluorescence. The expressions of receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) were measured by western blot. RESULTS Knockdown of periostin inhibited osteogenic differentiation and promoted adipogenic differentiation of DFSCs. In an inflammatory microenvironment, knockdown of periostin attenuated the proliferation and osteogenic differentiation of DFSCs. Knockdown of periostin inhibited the formation of extracellular matrix collagen I (COL-I), fibronectin, and laminin in DFSC sheets, but did not affect the expression of osteogenesis-related markers alkaline phosphatase (ALP) and osteocalcin (OCN). In the inflammatory microenvironment, knocking down periostin inhibited the expression of OCN and OPG in DFSC sheets, and promoted the expression of RANKL. CONCLUSION Periostin played a key role in maintaining the osteogenic abilities of DFSCs and DFSC sheets in the inflammatory microenvironment and might be an important molecule in the process of DFSCs coping with inflammatory microenvironment and promoting periodontal tissues regeneration.
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Affiliation(s)
- Xiuqun Wei
- State Key Laboratory of Oral Diseases, &National Clinical Research Center for Oral Diseases, & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu 610041, PR China; Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu 610041, PR China; Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Qian Liu
- State Key Laboratory of Oral Diseases, &National Clinical Research Center for Oral Diseases, & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu 610041, PR China; Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu 610041, PR China; Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Li Liu
- State Key Laboratory of Oral Diseases, &National Clinical Research Center for Oral Diseases, & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu 610041, PR China; Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu 610041, PR China; Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Weidong Tian
- State Key Laboratory of Oral Diseases, &National Clinical Research Center for Oral Diseases, & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu 610041, PR China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Yafei Wu
- State Key Laboratory of Oral Diseases, &National Clinical Research Center for Oral Diseases, & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu 610041, PR China; Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China.
| | - Shujuan Guo
- State Key Laboratory of Oral Diseases, &National Clinical Research Center for Oral Diseases, & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu 610041, PR China; Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu 610041, PR China; Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China.
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Parker J, Hockney S, Blaschuk OW, Pal D. Targeting N-cadherin (CDH2) and the malignant bone marrow microenvironment in acute leukaemia. Expert Rev Mol Med 2023; 25:e16. [PMID: 37132370 PMCID: PMC10407222 DOI: 10.1017/erm.2023.13] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 03/13/2023] [Accepted: 05/01/2023] [Indexed: 05/04/2023]
Abstract
This review discusses current research on acute paediatric leukaemia, the leukaemic bone marrow (BM) microenvironment and recently discovered therapeutic opportunities to target leukaemia-niche interactions. The tumour microenvironment plays an integral role in conferring treatment resistance to leukaemia cells, this poses as a key clinical challenge that hinders management of this disease. Here we focus on the role of the cell adhesion molecule N-cadherin (CDH2) within the malignant BM microenvironment and associated signalling pathways that may bear promise as therapeutic targets. Additionally, we discuss microenvironment-driven treatment resistance and relapse, and elaborate the role of CDH2-mediated cancer cell protection from chemotherapy. Finally, we review emerging therapeutic approaches that directly target CDH2-mediated adhesive interactions between the BM cells and leukaemia cells.
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Affiliation(s)
- Jessica Parker
- Department of Applied Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, UK
| | - Sean Hockney
- Department of Applied Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, UK
| | | | - Deepali Pal
- Department of Applied Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, UK
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Herschel Building Level 6, Brewery Lane, Newcastle upon Tyne NE1 7RU, UK
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15
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Shen L, He Y, Chen S, He L, Zhang Y. PTHrP Modulates the Proliferation and Osteogenic Differentiation of Craniofacial Fibrous Dysplasia-Derived BMSCs. Int J Mol Sci 2023; 24:ijms24087616. [PMID: 37108778 PMCID: PMC10146947 DOI: 10.3390/ijms24087616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/17/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
Fibrous dysplasia (FD) is a skeletal stem cell disease caused by mutations in the guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (GNAS) gene, which results in the abnormal accumulation of cyclic adenosine monophosphate (cAMP) and hyperactivation of downstream signaling pathways. Parathyroid hormone-related protein (PTHrP) is secreted by the osteoblast lineage and is involved in various physiological and pathological activities of bone. However, the association between the abnormal expression of PTHrP and FD, as well as its underlying mechanism, remains unclear. In this study, we discovered that FD patient-derived bone marrow stromal cells (FD BMSCs) expressed significantly higher levels of PTHrP during osteogenic differentiation and exhibited greater proliferation capacity but impaired osteogenic ability compared to normal control patient-derived BMSCs (NC BMSCs). Continuous exogenous PTHrP exposure on the NC BMSCs promoted the FD phenotype in both in vitro and in vivo experiments. Through the PTHrP/cAMP/PKA axis, PTHrP could partially influence the proliferation and osteogenesis capacity of FD BMSCs via the overactivation of the Wnt/β-Catenin signaling pathway. Furthermore, PTHrP not only directly modulated cAMP/PKA/CREB transduction but was also demonstrated as a transcriptional target of CREB. This study provides novel insight into the possible pathogenesis involved in the FD phenotype and enhances the understanding of its molecular signaling pathways, offering theoretical evidence for the feasibility of potential therapeutic targets for FD.
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Affiliation(s)
- Lihang Shen
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Yang He
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Shuo Chen
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Linhai He
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China
- First Clinical Division, Peking University School and Hospital of Stomatology, Beijing 100034, China
| | - Yi Zhang
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China
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Xu K, Zhang L, Yu N, Ren Z, Wang T, Zhang Y, Zhao X, Yu T. Effects of advanced glycation end products (AGEs) on the differentiation potential of primary stem cells: a systematic review. Stem Cell Res Ther 2023; 14:74. [PMID: 37038234 PMCID: PMC10088298 DOI: 10.1186/s13287-023-03324-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 03/27/2023] [Indexed: 04/12/2023] Open
Abstract
The formation and accumulation of advanced glycation end products (AGEs) have been associated with aging and the development, or worsening, of many degenerative diseases, such as atherosclerosis, chronic kidney disease, and diabetes. AGEs can accumulate in a variety of cells and tissues, and organs in the body, which in turn induces oxidative stress and inflammatory responses and adversely affects human health. In addition, under abnormal pathological conditions, AGEs create conditions that are not conducive to stem cell differentiation. Moreover, an accumulation of AGEs can affect the differentiation of stem cells. This, in turn, leads to impaired tissue repair and further aggravation of diabetic complications. Therefore, this systematic review clearly outlines the effects of AGEs on cell differentiation of various types of primary isolated stem cells and summarizes the possible regulatory mechanisms and interventions. Our study is expected to reveal the mechanism of tissue damage caused by the diabetic microenvironment from a cellular and molecular point of view and provide new ideas for treating complications caused by diabetes.
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Affiliation(s)
- Kuishuai Xu
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Liang Zhang
- Department of Abdominal Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Ning Yu
- Department of Abdominal Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Zhongkai Ren
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Tianrui Wang
- Department of Traumatology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Yingze Zhang
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Xia Zhao
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
| | - Tengbo Yu
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
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Lin Y, Jin L, Yang Y. Periodontal ligament cells from patients with treated stable periodontitis: Characterization and osteogenic differentiation potential. J Periodontal Res 2023; 58:237-246. [PMID: 36567428 DOI: 10.1111/jre.13085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 11/22/2022] [Accepted: 12/12/2022] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND OBJECTIVE Periodontal ligament progenitor cells (PDL cells) isolated from patients with inflammatory periodontitis have impaired regenerative capacity, but it is unknown whether this capacity can be recovered upon treatment and stabilization of the periodontal condition. The study aimed to investigate the expression of surface markers and the proliferation and osteogenic potential of PDL cells isolated from patients with treated stable periodontitis (S-PDL cells), periodontally healthy individuals (H-PDL cells), and patients with inflammatory periodontitis (I-PDL cells). METHODS H-PDL, I-PDL, and S-PDL cells were isolated from the extracted teeth of individuals who (1) were periodontally healthy, (2) had inflammatory periodontitis, and (3) had treated stable periodontitis, respectively. The expression levels of surface markers and the proliferative and osteogenic capacities of the PDL cells were assessed. RESULTS PDL cells derived from all three sources exhibited mesenchymal stem cell (MSC) characteristics. They were positive for MSC-related markers and negative for a hematopoiesis-related marker. However, S-PDL cells had higher proliferation rates, higher expression levels of osteogenic markers, higher alkaline phosphatase activity, and more calcium nodules than I-PDL cells. But all of these parameters remained lower in S-PDL cells than in H-PDL cells. CONCLUSIONS S-PDL cells proliferated faster and had greater osteogenic potential than I-PDL cells, although these values remained lower than those in H-PDL cells.
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Affiliation(s)
- Yifan Lin
- Paediatric Dentistry and Orthodontics, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China
| | - Lijian Jin
- Periodontology and Implant Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China
| | - Yanqi Yang
- Paediatric Dentistry and Orthodontics, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China
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18
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Wei X, Guo S, Liu Q, Liu L, Huo F, Wu Y, Tian W. Dental Follicle Stem Cells Promote Periodontal Regeneration through Periostin-Mediated Macrophage Infiltration and Reprogramming in an Inflammatory Microenvironment. Int J Mol Sci 2023; 24:ijms24076353. [PMID: 37047322 PMCID: PMC10094259 DOI: 10.3390/ijms24076353] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/18/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Dental follicle stem cells (DFSCs) have been verified to promote periodontal regeneration in an inflammatory microenvironment. When coping with inflammatory stimulation, DFSCs highly express periostin, a bioactive molecule closely related to periodontal homeostasis. It is worth exploring whether and how periostin plays a role in the promotion of periodontal regeneration by DFSCs. By tracking the fate of DFSCs, it was found that DFSCs significantly contributed to periodontal regeneration in rat periodontal defects while they had a low survival rate. They highly expressed periostin and improved the immune microenvironment in the defect area, especially via the recruitment and reprogramming of macrophages. Silencing periostin attenuated the effects of DFSCs in promoting periodontal regeneration and regulating macrophages. Recombinant human periostin (rhPeriostin) could not only directly promote macrophage reprogramming through the integrin αM/phosphorylated extracellular signal-regulated kinase (p-Erk)/Erk signaling pathway, but it also exhibited the potential to promote periodontal regeneration in rats when loaded in a collagen matrix. These results indicated that periostin is actively involved in the process by which DFSCs promote periodontal regeneration through the regulation of macrophages and is a promising molecular agent to promote periodontal regeneration. This study provides new insight into the mechanism by which DFSCs promote periodontal regeneration and suggests a new approach for periodontal regeneration therapy.
