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Stieger RB, Lilaj B, Hönigl GP, Pock S, Cvikl B. Flow Cytometry Illuminates Dental Stem Cells: a Systematic Review of Immunomodulatory and Regenerative Breakthroughs. Stem Cell Rev Rep 2025:10.1007/s12015-025-10883-y. [PMID: 40279028 DOI: 10.1007/s12015-025-10883-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/08/2025] [Indexed: 04/26/2025]
Abstract
BACKGROUND Dental stem cells hold significant potential in regenerative medicine due to their multipotency, accessibility, and immunomodulatory effects. Flow cytometry is a critical tool for analyzing these cells, particularly in identifying and characterizing immunomodulatory markers that enhance their clinical applications. This systematic review aims to answer the question: "How does flow cytometry facilitate the identification and characterization of immunomodulatory markers in dental stem cells to enhance their application in regenerative medicine?". METHODS An exhaustive literature search was conducted in PubMed, retrieving 430 studies, of which 284 met inclusion criteria. Studies were selected based on the use of flow cytometry to analyze immunomodulatory markers in dental stem cells, focusing on methodologies, key findings, and challenges. RESULTS Of the 284 articles, 229 employed flow cytometry, with 115 reporting relevant results. Flow cytometry revealed important insights into the immunological interactions of various dental stem cells, including dental pulp stem cells, stem cells from human exfoliated deciduous teeth, periodontal ligament stem cells, and stem cells from the apical papilla, by identifying and characterizing immunomodulatory markers such as PD-L1, IDO, and TGF-β1. CONCLUSIONS Flow cytometry is essential for advancing the understanding of dental stem cells' immunomodulatory properties. Standardization of methodologies is required to overcome technical challenges and enhance the clinical applications of dental stem cells in regenerative medicine and immunotherapy.
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Affiliation(s)
- Robert B Stieger
- Department of Conservative Dentistry, Sigmund Freud University, Vienna, Austria.
| | - Bledar Lilaj
- Department of Conservative Dentistry, Sigmund Freud University, Vienna, Austria
| | - Gernot P Hönigl
- Department of Conservative Dentistry, Sigmund Freud University, Vienna, Austria
| | - Sophie Pock
- Department of Conservative Dentistry, Sigmund Freud University, Vienna, Austria
| | - Barbara Cvikl
- Department of Conservative Dentistry, Sigmund Freud University, Vienna, Austria.
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Miteva M, Mihaylova Z, Mitev V, Aleksiev E, Stanimirov P, Praskova M, Dimitrova VS, Vasileva A, Calenic B, Constantinescu I, Perlea P, Ishkitiev N. A Review of Stem Cell Attributes Derived from the Oral Cavity. Int Dent J 2024; 74:1129-1141. [PMID: 38582718 PMCID: PMC11561491 DOI: 10.1016/j.identj.2024.03.008] [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: 01/09/2024] [Revised: 02/29/2024] [Accepted: 03/12/2024] [Indexed: 04/08/2024] Open
Abstract
Oral cavity stem cells (OCSCs) have been the focus of intense scientific efforts due to their accessibility and stem cell properties. The present work aims to compare the different characteristics of 6 types of dental stem cells derived from the oral cavity: dental pulp stem cells (DPSC), stem cells from human exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSC), stem cells from the apical papilla (SCAP), bone marrow mesenchymal stem cells (BMSC), and gingival mesenchymal stem cells (GMSC). Using immunofluorescence and real-time polymerase chain reaction techniques, we analysed the cells for stem cell, differentiation, adhesion, and extracellular matrix markers; the ability to proliferate in vitro; and multilineage differentiation potential. Markers such as vimentin, CD44, alkaline phosphatase, CD146, CD271, CD49f, Oct 3/4, Sox 9, FGF7, nestin, and BMP4 showed significant differences in expression levels, highlighting the heterogeneity and unique characteristics of each cell type. At the same time, we confirmed that all cell types successfully differentiated into osteogenic, chondrogenic, or adipose lineages, with different readiness. In conclusion, our study reveals the distinct properties and potential applications of various dental-derived stem cells. These findings contribute to a deeper understanding of OCSCs and their significance in future clinical applications.