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Affiliation(s)
- Xiuqun Wei
- State Key Laboratory of Oral Diseases, & National Clinical Research Center for Oral Diseases, & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu 610041, China
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Shujuan Guo
- State Key Laboratory of Oral Diseases, & National Clinical Research Center for Oral Diseases, & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu 610041, China
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Qian Liu
- State Key Laboratory of Oral Diseases, & National Clinical Research Center for Oral Diseases, & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu 610041, China
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Li Liu
- State Key Laboratory of Oral Diseases, & National Clinical Research Center for Oral Diseases, & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu 610041, China
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Fangjun Huo
- State Key Laboratory of Oral Diseases, & National Clinical Research Center for Oral Diseases, & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu 610041, China
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu 610041, China
| | - Yafei Wu
- State Key Laboratory of Oral Diseases, & National Clinical Research Center for Oral Diseases, & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Correspondence: (Y.W.); (W.T.)
| | - Weidong Tian
- State Key Laboratory of Oral Diseases, & National Clinical Research Center for Oral Diseases, & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Correspondence: (Y.W.); (W.T.)
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Kornsuthisopon C, Tompkins KA, Osathanon T. Tideglusib enhances odontogenic differentiation in human dental pulp stem cells in vitro. Int Endod J 2023; 56:369-384. [PMID: 36458950 DOI: 10.1111/iej.13877] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/29/2022] [Accepted: 11/30/2022] [Indexed: 12/03/2022]
Abstract
AIM Tideglusib is a small molecule agonist of the canonical Wnt pathway. The present study investigated the influence of Tideglusib on human dental pulp stem cell (hDPSC) proliferation, apoptosis, migration and odonto/osteogenic differentiation. METHODOLOGY hDPSCs were treated with 50, 100 nM or 200 nM Tideglusib. β-catenin accumulation was detected by immunofluorescence staining. Colony-forming unit ability was assessed by staining with Coomassie blue. Cell cycle progression and cell apoptosis were investigated using flow cytometry. Cell migration was examined using an in vitro wound-healing assay. Osteogenic differentiation was examined using alkaline phosphatase (ALP) staining, alizarin red S staining and osteogenic-related gene expression. The gene expression profile was examined using a high-throughput RNA sequencing technique. All experiments were repeated using cells derived from at least four different donors (n = 4). The Mann-Whitney U-test was used to identify significant differences between two independent group comparisons. For three or more group comparisons, statistical differences were assessed using the Kruskal-Wallis test followed by pairwise comparison. The significance level was set at 5% (p < .05). RESULTS Tideglusib activated the Wnt signalling pathway in hDPSCs as demonstrated by an increase in cytoplasmic β-catenin accumulation and nuclear translocation. Tideglusib did not affect hDPSC proliferation, cell cycle progression, cell apoptosis or cell migration. In contrast, 50 and 100 nM Tideglusib significantly enhanced mineralization and osteogenic marker gene expression (RUNX2, ALP, BMP2 and DSPP; p < .05). CONCLUSIONS Tideglusib enhanced the odonto/osteogenic differentiation of hDPSCs. Therefore, incorporating this bioactive molecule in a pulp-capping material could be a promising strategy to promote dentine repair.
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Affiliation(s)
- Chatvadee Kornsuthisopon
- Dental Stem Cell Biology Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Kevin A Tompkins
- Office of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Thanaphum Osathanon
- Dental Stem Cell Biology Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.,Office of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.,Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
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20
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Molecular Basis beyond Interrelated Bone Resorption/Regeneration in Periodontal Diseases: A Concise Review. Int J Mol Sci 2023; 24:ijms24054599. [PMID: 36902030 PMCID: PMC10003253 DOI: 10.3390/ijms24054599] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/19/2023] [Accepted: 02/06/2023] [Indexed: 03/02/2023] Open
Abstract
Periodontitis is the sixth most common chronic inflammatory disease, destroying the tissues supporting the teeth. There are three distinct stages in periodontitis: infection, inflammation, and tissue destruction, where each stage has its own characteristics and hence its line of treatment. Illuminating the underlying mechanisms of alveolar bone loss is vital in the treatment of periodontitis to allow for subsequent reconstruction of the periodontium. Bone cells, including osteoclasts, osteoblasts, and bone marrow stromal cells, classically were thought to control bone destruction in periodontitis. Lately, osteocytes were found to assist in inflammation-related bone remodeling besides being able to initiate physiological bone remodeling. Furthermore, mesenchymal stem cells (MSCs) either transplanted or homed exhibit highly immunosuppressive properties, such as preventing monocytes/hematopoietic precursor differentiation and downregulating excessive release of inflammatory cytokines. In the early stages of bone regeneration, an acute inflammatory response is critical for the recruitment of MSCs, controlling their migration, and their differentiation. Later during bone remodeling, the interaction and balance between proinflammatory and anti-inflammatory cytokines could regulate MSC properties, resulting in either bone formation or bone resorption. This narrative review elaborates on the important interactions between inflammatory stimuli during periodontal diseases, bone cells, MSCs, and subsequent bone regeneration or bone resorption. Understanding these concepts will open up new possibilities for promoting bone regeneration and hindering bone loss caused by periodontal diseases.
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21
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Hu Y, Wang Z, Fan C, Gao P, Wang W, Xie Y, Xu Q. Human gingival mesenchymal stem cell-derived exosomes cross-regulate the Wnt/β-catenin and NF-κB signalling pathways in the periodontal inflammation microenvironment. J Clin Periodontol 2023; 50:796-806. [PMID: 36843393 DOI: 10.1111/jcpe.13798] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/24/2023] [Accepted: 02/21/2023] [Indexed: 02/28/2023]
Abstract
AIM To examine the immunomodulatory effect of exosomes originating from gingival mesenchymal stem cells (GMSC-Exo) on periodontal bone regeneration and its role in the regulation of the nuclear-factor kappaB (NF-κB) and Wnt/β-catenin pathways in the periodontal inflammatory microenvironment. MATERIALS AND METHODS First, periodontal ligament stem cells (PDLSCs) were treated with GMSC-Exo or Porphyromonas gingivalis-derived lipopolysaccharide (P.g-LPS) in vitro. Quantitative real-time PCR (qRT-PCR) and western blot were carried out to detect the expressions of osteogenic differentiation-related factors in cells. Further, PDLSCs were treated with P.g-LPS or inhibitors. The expression of NF-κB pathway-related factors as well as of Wnt/β-catenin pathway-related factors were detected by qRT-PCR and western blot. RESULTS GMSC-Exo treatment promoted the expression of osteogenic differentiation-related factors within PDLSCs in both normal and inflammatory environments. Further investigations showed that GMSC-Exo could also inhibit the P.g-LPS-induced activation of the NF-κB pathway, leading to the up-regulation of the Wnt/β-catenin pathway. When the Wnt/β-catenin signalling was blocked, the inhibitory effect of GMSC-Exo on the NF-κB pathway was abolished. CONCLUSIONS GMSC-Exo could promote the osteogenic differentiation of PDLSCs. There could be mutually exclusive regulatory roles between the NF-κB and Wnt/β-catenin signalling pathways in a periodontal inflammatory environment. GMSC-Exo exhibited an effective cross-regulation ability for both pathways.
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Affiliation(s)
- Yingzhe Hu
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, China.,School of Stomatology of Qingdao University, Qingdao, China
| | - Zhiguo Wang
- Department of Burn and Plastic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chun Fan
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, China.,School of Stomatology of Qingdao University, Qingdao, China
| | - Pengyu Gao
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, China.,School of Stomatology of Qingdao University, Qingdao, China
| | - Wenxuan Wang
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, China.,School of Stomatology of Qingdao University, Qingdao, China
| | - Yutong Xie
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, China.,School of Stomatology of Qingdao University, Qingdao, China
| | - Quanchen Xu
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, China
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22
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Cyclic di-adenosine monophosphate regulates the osteogenic and adipogenic differentiation of hPDLSCs via MAPK and NF-κB signaling. Acta Biochim Biophys Sin (Shanghai) 2023; 55:426-437. [PMID: 36825442 PMCID: PMC10160224 DOI: 10.3724/abbs.2023018] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2023] Open
Abstract
Cyclic di-adenosine monophosphate (c-di-AMP) is a bacterial second messenger that can be recognized by infected host cells and activate the immunoinflammatory response. The purpose of this study is to demonstrate the effect of c-di-AMP on the differentiation of human periodontal ligament stem cells (hPDLSCs) and its underlying mechanisms. In the present study, we find that the gingival crevicular fluid (GCF) of patients with chronic periodontitis has a higher expression level of c-di-AMP than that of healthy people. In vitro, c-di-AMP influences the differentiation of hPDLSCs by upregulating Toll-like receptors (TLRs); specifically, it inhibits osteogenic differentiation by activating NF-κB and ERK/MAPK and promotes adipogenic differentiation through the NF-κB and p38/MAPK signaling pathways. Inhibitors of TLRs or activated pathways reduce the changes induced by c-di-AMP. Our results establish the potential correlation among bacterial c-di-AMP, periodontal tissue homeostasis and chronic periodontitis pathogenesis.
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23
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Alqahtani S, Butcher MC, Ramage G, Dalby MJ, McLean W, Nile CJ. Acetylcholine Receptors in Mesenchymal Stem Cells. Stem Cells Dev 2023; 32:47-59. [PMID: 36355611 DOI: 10.1089/scd.2022.0201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are well known for their regenerative potential. Even though the ability of MSCs to proliferate and differentiate has been studied extensively, there remains much to learn about the signaling mechanisms and pathways that control proliferation and influence the differentiation phenotype. In recent years, there has been growing evidence for the utility of non-neuronal cholinergic signaling systems and that acetylcholine (ACh) plays an important ubiquitous role in cell-to-cell communication. Indeed, cholinergic signaling is hypothesized to occur in stem cells and ACh synthesis, as well as in ACh receptor (AChR) expression, has been identified in several stem cell populations, including MSCs. Furthermore, AChRs have been found to influence MSC regenerative potential. In humans, there are two major classes of AChRs, muscarinic AChRs and nicotinic AChRs, with each class possessing several subtypes or subunits. In this review, the expression and function of AChRs in different types of MSC are summarized with the aim of highlighting how AChRs play a pivotal role in regulating MSC regenerative function.
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Affiliation(s)
- Saeed Alqahtani
- School of Medicine Dentistry and Nursing and University of Glasgow, Glasgow, United Kingdom
| | - Mark C Butcher
- School of Medicine Dentistry and Nursing and University of Glasgow, Glasgow, United Kingdom
| | - Gordon Ramage
- School of Medicine Dentistry and Nursing and University of Glasgow, Glasgow, United Kingdom
| | - Matthew J Dalby
- School of Molecular Biosciences, University of Glasgow, Glasgow, United Kingdom
| | - William McLean
- School of Medicine Dentistry and Nursing and University of Glasgow, Glasgow, United Kingdom
| | - Christopher J Nile
- Faculty of Medical Sciences, School of Dental Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
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24
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Sarmiento Alarcón A, Troncoso-Ortiz EJ, Machado CA, Fernández Paniura A. Implementation of Controlled Physical Activity Programs. PHYSICAL ACTIVITY AND BARIATRIC SURGERY 2023:139-153. [DOI: 10.1007/978-3-031-26614-0_15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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25
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Rumman M, Dhawan J. PTPRU, a quiescence-induced receptor tyrosine phosphatase negatively regulates osteogenic differentiation of human mesenchymal stem cells. Biochem Biophys Res Commun 2022; 636:41-49. [DOI: 10.1016/j.bbrc.2022.10.062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 10/18/2022] [Indexed: 11/02/2022]
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26
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Ghafouri-Fard S, Dashti S, Gholami L, Badrlou E, Sadeghpour S, Hussen BM, Hidayat HJ, Nazer N, Shadnoush M, Sayad A, Arefian N. Expression analysis of Wnt signaling pathway related lncRNAs in periodontitis: A pilot case-control study. HUMAN GENE 2022; 33:201069. [DOI: 10.1016/j.humgen.2022.201069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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27
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Wu D, Zhao L, Sui B, Tan L, Lu L, Mao X, Liao G, Shi S, Cao Y, Yang X, Kou X. An Appearance Data-Driven Model Visualizes Cell State and Predicts Mesenchymal Stem Cell Regenerative Capacity. SMALL METHODS 2022; 6:e2200087. [PMID: 35674483 DOI: 10.1002/smtd.202200087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 04/14/2022] [Indexed: 06/15/2023]
Abstract
Mesenchymal stem cells (MSCs) are widely used in treating various diseases. However, lack of a reliable evaluation approach to characterize the potency of MSCs has dampened their clinical applications. Here, a function-oriented mathematical model is established to evaluate and predict the regenerative capacity (RC) of MSCs. Processed by exhaustive testing, the model excavates four optimal fitted indices, including nucleus roundness, nucleus/cytoplasm ratio, side-scatter height, and ERK1/2 from the given index combinations. Notably, three of them except ERK1/2 are cell appearance-associated features. The predictive power of the model is validated via screening experiments of these indices by predicting the RC of newly enrolled and chemical inhibitor-treated MSCs. Further RNA-sequencing analysis reveals that cell appearance-based indices may serve as major indicators to visualize the results of integration-weighted signals in and out of cells and reflect MSC stemness. In general, this study proposes an appearance data-driven predictive model for the RC and stemness of MSCs.
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Affiliation(s)
- Di Wu
- Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
- Hospital of Stomatology, Guanghua School of Stomatology, Department of Oral and Maxillofacial Surgery, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
- Hospital of Stomatology, Guanghua School of Stomatology, Department of Orthodontics, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
| | - Lu Zhao
- Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
| | - Bingdong Sui
- Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Lingping Tan
- Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
| | - Lu Lu
- Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
| | - Xueli Mao
- Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
| | - Guiqing Liao
- Hospital of Stomatology, Guanghua School of Stomatology, Department of Oral and Maxillofacial Surgery, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
| | - Songtao Shi
- Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
- Key Laboratory of Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yang Cao
- Hospital of Stomatology, Guanghua School of Stomatology, Department of Orthodontics, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
| | - Xiaobao Yang
- School of Physics and Optoelectronics, South China University of Technology, Guangzhou, 510640, China
| | - Xiaoxing Kou
- Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
- Key Laboratory of Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China
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Wang D, Cao H, Hua W, Gao L, Yuan Y, Zhou X, Zeng Z. Mesenchymal Stem Cell-Derived Extracellular Vesicles for Bone Defect Repair. MEMBRANES 2022; 12:membranes12070716. [PMID: 35877919 PMCID: PMC9315966 DOI: 10.3390/membranes12070716] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/17/2022] [Accepted: 07/18/2022] [Indexed: 12/12/2022]
Abstract
The repair of critical bone defects is a hotspot of orthopedic research. With the development of bone tissue engineering (BTE), there is increasing evidence showing that the combined application of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) (MSC-EVs), especially exosomes, with hydrogels, scaffolds, and other bioactive materials has made great progress, exhibiting a good potential for bone regeneration. Recent studies have found that miRNAs, proteins, and other cargo loaded in EVs are key factors in promoting osteogenesis and angiogenesis. In BTE, the expression profile of the intrinsic cargo of EVs can be changed by modifying the gene expression of MSCs to obtain EVs with enhanced osteogenic activity and ultimately enhance the osteoinductive ability of bone graft materials. However, the current research on MSC-EVs for repairing bone defects is still in its infancy, and the underlying mechanism remains unclear. Therefore, in this review, the effect of bioactive materials such as hydrogels and scaffolds combined with MSC-EVs in repairing bone defects is summarized, and the mechanism of MSC-EVs promoting bone defect repair by delivering active molecules such as internal miRNAs is further elucidated, which provides a theoretical basis and reference for the clinical application of MSC-EVs in repairing bone defects.
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Affiliation(s)
- Dongxue Wang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
| | - Hong Cao
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China; (H.C.); (Y.Y.)
| | - Weizhong Hua
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
| | - Lu Gao
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
| | - Yu Yuan
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China; (H.C.); (Y.Y.)
| | - Xuchang Zhou
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China; (H.C.); (Y.Y.)
- Correspondence: (X.Z.); (Z.Z.)
| | - Zhipeng Zeng
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
- Correspondence: (X.Z.); (Z.Z.)
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29
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Singhatanadgit W, Kitpakornsanti S, Toso M, Pavasant P. IFNγ-primed periodontal ligament cells regulate T-cell responses via IFNγ-inducible mediators and ICAM-1-mediated direct cell contact. ROYAL SOCIETY OPEN SCIENCE 2022; 9:220056. [PMID: 35911203 PMCID: PMC9326268 DOI: 10.1098/rsos.220056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 07/04/2022] [Indexed: 06/15/2023]
Abstract
Periodontal ligament (PDL) cells help maintain tissue homeostasis by balancing PDL tissue inflammation and regeneration. However, the mechanisms by which interferon γ (IFNγ) modulate this process are not yet fully understood. The present study aimed to examine the effect of primed and non-primed PDL cells with IFNγ on the viability and differentiation of T lymphocytes and its functional consequences. The results showed that IFNγ-primed PDL cells possessed enhanced immunosuppression by suppressing T-lymphocyte viability and directing T-lymphocyte differentiation towards a higher T helper (Th) Th2/Th1 ratio. Suppression of T-cell viability was mainly mediated by IFNγ-inducible secreted mediators, which was prevented in the presence of direct cell contact, probably by intercellular adhesion molecule-1 (ICAM-1)-induced PI3 K-mediated transforming growth factor β1 expression in PDL cells. By contrast, ICAM-1 activation augmented IFNγ-induced IFNγ and interleukin-6 expression in PDL cells, which in turn modulated T-cell differentiation. The resulting interaction between these two cell types activated macrophage and suppressed osteoclast differentiation. In conclusion, the results have shown, for the first time to our knowledge, that primed and non-primed PDL cells with IFNγ differentially control T-cell responses via IFNγ-inducible mediators and ICAM-1-mediated direct cell contact, suggesting the role of PDL cells in shifting an inflammatory phase towards a regenerative phase.
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Affiliation(s)
- Weerachai Singhatanadgit
- Oral and Maxillofacial Surgery Unit, Faculty of Dentistry, Thammasat University, Rangsit Campus, Pathumthani, Thailand
- Research Unit in Mineralized Tissue Reconstruction, Thammasat University, Rangsit Campus, Pathumthani, Thailand
| | - Setthawut Kitpakornsanti
- Research Unit in Mineralized Tissue Reconstruction, Thammasat University, Rangsit Campus, Pathumthani, Thailand
| | - Montree Toso
- Research Unit in Mineralized Tissue Reconstruction, Thammasat University, Rangsit Campus, Pathumthani, Thailand
- Stem Cell for Life Research Center, Greater Pharma Manufacturing Co. Ltd, Nakhon Pathom, Thailand
| | - Prasit Pavasant
- Center of Excellence in Regenerative Dentistry, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
- Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
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Qin R, Cui Z, Zhou H, Guo R, Yao X, Wang T, Qin X, He X. Effect of lentivirus-mediated BMP2 from autologous tooth on the proliferative and osteogenic capacity of human periodontal ligament cells. J Periodontal Res 2022; 57:869-879. [PMID: 35730345 DOI: 10.1111/jre.13025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 04/28/2022] [Accepted: 05/29/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND AND OBJECTIVE Periodontitis is a chronic progressive inflammation that invades periodontal supporting tissues, in which periodontal tissue regeneration engineering offers new hope for prevention and treatment, including seed cells, scaffolds, and growth factors. In recent years, scholars have shown that autologous teeth can be used as new bone tissue repair materials for periodontal regeneration and bone tissue repair. The aim of this study was to establish a human periodontal ligament cell line that expresses the human bone morphogenetic protein 2 gene (BMP2) in a stable manner using lentiviral mediation in order to explore the effect of BMP2 from autologous tooth on the proliferative and osteogenic capacity of human periodontal ligament cells (hPDLCs). MATERIALS AND METHODS Human periodontal ligament cells were cultured, subcultured, and identified, and then homologous recombinant lentivirus plasmid plv-BMP2 was constructed and transfected into the third passage (P3 ) hPDLCs. After that, the effect of BMP2 on its proliferation was detected by CCK-8, at the same time, the osteogenic induction of hPDLCs was carried out at 7, 14, and 21 days, and then the effect of BMP2 on its osteogenic ability was detected by alizarin red staining, alkaline phosphatase activity determination, and the mRNA expression levels of osteogenic-related genes using real-time fluorescence quantitative PCR, including alkaline phosphatase, runt-related transcription factor 2, bone sialoprotein, osteocalcin, osteopontin, and collagen I. Finally, spss26.0 software was used for statistical processing. RESULTS The results showed that cells transfected with the homologous recombinant lentiviral plasmid pLV-BMP2 had a similar morphology to normal hPDLCs, showing a typical radial arrangement; the cell proliferative capacity of the pLV-BMP2 group as measured by CCK-8 was enhanced compared with the control group and the pLV-puro group (p < .05); alizarin red staining and alkaline phosphatase activity assay showed that the osteogenic ability of pLV-BMP2 was significantly enhanced compared with the control and pLV-puro groups (p < .01), and the findings of real-time fluorescence-based quantitative PCR showed high expression of osteogenic-related genes in pLV-BMP2 group (p < .01). CONCLUSION In conclusion, a stable periodontal ligament cell line overexpressing BMP2 was successfully established by a lentivirus-mediated method, which proved that BMP2 has a strong ability to promote the proliferation and osteogenesis of hPDLCs, thereby providing an opportunity for the study of periodontal tissue regeneration as well as providing an experimental basis for the application of autologous teeth as a new type of bone repair material for periodontal therapy and even for maxillofacial bone tissue repair.
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Affiliation(s)
- Ruoshan Qin
- Department of Prosthodontics, School of Dentistry, Lanzhou University, Lanzhou, Gansu, China
| | - Ziwei Cui
- Department of Prosthodontics, School of Dentistry, Lanzhou University, Lanzhou, Gansu, China
| | - Hongli Zhou
- Department of Prosthodontics, School of Dentistry, Lanzhou University, Lanzhou, Gansu, China
| | - Ru Guo
- Department of Prosthodontics, School of Dentistry, Lanzhou University, Lanzhou, Gansu, China
| | - Xuanxuan Yao
- Department of Prosthodontics, School of Dentistry, Lanzhou University, Lanzhou, Gansu, China
| | - Tao Wang
- Department of Prosthodontics, School of Dentistry, Lanzhou University, Lanzhou, Gansu, China
| | - Xiaodong Qin
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, China
| | - Xiangyi He
- Department of Prosthodontics, School of Dentistry, Lanzhou University, Lanzhou, Gansu, China
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Chen M, Lin X, Zhang L, Hu X. Effects of nuclear factor-κB signaling pathway on periodontal ligament stem cells under lipopolysaccharide-induced inflammation. Bioengineered 2022; 13:7951-7961. [PMID: 35297308 PMCID: PMC9208442 DOI: 10.1080/21655979.2022.2051690] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Lipopolysaccharide (LPS) induces inflammatory stress and apoptosis. This study focused on the effect of nuclear factor kappa B (NF-κB) signaling pathway on proliferation and osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) after LPS induction and its mechanism. We first isolated hPDLSCs from human tooth root samples in vitro. Then, flow cytometry detected positive expression of cell surface antigens CD146 and STRO-1 and negative expression of CD45, suggesting the hPDLSCs were successfully isolated. LPS significantly induced increased apoptosis and diminished proliferation of hPDLSCs. The NF-κB pathway agonist phorbol 12-myristate 13-acetate (PMA) or p65 overexpression inhibited the proliferation of LPS-treated hPDLSCs and promoted apoptosis. PMA also promoted LPS-induced up-regulation of the expression of inflammatory factors TNF-α and IL-6 and down-regulation of the expression of anti-inflammatory factor IL-10. Additionally, LPS was confirmed to lead to a reduction of alkaline phosphatase (ALP) activity, calcium nodules, and expression of osteogenic markers Runt-related transcription factor 2 (Runx2) and osteopontin. This reduction could be promoted by PMA. Western blotting further indicated that PMA could promote LPS-induced decrease of expression of p65 (cytoplasm), and total cellular proteins IKKα and IKKβ in hPDLSCs, while protein expression of p-IκBα (cytoplasm) and p65 (nucleus), and p-IκBα/IκBα ratio was elevated. By contrast, inhibition of the NF-κB pathway (PDTC) or small-interfering RNA targeting NF-κB/p65 (p65 siRNA) showed the opposite results. In conclusion, activation of NF-κB signaling in LPS-induced inflammatory environment can inhibit the proliferation and osteogenic differentiation of hPDLSCs. This study provides a theory foundation for the clinical treatment of periodontitis.
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Affiliation(s)
- Mingyue Chen
- Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China
| | - Xiaobo Lin
- Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China
| | - Li Zhang
- Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China
| | - Xiaoli Hu
- Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China.,Department of Rehabilitation, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China
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Lei F, Li M, Lin T, Zhou H, Wang F, Su X. Treatment of inflammatory bone loss in periodontitis by stem cell-derived exosomes. Acta Biomater 2022; 141:333-343. [PMID: 34979326 DOI: 10.1016/j.actbio.2021.12.035] [Citation(s) in RCA: 106] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 12/08/2021] [Accepted: 12/28/2021] [Indexed: 02/07/2023]
Abstract
Periodontitis is the primary cause of tooth loss, but there is no effective treatment to repair inflammatory bone loss in periodontitis. Exosomes emerge as essential paracrine factors of mesenchymal stem cells (MSCs) that mediated tissue regeneration. Here, we investigated the potential of exosomes secreted by periodontal ligament stem cells (PDLSCs) as therapeutics for the bone defect in periodontitis. Exosomes secreted from PDLSCs derived from healthy periodontal ligaments (h-PDLSCs) and their function were evaluated on PDLSCs isolated from the inflammatory periodontal ligament of periodontitis patients (i-PDLSCs). Treatment of exosomes of h-PDLSCs led to an increase in the formation of mineralized nodules and the expressions of osteogenic genes and proteins in i-PDLSCs. Mechanistically, h-PDLSCs-exosomes suppressed the over-activation of canonical Wnt signaling to recover the osteogenic differentiation capacity of i-PDLSCs. To evaluate the therapeutic of exosomes on inflammatory bone loss, h-PDLSCs-exosomes loaded with Matrigel or β-TCP were employed to repair bone defects in rat models of periodontitis. Compared to the vehicle-treated control group, h-PDLSCs-exosomes-treated rats resulted in more bone formation in the defect of alveolar bone. In conclusion, these results demonstrated that exosomes derived from healthy PDLSCs could rescue the osteogenesis capacity of endogenous stem cells under an inflammatory environment and promote regeneration of alveolar bone. Our findings suggest that MSCs-derived exosome is an effective and practical cell-free MSC therapeutic for the treatment of periodontitis. STATEMENT OF SIGNIFICANCE: There is no effective treatment to repair inflammatory bone loss in periodontitis. As essential paracrine factors of PDLSCs, exosomes might mediate tissue regeneration during stem cell therapy. Here, we reported that exosomes secreted from healthy PDLSCs promoted the osteogenic differentiation of PDLSCs derived from periodontitis tissue. Healthy PDLSCs-exosomes treatment resulted in accelerated bone formation in the defect of alveolar bone in rat models of periodontitis. Mechanistically, h-PDLSCs-exosomes suppressed the over-activation of canonical Wnt signaling to recover the osteogenic differentiation capacity of inflammatory PDLSCs. These findings suggest that MSCs-derived exosome is an effective and practical cell-free MSC therapeutic for the treatment of periodontitis.
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Ma L, Rao N, Jiang H, Dai Y, Yang S, Yang H, Hu J. Small extracellular vesicles from dental follicle stem cells provide biochemical cues for periodontal tissue regeneration. Stem Cell Res Ther 2022; 13:92. [PMID: 35241181 PMCID: PMC8895915 DOI: 10.1186/s13287-022-02767-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 02/08/2022] [Indexed: 11/20/2022] Open
Abstract
Background Treatments based on stem cell-derived small extracellular vesicles (sEVs) have been explored as an alternative to stem cell transplantation-based therapies in periodontal regeneration. Dental follicle stem cells (DFSCs) have shown great potential for regenerative medicine applications. However, it is unclear whether sEVs derived from DFSCs (DFSCs-sEVs) could be used in periodontal regeneration. This study investigates whether DFSCs-sEVs could regenerate damaged periodontal tissue and the potential underlying mechanism. Methods DFSCs-sEVs were isolated and identified, and periodontal ligament stem cells (PDLSCs) were cocultured with the isolated sEVs. The effect of DFSCs-sEVs on the biological behaviour of PDLSCs was examined using EdU assay, CCK-8 assay, cell cycle analysis, wound healing, alizarin red staining, qRT-PCR, and western blot analysis. RNA sequencing and functional enrichment analysis were used to detect the signal pathway involved in the effect of DFSCs-sEVs on PDLSCs. PDLSCs were pretreated with ERK1/2 or p38 MAPK inhibitors to investigate the possible involvement of the ERK1/2 and p38 MAPK pathways. Additionally, DFSCs-sEVs were combined with collagen sponges and transplanted into the periodontal defects in SD rats, and then, pathological changes in periodontal tissue were examined using haematoxylin and eosin (HE) staining and micro-CT. Results PDLSCs could internalize DFSCs-sEVs, thereby enhancing the proliferation assessed using EdU assay, CCK-8 assay and cell cycle analysis. DFSCs-sEVs significantly enhanced the migration of PDLSCs. DFSCs-sEVs promoted osteogenic differentiation of PDLSCs, showing deep Alizarin red staining, upregulated osteogenic genes (RUNX2, BSP, COL1), and upregulated protein expression (RUNX2, BSP, COL1, ALP). We found that p38 MAPK signalling was activated via phosphorylation. Inhibition of this signalling pathway with a specific inhibitor (SB202190) partially weakened the enhanced proliferation. After DFSCs-sEVs transplantation, new periodontal ligament-like structures and bone formation were observed in the damaged periodontal area in rats. Labelled DFSCs-sEVs were observed in the newly formed periodontal ligament and soft tissue of the defect area. Conclusions Our study demonstrated that DFSCs-sEVs promoted periodontal tissue regeneration by promoting the proliferation, migration, and osteogenic differentiation of PDLSCs. The effect of DFSCs-sEVs in promoting PDLSCs proliferation may be partially attributed to the activation of p38 MAPK signalling pathway. DFSCs-sEVs provide us with a novel strategy for periodontal regeneration in the future. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02767-6.
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Affiliation(s)
- Liya Ma
- Yunnan Key Laboratory of Stomatology and Department of Dental Research, The Affiliated Stomatology Hospital of Kunming Medical University, Kunming, 650500, Yunnan, People's Republic of China.,Department of Orthodontics, The Affiliated Stomatology Hospital of Kunming Medical University, Kunming, 650500, Yunnan, People's Republic of China
| | - Nanquan Rao
- Yunnan Key Laboratory of Stomatology and Department of Dental Research, The Affiliated Stomatology Hospital of Kunming Medical University, Kunming, 650500, Yunnan, People's Republic of China
| | - Hui Jiang
- Yunnan Key Laboratory of Stomatology and Department of Dental Research, The Affiliated Stomatology Hospital of Kunming Medical University, Kunming, 650500, Yunnan, People's Republic of China
| | - Yuzhe Dai
- Yunnan Key Laboratory of Stomatology and Department of Dental Research, The Affiliated Stomatology Hospital of Kunming Medical University, Kunming, 650500, Yunnan, People's Republic of China
| | - Songtao Yang
- Yunnan Key Laboratory of Stomatology and Department of Dental Research, The Affiliated Stomatology Hospital of Kunming Medical University, Kunming, 650500, Yunnan, People's Republic of China
| | - Hefeng Yang
- Yunnan Key Laboratory of Stomatology and Department of Dental Research, The Affiliated Stomatology Hospital of Kunming Medical University, Kunming, 650500, Yunnan, People's Republic of China.
| | - Jiangtian Hu
- Department of Orthodontics, The Affiliated Stomatology Hospital of Kunming Medical University, Kunming, 650500, Yunnan, People's Republic of China.
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Zhang Z, Deng M, Hao M, Tang J. Stem Cell Therapy in Chronic Periodontitis: Host Limitations and Strategies. FRONTIERS IN DENTAL MEDICINE 2022. [DOI: 10.3389/fdmed.2021.833033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The treatment of chronic periodontitis is undergoing a transition from simple plaque removal and replacement with substitute materials to regenerative therapy, in which stem cells play an important role. Although stem cell-based periodontal reconstruction has been widely explored, few clinical regeneration studies have been reported. The inflammatory lesions under the impact of host factors such as local microbial–host responses, may impede the regenerative properties of stem cells and destroy their living microenvironment. Furthermore, systemic diseases, in particular diabetes mellitus, synergistically shape the disordered host-bacterial responses and exacerbate the dysfunction of resident periodontal ligament stem cells (PDLSCs), which ultimately restrain the capacity of mesenchymal stromal cells (MSCs) to repair the damaged periodontal tissue. Accordingly, precise regulation of an instructive niche has become a promising approach to facilitate stem cell-based therapeutics for ameliorating periodontitis and for periodontal tissue regeneration. This review describes host limitations and coping strategies that influence resident or transplanted stem cell-mediated periodontal regeneration, such as the management of local microbial–host responses and rejuvenation of endogenous PDLSCs. More importantly, we recommend that active treatments for systemic diseases would also assist in recovering the limited stem cell function on the basis of amelioration of the inflammatory periodontal microenvironment.
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Yang Y, Ren D, Zhao D, Zhang B, Ye R. MicroRNA-203 mediates P. gingivalis LPS-induced inflammation and differentiation of periodontal ligament cells. Oral Dis 2022; 29:1715-1725. [PMID: 35034420 DOI: 10.1111/odi.14132] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 12/07/2021] [Accepted: 01/09/2022] [Indexed: 02/05/2023]
Abstract
AIM In this study, we aimed to explore the effects of microRNA-203 (miR-203) on P. gingivalis lipopolysaccharide (P.g. LPS)-stimulated periodontal ligament cells (PDLCs) and identify potential molecular targets for periodontitis treatment. METHODS PDLCs were stimulated by P.g. LPS, followed by quantification of miR-203 and AP-1 expression. Next, loss- and gain-of-function experiments were applied in P.g. LPS-induced PDLCs. The proliferation, apoptosis, and differentiation of PDLCs were determined and mineralized nodule numbers were counted. Functional assays were used to identify interactions among miR-203, activator protein 1 (AP-1), and intercellular adhesion molecule 1 (ICAM-1). In addition, expression of osteogenesis-related genes and release of proinflammatory factors were analyzed. RESULTS miR-203 was found to be downregulated while AP-1 was upregulated in PDLCs stimulated by P.g. LPS. The overexpression of miR-203 promoted P.g. LPS-stimulated PDLC proliferation and differentiation, inhibited apoptosis, and increased the number of mineralized nodules. miR-203 was verified to downregulate AP-1/ICAM-1 axis. miR-203 overexpression reduced the secretion of proinflammatory factors while increasing expression of osteogenesis-related genes in P.g. LPS-stimulated PDLCs, which was reversed by overexpressing AP-1 and ICAM-1. CONCLUSION These experimental data demonstrated the potential inhibitory effects of overexpressed miR-203 on periodontitis development by promoting PDLC differentiation and suppressing inflammatory responses through AP-1/ICAM-1 axis.
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Affiliation(s)
- Yang Yang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, 610041, Sichuan, China.,Department of General Dentistry, West China Hospital of Stomatology, Sichuan University, 610041, Sichuan, China
| | - Dongping Ren
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, 610041, Sichuan, China.,Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, 610041, Sichuan, China
| | - Duo Zhao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, 610041, Sichuan, China.,Department of General Dentistry, West China Hospital of Stomatology, Sichuan University, 610041, Sichuan, China
| | - Bo Zhang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, 610041, Sichuan, China.,Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, 610041, Sichuan, China
| | - Rui Ye
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, 610041, Sichuan, China.,Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, 610041, Sichuan, China
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Guan X, He Y, Li Y, Shi C, Wei Z, Zhao R, Han Y, Pan L, Yang J, Hou TZ. Gremlin aggravates periodontitis via activating the NF-κB signaling pathway. J Periodontol 2022; 93:1589-1602. [PMID: 34993960 DOI: 10.1002/jper.21-0474] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 10/27/2021] [Accepted: 11/20/2021] [Indexed: 11/06/2022]
Abstract
BACKGROUND Gremlin has been reported to regulate inflammation and osteogenesis. Periodontitis is a destructive disease degenerating periodontal tissues, therefore leads to alveolar bone resorption and tooth loss. Based on the importance of Gremlin's bio-activity, the aim of this study is to, in vivo and in vitro, unveil the function of Gremlin in regulating the development of periodontitis and its consequent effects on alveolar bone loss. METHODS Clinical specimens were used to determine the expression of Gremlin in periodontal tissues by immunohistochemical staining and western blot. Then utilizing the rat periodontitis model to investigate the function of gremlin-regulated nuclear factor-kappa B (NF-κB) pathway during the development of periodontal inflammation and the alveolar bone loss. Lastly, the regulation of the osteogenesis of human periodontal ligament stem cells (hPDLSCs) by Gremlin under inflamed condition was analyzed by alkaline phosphatase (ALP) and alizarin red staining (ARS). RESULTS We found clinically and experimentally that the expression of Gremlin is markedly increased in periodontitis tissues. Interestingly, we revealed that Gremlin regulated the progress of periodontitis via regulating the activities of NF-κB pathway and interleukin-1β (IL-1β). Notably, we observed that Gremlin influenced the osteogenesis of hPDLSCs. Thus, our present study identified Gremlin as a new key regulator for development of periodontitis. CONCLUSIONS Our current study illustrated that Gremlin acts as a crucial mediator and possibly serves as a potential diagnostic marker for periodontitis. Discovery of new factors involved in the pathophysiology of periodontitis could contribute to the development of novel therapeutic treatment for the disease. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Xiaoyue Guan
- The Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Endodontics, Stomatological Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
| | - Yani He
- The Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Endodontics, Stomatological Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
| | - Yingxue Li
- The Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Endodontics, Stomatological Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
| | - Chen Shi
- The Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Endodontics, Stomatological Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
| | - Zhichen Wei
- The Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Endodontics, Stomatological Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
| | - Rui Zhao
- The Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Endodontics, Stomatological Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
| | - Yue Han
- The Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Endodontics, Stomatological Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
| | - Lifei Pan
- The Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Endodontics, Stomatological Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
| | - Jianmin Yang
- The Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Tie Zhou Hou
- The Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Endodontics, Stomatological Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China
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Okić-Đorđević I, Obradović H, Kukolj T, Petrović A, Mojsilović S, Bugarski D, Jauković A. Dental mesenchymal stromal/stem cells in different microenvironments— implications in regenerative therapy. World J Stem Cells 2021; 13:1863-1880. [PMID: 35069987 PMCID: PMC8727232 DOI: 10.4252/wjsc.v13.i12.1863] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/15/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Current research data reveal microenvironment as a significant modifier of physical functions, pathologic changes, as well as the therapeutic effects of stem cells. When comparing regeneration potential of various stem cell types used for cytotherapy and tissue engineering, mesenchymal stem cells (MSCs) are currently the most attractive cell source for bone and tooth regeneration due to their differentiation and immunomodulatory potential and lack of ethical issues associated with their use. The microenvironment of donors and recipients selected in cytotherapy plays a crucial role in regenerative potential of transplanted MSCs, indicating interactions of cells with their microenvironment indispensable in MSC-mediated bone and dental regeneration. Since a variety of MSC populations have been procured from different parts of the tooth and tooth-supporting tissues, MSCs of dental origin and their achievements in capacity to reconstitute various dental tissues have gained attention of many research groups over the years. This review discusses recent advances in comparative analyses of dental MSC regeneration potential with regards to their tissue origin and specific microenvironmental conditions, giving additional insight into the current clinical application of these cells.
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Affiliation(s)
- Ivana Okić-Đorđević
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Hristina Obradović
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Tamara Kukolj
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Anđelija Petrović
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Slavko Mojsilović
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Diana Bugarski
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Aleksandra Jauković
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
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EZH2 Regulates Lipopolysaccharide-Induced Periodontal Ligament Stem Cell Proliferation and Osteogenesis through TLR4/MyD88/NF- κB Pathway. Stem Cells Int 2021; 2021:7625134. [PMID: 34899921 PMCID: PMC8654561 DOI: 10.1155/2021/7625134] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 11/11/2021] [Accepted: 11/12/2021] [Indexed: 12/19/2022] Open
Abstract
Background Periodontitis induced by bacteria especially Gram-negative bacteria is the most prevalent chronic inflammatory disease worldwide. Emerging evidence supported that EZH2 plays a significant role in the inflammatory response of periodontal tissues. However, little information is available regarding the underlying mechanism of EZH2 in periodontitis. This study is aimed at determining the potential role and underlying mechanism of EZH2 in periodontitis. Methods The protein levels of EZH2, H3K27ME, p-p65, p-IKB, TLR4, MyD88, Runx2, and OCN were examined by western blot assay. Proliferation was evaluated by CCK8 assay. The levels of TNFα, IL1β, and IL6 were detected by ELISA assay. Migration was detected by wound healing assay. The distribution of p65 was detected by immunofluorescence. The formation of mineralized nodules was analyzed using alizarin red staining. Results LPS stimulation significantly promoted EZH2 and H3K27me3 expression in primary human periodontal ligament stem cells (PDLSCs). Targeting EZH2 prevented LPS-induced upregulation of the inflammatory cytokines and inhibition of cell proliferation and migration. Furthermore, EZH2 knockdown attenuated the TLR4/MyD88/NF-κB signaling to facilitate PDLSC osteogenesis. Conclusions Modulation of the NF-κB pathway through the inhibition of EZH2 may offer a new perspective on the treatment of chronic apical periodontitis.
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Zhou Q, Ren X, Oberoi MK, Bedar M, Caprini RM, Dewey MJ, Kolliopoulos V, Yamaguchi DT, Harley BA, Lee JC. β-Catenin Limits Osteogenesis on Regenerative Materials in a Stiffness-Dependent Manner. Adv Healthc Mater 2021; 10:e2101467. [PMID: 34585526 PMCID: PMC8665088 DOI: 10.1002/adhm.202101467] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/22/2021] [Indexed: 12/30/2022]
Abstract
Targeted refinement of regenerative materials requires mechanistic understanding of cell-material interactions. The nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) scaffold is shown to promote skull regeneration in vivo without additive exogenous growth factors or progenitor cells, suggesting potential for clinical translation. This work evaluates modulation of MC-GAG stiffness on canonical Wnt (cWnt) signaling. Primary human bone marrow-derived mesenchymal stem cells (hMSCs) are differentiated on two MC-GAG scaffolds (noncrosslinked, NX-MC, 0.3 kPa vs conventionally crosslinked, MC, 3.9 kPa). hMSCs increase expression of activated β-catenin, the major cWnt intracellular mediator, and the mechanosensitive YAP protein with near complete subcellular colocalization on stiffer MC scaffolds. Overall Wnt pathway inhibition reduces activated β-catenin and osteogenic differentiation, while elevating BMP4 and phosphorylated Smad1/5 (p-Smad1/5) expression on MC, but not NX-MC. Unlike Wnt pathway downregulation, isolated canonical Wnt inhibition with β-catenin knockdown increases osteogenic differentiation and mineralization specifically on the stiffer MC. β-catenin knockdown also increases p-Smad1/5, Runx2, and BMP4 expression only on the stiffer MC material. Thus, while stiffness-induced activation of the Wnt and mechanotransduction pathways promotes osteogenesis on MC-GAG, activated β-catenin is a limiting agent and may serve as a useful target or readout for optimal modulation of stiffness in skeletal regenerative materials.
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Affiliation(s)
- Qi Zhou
- Division of Plastic and Reconstructive Surgery, UCLA David Geffen School of Medicine, Los Angeles, CA 90095
- Research Service, Greater Los Angeles VA Healthcare System, Los Angeles, CA 90073
- UCLA Molecular Biology Institute, Los Angeles, CA 90095
| | - Xiaoyan Ren
- Division of Plastic and Reconstructive Surgery, UCLA David Geffen School of Medicine, Los Angeles, CA 90095
- Research Service, Greater Los Angeles VA Healthcare System, Los Angeles, CA 90073
- UCLA Molecular Biology Institute, Los Angeles, CA 90095
| | - Michelle K. Oberoi
- Division of Plastic and Reconstructive Surgery, UCLA David Geffen School of Medicine, Los Angeles, CA 90095
- Research Service, Greater Los Angeles VA Healthcare System, Los Angeles, CA 90073
- UCLA Molecular Biology Institute, Los Angeles, CA 90095
| | - Meiwand Bedar
- Division of Plastic and Reconstructive Surgery, UCLA David Geffen School of Medicine, Los Angeles, CA 90095
- Research Service, Greater Los Angeles VA Healthcare System, Los Angeles, CA 90073
- UCLA Molecular Biology Institute, Los Angeles, CA 90095
| | - Rachel M. Caprini
- Division of Plastic and Reconstructive Surgery, UCLA David Geffen School of Medicine, Los Angeles, CA 90095
- Research Service, Greater Los Angeles VA Healthcare System, Los Angeles, CA 90073
- UCLA Molecular Biology Institute, Los Angeles, CA 90095
| | - Marley J. Dewey
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801
| | - Vasiliki Kolliopoulos
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801
| | - Dean T. Yamaguchi
- Research Service, Greater Los Angeles VA Healthcare System, Los Angeles, CA 90073
| | - Brendan A.C. Harley
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801
| | - Justine C. Lee
- Division of Plastic and Reconstructive Surgery, UCLA David Geffen School of Medicine, Los Angeles, CA 90095
- Research Service, Greater Los Angeles VA Healthcare System, Los Angeles, CA 90073
- UCLA Molecular Biology Institute, Los Angeles, CA 90095
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Go YY, Chae SW, Song JJ. Comprehensive analysis of human chorionic membrane extracts regulating mesenchymal stem cells during osteogenesis. Cell Prolif 2021; 55:e13160. [PMID: 34841608 PMCID: PMC8780910 DOI: 10.1111/cpr.13160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/22/2021] [Accepted: 11/02/2021] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE Human chorionic membrane extracts (CMEs) from placenta are known to be a natural biomaterial for bone regeneration, with their excellent osteogenic efficacy on osteoblasts. However, little is known about the regulatory mechanism involved. METHODS AND RESULTS We have shown the in vitro and in vivo bone-forming ability of CME using human osteoblasts and bone defect animal models, suggesting that CME greatly enhances osteogenesis by providing an osteoconductive environment for the osteogenesis of osteoblasts. Proteomic analysis revealed that CME contained several osteogenesis-related stimulators such as osteopontin, osteomodulin, Thy-1, netrin 4, retinol-binding protein and DJ-1. Additionally, 23 growth factors/growth factor-related proteins were found in CME, which may trigger mitogen-activated protein kinase (MAPK) signalling as a specific cellular signalling pathway for osteogenic differentiation. Microarray analysis showed four interaction networks (chemokine, Wnt signalling, angiogenesis and ossification), indicating the possibility that CME can promote osteogenic differentiation through a non-canonical Wnt-mediated CXCL signalling-dependent pathway. CONCLUSIONS The results of this study showed the function and mechanism of action of CME during the osteogenesis of osteoblasts and highlighted a novel strategy for the use of CME as a biocompatible therapeutic material for bone regeneration.
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Affiliation(s)
- Yoon Young Go
- Department of Otorhinolaryngology-Head and Neck Surgery, Korea University Guro Hospital, Seoul, Republic of Korea.,Institute for Health Care Convergence Center, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Sung-Won Chae
- Department of Otorhinolaryngology-Head and Neck Surgery, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Jae-Jun Song
- Department of Otorhinolaryngology-Head and Neck Surgery, Korea University Guro Hospital, Seoul, Republic of Korea.,Institute for Health Care Convergence Center, Korea University Guro Hospital, Seoul, Republic of Korea
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Yu J, Chen S, Lei S, Li F, Wang Y, Shu X, Xu W, Tang X. The Effects of Porphyromonas gingivalis on Inflammatory and Immune Responses and Osteogenesis of Mesenchymal Stem Cells. Stem Cells Dev 2021; 30:1191-1201. [PMID: 34628938 DOI: 10.1089/scd.2021.0068] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are increasingly used in tissue regeneration, not only because of their multilineage differentiation ability, but also because of their immunomodulatory function, which allows them to play a role in the inflammatory milieu, especially in periodontitis. Porphyromonas gingivalis (P. gingivalis) is an important pathogen associated with the progression of periodontitis. Heterogeneous MSC sources show differences in their inflammatory-immune responsiveness and osteogenesis capabilities when exposed to P. gingivalis and its virulence factors. This article reviews the promoted inflammatory and immune responses of periodontal ligament stem cells, which are potential pitfalls in bone regeneration. MSCs from other sources showed contradictory inflammatory and immune reactions in the few studies on this topic. We also summarize the mechanisms involved in the inflammatory, immune responses and osteogenic potential of MSCs exposed to P. gingivalis and its virulence factors to inform an improved utilization of MSCs in regenerative therapies for periodontitis.
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Affiliation(s)
- Jingjun Yu
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Shuangshuang Chen
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Shuang Lei
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Fulong Li
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Yan Wang
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Xiufang Shu
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Wanlin Xu
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Xiaolin Tang
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
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Zhou T, Rong M, Wang Z, Chu H, Chen C, Zhang J, Tian Z. Conditioned medium derived from 3D tooth germs: A novel cocktail for stem cell priming and early in vivo pulp regeneration. Cell Prolif 2021; 54:e13129. [PMID: 34585454 PMCID: PMC8560607 DOI: 10.1111/cpr.13129] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/13/2021] [Accepted: 09/03/2021] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Conditioned medium (CM) from 2D cell culture can mitigate the weakened regenerative capacity of the implanted stem cells. However, the capacity of 3D CM to prime dental pulp stem cells (DPSCs) for pulp regeneration and its protein profile are still elusive. We aim to investigate the protein profile of CM derived from 3D tooth germs, and to unveil its potential for DPSCs-based pulp regeneration. MATERIALS AND METHODS We prepared CM of 3D ex vivo cultured tooth germ organs (3D TGO-CM) and CM of 2D cultured tooth germ cells (2D TGC-CM) and applied them to prime DPSCs. Influences on cell behaviours and protein profiles of CMs were compared. In vivo pulp regeneration of CMs-primed DPSCs was explored using a tooth root fragment model on nude mice. RESULTS TGO-CM enhanced DPSCs proliferation, migration, in vitro mineralization, odontogenic differentiation, and angiogenesis performances. The TGO-CM group generated superior pulp structures, more odontogenic cells attachment, and enhanced vasculature at 4 weeks post-surgery, compared with the TGC-CM group. Secretome analysis revealed that TGO-CM contained more odontogenic and angiogenic growth factors and fewer pro-inflammatory cytokines. Mechanisms leading to the differential CM profiles may be attributed to the cytokine-cytokine receptor interaction and PI3K-Akt signalling pathway. CONCLUSIONS The unique secretome profile of 3D TGO-CM made it a successful priming cocktail to enhance DPSCs-based early pulp regeneration.
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Affiliation(s)
- Tengfei Zhou
- Department of Periodontology and Oral Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Mingdeng Rong
- Department of Periodontology and Oral Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Zijie Wang
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hongxing Chu
- Department of Periodontology and Oral Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Chuying Chen
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiayi Zhang
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhihui Tian
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- School of Stomatology, Southern Medical University, Guangzhou, China
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Li Y, Liu A, Zhang L, Wang Z, Hui N, Zhai Q, Zhang L, Jin Z, Jin F. Epithelial Cell Rests of Malassez Provide a Favorable Microenvironment for Ameliorating the Impaired Osteogenic Potential of Human Periodontal Ligament Stem Cells. Front Physiol 2021; 12:735234. [PMID: 34707510 PMCID: PMC8542701 DOI: 10.3389/fphys.2021.735234] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 09/14/2021] [Indexed: 12/26/2022] Open
Abstract
Human periodontal ligament stromal/stem cells (PDLSCs) are ideal candidates for periodontal regeneration and are of significant importance in clinical practice. However, PDLSCs derived from diseased microenvironments exert impaired behavior, which leads to the failure of periodontal regeneration. The epithelial cell rests of Malassez (ERM), which are involved in periodontal homeostasis, are residual cells from Hertwig's epithelial root sheath (HERS). However, the function of ERM remains largely unknown. Therefore, the aim of this study was to evaluate the effect of ERM on the osteogenic potential of PDLSCs from an impaired microenvironment. PDLSCs from healthy donors (H-PDLSCs), periodontitis donors (P-PDLSCs) and human ERM were harvested. Osteogenic evaluation showed a lower osteogenic potential of P-PDLSCs compared to that of H-PDLSCs. Then, we co-cultured ERM with P-PDLSCs, and the data showed that ERM promoted the expression of osteogenic genes and proteins in P-PDLSCs. In addition, we collected the PDLSCs from aged donors (A-PDLSCs) and analyzed the osteogenesis capacity of the A-PDLSCs and A-PDLSCs + ERM groups, which displayed similar results to P-PDLSCs. Finally, we evaluated the Wnt pathway, which is associated with osteogenic differentiation of stromal/stem cells, in A-PDLSCs + ERM and P-PDLSCs + ERM groups, which indicated that suppression of the Wnt pathway may result in an increase in the osteogenic properties of A-PDLSCs + ERM and P-PDLSCs + ERM groups. Taken together, the above findings shed new light on the function of ERM and provide a novel therapeutic for optimizing PDLSCs-based periodontal regeneration.
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Affiliation(s)
- Yanjiao Li
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontic, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Anqi Liu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontic, School of Stomatology, The Fourth Military Medical University, Xi'an, China.,Department of Stomatology, The 985 Hospital of PLA, Taiyuan, China
| | - Liqiang Zhang
- Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, China.,State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Zhiwei Wang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontic, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Nana Hui
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontic, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Qiming Zhai
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontic, School of Stomatology, The Fourth Military Medical University, Xi'an, China.,Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, China.,State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Lishu Zhang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontic, School of Stomatology, The Fourth Military Medical University, Xi'an, China.,Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, China.,State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Zuolin Jin
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontic, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Fang Jin
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontic, School of Stomatology, The Fourth Military Medical University, Xi'an, China.,State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, China
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Kumar BM, Rao S, Talwar A, Shetty V. Minimal influence of chronic inflammation on the potency and differentiation characteristics of gingiva-derived mesenchymal stem cells-An in vitro study. J Indian Soc Periodontol 2021; 25:379-385. [PMID: 34667379 PMCID: PMC8452161 DOI: 10.4103/jisp.jisp_410_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 12/20/2020] [Accepted: 12/25/2020] [Indexed: 11/21/2022] Open
Abstract
Objective: Gingiva-derived mesenchymal stem cells (GMSCs) have been identified and characterized from healthy tissues. However, reports on the influence of chronic inflammation on their stemness characteristics are sparse. The present study evaluated the potency and differentiation ability of GMSCs from periodontally healthy GMSC (H-GMSC) and inflamed GMSC (I-GMSC) tissues. Materials and Methods: Established H-GMSCs and I-GMSCs were evaluated on their potency characteristics, such as morphology, viability, proliferation rate, population doubling time, colony-forming ability, expression of stemness markers, and mesenchymal differentiation potential. Results: H-GMSCs and I-GMSCs exhibited fibroblast-like morphology and showed >95% viability with high proliferation potential and shorter doubling time. H-GMSCs showed fewer and smaller colonies, whereas I-GMSCs exhibited multiple and larger colonies. The evaluation of stemness markers revealed that both H-GMSCs and I-GMSCs were weakly positive for stage-specific embryonic antigen-4, Stro1, and CD105 (Endoglin), strongly positive for CD73 and CD90, and negative for the hematopoietic cell markers, CD34 and CD45. H-GMSCs showed a slightly higher osteogenic potential when compared to I-GMSCs, while I-GMSCs had a higher adipogenic potential than H-GMSCs. Conclusion: The findings showed that the inflammatory environment might have a stimulatory effect on the growth kinetics and ability of colony formation in GMSCs. However, varied osteogenic and adipogenic differentiation was observed between H-GMSCs and I-GMSCs.
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Affiliation(s)
- Basavarajappa Mohana Kumar
- Nitte (Deemed to be University), K. S. Hegde Medical Academy, Nitte University Centre for Stem Cell Research and Regenerative Medicine, Mangalore, Karnataka, India
| | - Shama Rao
- Nitte (Deemed to be University), K. S. Hegde Medical Academy, Nitte University Centre for Stem Cell Research and Regenerative Medicine, Mangalore, Karnataka, India
| | - Avaneendra Talwar
- Nitte (Deemed to be University), A. B. Shetty Memorial Institute of Dental Sciences, Department of Periodontics, Mangalore, Karnataka, India
| | - Veena Shetty
- Nitte (Deemed to be University), K. S. Hegde Medical Academy, Nitte University Centre for Stem Cell Research and Regenerative Medicine, Mangalore, Karnataka, India
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Yang P, Li C, Kou Y, Jiang Y, Li D, Liu S, Lu Y, Hasegawa T, Li M. Notum suppresses the osteogenic differentiation of periodontal ligament stem cells through the Wnt/Beta catenin signaling pathway. Arch Oral Biol 2021; 130:105211. [PMID: 34352447 DOI: 10.1016/j.archoralbio.2021.105211] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 07/16/2021] [Accepted: 07/17/2021] [Indexed: 11/16/2022]
Abstract
OBJECTIVES The aims of this study were to explore: (ⅰ) the effect of Notum on periodontitis in vivo; (ⅱ) the effect of Notum on the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) in vitro; and (ⅲ) the potential mechanism of Notum in inhibiting the osteogenic differentiation of hPDLSCs. DESIGN C57BL/6J mice were randomly assigned into two groups: control group (n = 4) and periodontitis group (n = 4). Immunohistochemical staining was used to evaluate the expression of Notum. In in vitro experiments, Western blot, qRT- PCR and ELISA were used to examine the expression of Notum in a lipopolysaccharide-induced inflammation model. Alkaline phosphatase staining was used to evaluate alkaline phosphatase activity. Western blot and qRT - PCR were used to measure the expression of osteogenic-related markers after adding human recombinant Notum and Notum inhibitor ABC99. In addition, LiCl, an agonist of the Wnt/Beta-catenin signaling pathway, was added to explore using Western blot whether Notum was involved in regulating the osteogenic differentiation of human periodontal ligament stem cells through the Wnt/Beta-catenin signaling pathway. RESULTS Notum was highly expressed in periodontal tissues of mice and lipopolysaccharide-induced inflammation cell model. The protein and messenger ribonucleic acid levels of hPDLSCs osteogenic markers were reduced after adding human recombinant Notum. However, the inhibitory effect of Notum on the osteogenic differentiation of hPDLSCs could be significantly reversed by adding LiCl. CONCLUSION These results demonstrated that Notum inhibited the osteogenic differentiation of hPDLSCs probably via the Wnt/Beta-catenin the downstream signaling pathway.
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Affiliation(s)
- Panpan Yang
- Department of Bone Metabolism, 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, 250012, China
| | - Congshan Li
- Department of Bone Metabolism, 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, 250012, China
| | - Yuying Kou
- Department of Bone Metabolism, 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, 250012, China
| | - Yujun Jiang
- Department of Bone Metabolism, 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, 250012, China
| | - Dongfang Li
- Department of Bone Metabolism, 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, 250012, China
| | - Shanshan Liu
- Department of Bone Metabolism, 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, 250012, China
| | - Yupu Lu
- Department of Bone Metabolism, 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, 250012, China
| | - Tomoka Hasegawa
- Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo, 060-8586, Japan
| | - Minqi Li
- Department of Bone Metabolism, 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, 250012, China.
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Zhang Z, Deng M, Hao M, Tang J. Periodontal ligament stem cells in the periodontitis niche: inseparable interactions and mechanisms. J Leukoc Biol 2021; 110:565-576. [PMID: 34043832 DOI: 10.1002/jlb.4mr0421-750r] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 04/25/2021] [Accepted: 05/09/2021] [Indexed: 12/13/2022] Open
Abstract
Periodontitis is characterized by the periodontium's pathologic destruction due to the host's overwhelmed inflammation to the dental plaque. The bacterial infections and subsequent host immune responses have shaped a distinct microenvironment, which generally affects resident periodontal ligament stem cells (PDLSCs). Interestingly, recent studies have revealed that impaired PDLSCs may also contribute to the disturbance of periodontal homeostasis. The putative vicious circle underlying the interesting "positive feedback" of PDLSCs in the periodontitis niche remains a hot research topic, whereas the inseparable interactions between resident PDLSCs and the periodontitis niche are still not fully understood. This review provides a microscopic view on the periodontitis progression, especially the quick but delicate immune responses to oral dysbacterial infections. We also summarize the interesting crosstalk of the resident PDLSCs with their surrounding periodontitis niche and potential mechanisms. Particularly, the microenvironment reduces the osteogenic properties of resident PDLSCs, which are closely related to their reparative activity. Reciprocally, these impaired PDLSCs may disrupt the microenvironment by aggravating the host immune responses, promoting aberrant angiogenesis, and facilitating the osteoclastic activity. We further recommend that more in-depth studies are required to elucidate the interactions of PDLSCs with the periodontal microenvironment and provide novel interventions for periodontitis.
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Affiliation(s)
- Zhiyu Zhang
- Hunan Key Laboratory of Oral Health Research & Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Xiangya School of Stomatology, Xiangya Stomatological Hospital, Central South University, Changsha, Hunan, China
| | - Mengting Deng
- Hunan Key Laboratory of Oral Health Research & Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Xiangya School of Stomatology, Xiangya Stomatological Hospital, Central South University, Changsha, Hunan, China
| | - Meng Hao
- Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Sun Yat-sen University, Guangzhou, China
| | - Jianxia Tang
- Hunan Key Laboratory of Oral Health Research & Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Xiangya School of Stomatology, Xiangya Stomatological Hospital, Central South University, Changsha, Hunan, China
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Jiang Y, Liu JM, Huang JP, Lu KX, Sun WL, Tan JY, Li BX, Chen LL, Wu YM. Regeneration potential of decellularized periodontal ligament cell sheets combined with 15-deoxy-Δ 12,14-prostaglandin J 2 nanoparticles in a rat periodontal defect. Biomed Mater 2021; 16:045008. [PMID: 33793422 DOI: 10.1088/1748-605x/abee61] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Periodontitis is a chronic inflammatory disease characterized by loss of attachment and destruction of the periodontium. Decellularized sheet, as an advanced tissue regeneration engineering biomaterial, has been researched and applied in many fields, but its effects on periodontal regeneration remain unclear. In this study, the biological properties of decellularized human periodontal ligament cell (dHPDLC) sheets were evaluated in vitro. Polycaprolactone/gelatin (PCL/GE) nanofibers were fabricated as a carrier to enhance the mechanical strength of the dHPDLC sheet. 15-deoxy-[Formula: see text]-prostaglandin J2 (15d-PGJ2) nanoparticles were added for anti-inflammation and regeneration improvement. For in vivo analysis, dHPDLC sheets combined with 15d-PGJ2 nanoparticles, with or without PCL/GE, were implanted into rat periodontal defects. The periodontal regeneration effects were identified by microcomputed tomography (micro-CT) and histological staining, and immunohistochemistry. The results revealed that DNA content was reduced by 96.6%. The hepatocyte growth factor, vascular endothelial growth factor, and basic fibroblast growth factor were preserved but reduced. The expressions or distribution of collagen I and fibronectin were similar in dHPDLC and nondecellularized cell sheets. The dHPDLC sheets maintained the intact structure of the extracellular matrix. It could be recellularized by allogeneic human periodontal stem ligament cells and retain osteoinductive potential. Newly formed bone, cementum, and PDL were observed in dHPDLC sheets combined with 15d-PGJ2 groups, with or without PCL/GE nanofibers, for four weeks post-operation in vivo. Bringing together all these points, this new construct of dHPDLC sheets can be a potential candidate for periodontal regeneration in an inflammatory environment of the oral cavity.
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Affiliation(s)
- Yao Jiang
- Department of Periodontology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People's Republic of China. Key Laboratory of Oral Biomedical Research of Zhejiang Province, Zhejiang University School of Stomatology, Hangzhou, People's Republic of China
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Gholami L, Hendi SS, Saidijam M, Mahmoudi R, Tarzemany R, Arkian A, Afshar S, Fekrazad R. Near-infrared 940-nm diode laser photobiomodulation of inflamed periodontal ligament stem cells. Lasers Med Sci 2021; 37:449-459. [PMID: 33740139 DOI: 10.1007/s10103-021-03282-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 03/01/2021] [Indexed: 10/21/2022]
Abstract
Photobiomodulation (PBM) is an acceptable method of stimulating stem cells through its non-invasive absorption by the cell photoreceptors and the induction of cellular response. The current research was aimed at evaluating the effect of near-infrared PBM on proliferation and osteogenic differentiation in inflamed periodontal ligament stem cells (I-PDLSCs). I-PDLSCs were isolated and characterized. Third passage cells were irradiated with 940-nm laser at an output power of 100 mW in a continuous wave. A fluence of 4 J/cm2 in three sessions at 48-h intervals was applied and compared with non-irradiated controls. Cell viability and proliferation were evaluated by MTT assay. Alkaline phosphatase activity, quantitative Alizarin red staining test, and q-RT-PCR were used to evaluate the osteogenic properties of the I-PDLSCs in four groups of (a) osteogenic differentiation medium + laser (ODM + L), (b) osteogenic differentiation medium without laser (ODM), (c) non-osteogenic differentiation medium + laser (L), and (d) non-osteogenic differentiation medium (control). There was a non-significant increase in the viability of cells at 48- and 72-h post last laser irradiation. Alizarin red staining revealed no significant stimulatory effect of PBM at 14 and 21 days. However, alkaline phosphatase activity was significantly higher in the L + ODM group. Expression of osteogenic-related genes had a statistically significant increase at 21-day post irradiation. The irradiation used in the present study showed no significant increase in the proliferation of I-PDLSCs by PBM. However, expression levels of osteogenic-related genes and alkaline phosphatase activity were significantly increased in irradiated groups.
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Affiliation(s)
- Leila Gholami
- Department of Periodontics, Dental Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Seyedeh Sareh Hendi
- Department of Endodontics, School of Dentistry, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Massoud Saidijam
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Roghayeh Mahmoudi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Rana Tarzemany
- Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, Canada
| | - Aliasghar Arkian
- Dental Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Saeid Afshar
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Reza Fekrazad
- Radiation Sciences Research Center, Laser Research Center in Medical Sciences, AJA University of Medical Sciences, Tehran, Iran.,International Network for Photomedicine and Photo Dynamic Therapy (INPMPDT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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Ahmad P, Stoddart MJ, Della Bella E. The Role of Noncoding RNAs in Osteogenic Differentiation of Human Periodontal Ligament Stem Cells. CRANIOMAXILLOFACIAL TRAUMA & RECONSTRUCTION OPEN 2021. [DOI: 10.1177/2472751221999229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Chronic inflammatory diseases, including periodontitis, are the most common causes of bone tissue destruction. Periodontitis often leads to loss of connective tissue homeostasis and reduced alveolar bone levels. Human periodontal ligament stem cells (PDLSCs), a population of multipotent stem cells derived from periodontal ligament tissues, are considered as candidate cells for the regeneration of alveolar bone and periodontal tissues. Periodontitis impairs the osteogenic differentiation of human PDLSCs. Noncoding RNAs (ncRNAs), including long noncoding RNA (lncRNA), microRNA (miRNA), and circular RNA (circRNA), have been proposed as vital regulators influencing several differentiation processes including bone regeneration. Still, the molecular mechanisms of ncRNAs regulating osteogenic differentiation of human PDLSCs remain poorly understood. Exploring the influence of ncRNAs in the process of osteogenic differentiation of human PDLSCs may provide novel therapeutic strategies for tissue regeneration as the regeneration of the lost periodontium is the ultimate goal of periodontal therapy.
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Affiliation(s)
- Paras Ahmad
- AO Research Institute Davos, Davos Platz, Switzerland
| | - Martin J. Stoddart
- AO Research Institute Davos, Davos Platz, Switzerland
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, Freiburg im Breisgau, Germany
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Brito VGB, Patrocinio MS, Sousa MCL, Barreto AEA, Frasnelli SCT, Lara VS, Santos CF, Oliveira SHP. Mast cells contribute to alveolar bone loss in Spontaneously Hypertensive Rats with periodontal disease regulating cytokines production. PLoS One 2021; 16:e0247372. [PMID: 33661916 PMCID: PMC7932174 DOI: 10.1371/journal.pone.0247372] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 02/05/2021] [Indexed: 12/28/2022] Open
Abstract
Mast cells (MCs) play a pivotal role in inflammatory responses and had been studied in inflammatory bone disorders, however, their role in alveolar bone loss induced by periodontal disease (PD) is not yet fully understood. We, therefore, aimed to evaluate the effects of MCs depletion in the PD-induced alveolar bone loss in Wistar (W) and Spontaneously Hypertensive Rats (SHRs). PD was induced by ligating the lower first molars with silk thread one day after the MCs depletion, by the pre-treatment with compound 48/80 for 4 days. After 15 days of PD induction, the hemi-mandibles were surgically collected for qRT-PCR, histological analyses, immunostaining, and ELISA. Systolic blood pressure (SBP) was verified by tail plethysmography to confirm the hypertensive status, and SHR presented SBP >150 mmHg, and previous MC depletion alone or associated with PD did not alter this parameter. SHRs showed a more severe alveolar bone loss compared to W, and MC depletion significantly inhibited this response in both strains, with a more significant response in SHRs. MCs were less abundant in 48/80+PD groups, thus validating the previous MCs depletion in our model. PD increased the number of MC in the gingival tissue of SHR. Cytokine production (TNF-α, IL-6, IL-1β, and CXCL3) was constitutively higher in SHR and increased further after PD, which was also significantly reduced in the MCs-depleted animals. PD led to an increased expression of Opn, Rankl, Rank, Vtn, Itga5, Itgb5, Trap, and Ctsk in the mandible of W and SHRs, which was reversed in MCs-depleted animals. These results suggest that MCs significantly contributes to the PD-induced alveolar bone resorption, especially in the SHR, which is associated with a more severe PD progression compared to Wistar, partly explained by these cells contribution to the inflammatory status and mediator production, stimulating osteoclast-related response markers, which were reduced after MC depletion in our experimental model.
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Affiliation(s)
- Victor Gustavo Balera Brito
- Programa Multicêntrico de Pós-graduação em Ciências Fisiológicas, SBFis, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
- Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
| | - Mariana Sousa Patrocinio
- Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
| | | | - Ayná Emanuelli Alves Barreto
- Programa Multicêntrico de Pós-graduação em Ciências Fisiológicas, SBFis, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
- Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
| | | | - Vanessa Soares Lara
- Department of Biological Science, Bauru School of Dentistry, University of São Paulo (USP), SP, Brazil
| | - Carlos Ferreira Santos
- Department of Stomatology, Bauru School of Dentistry, University of São Paulo (USP), SP, Brazil
| | - Sandra Helena Penha Oliveira
- Programa Multicêntrico de Pós-graduação em Ciências Fisiológicas, SBFis, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
- Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
- * E-mail:
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