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Affiliation(s)
- Marina Miteva
- Department of Chemistry and Biochemistry, Medical Faculty, Medical University Sofia, Bulgaria
| | - Zornitsa Mihaylova
- Department of Dental, Oral and Maxillofacial Surgery, Faculty of Dental Medicine, Medical University Sofia, Bulgaria
| | - Vanyo Mitev
- Department of Chemistry and Biochemistry, Medical Faculty, Medical University Sofia, Bulgaria
| | - Evgeniy Aleksiev
- Department of Dental, Oral and Maxillofacial Surgery, Faculty of Dental Medicine, Medical University Sofia, Bulgaria
| | - Pavel Stanimirov
- Department of Dental, Oral and Maxillofacial Surgery, Faculty of Dental Medicine, Medical University Sofia, Bulgaria
| | - Maria Praskova
- Department of Chemistry and Biochemistry, Medical Faculty, Medical University Sofia, Bulgaria
| | - Violeta S Dimitrova
- Department of Chemistry and Biochemistry, Medical Faculty, Medical University Sofia, Bulgaria
| | - Anelia Vasileva
- Department of Chemistry and Biochemistry, Medical Faculty, Medical University Sofia, Bulgaria
| | - Bogdan Calenic
- Centre for Immunogenetics and Virology, Fundeni Clinical Institute, University of Medicine and Farmacy "Carol Davila," Bucharest, Romania.
| | - Ileana Constantinescu
- Centre for Immunogenetics and Virology, Fundeni Clinical Institute, University of Medicine and Farmacy "Carol Davila," Bucharest, Romania
| | - Paula Perlea
- Department of Endodontics, UMF Carol Davila, Bucharest, Romania.
| | - Nikolay Ishkitiev
- Department of Chemistry and Biochemistry, Medical Faculty, Medical University Sofia, Bulgaria
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Wu W, Jiang W, Zhou Y, Zhang Z, Li G, Tang C. Phthalate exposure aggravates periodontitis by activating NFκB pathway. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 275:116252. [PMID: 38547731 DOI: 10.1016/j.ecoenv.2024.116252] [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: 12/12/2023] [Revised: 03/12/2024] [Accepted: 03/20/2024] [Indexed: 04/12/2024]
Abstract
BACKGROUND Phthalates are widely used plasticizers, which were identified as risk factors in the development of many human diseases. However, the effects of phthalates in the periodontitis are unknown. We aimed to investigated the relationship of periodontitis and phthalate exposure as well as the underlying mechanisms. MATERIALS AND METHODS Univariate and multivariate logistic regressions were employed to evaluate the association between phthalate metabolites and periodontitis. The generalized additive model and piecewise logistic regression were conducted to investigate the dose-response relationship. Cell and animal models were used to explore the role and mechanism of DEHP in the development of periodontitis. Transcriptome sequencing, bioinformatics analysis, western blot, immunofluorescence and mice model of periodontitis were also employed. RESULTS MEHP (OR 1.14, 95% CI 1.05-1.24), MCPP (OR 1.08, 95% CI 1.00-1.17), MEHHP (OR 1.18, 95% CI 1.08-1.29), MEOHP (OR 1.18, 95% CI 1.07-1.29), MiBP (OR 1.15, 95% CI 1.04-1.28), and MECPP (OR 1.20, 95% CI 1.09-1.32) were independent risk factors. And MEHHP, the metabolite of DEHP, showed the relative most important effects on periodontitis with the highest weight (0.34) among all risk factors assessed. And the increase of inflammation and the activation of NFκB pathway in the periodontitis model mice and cells were observed. CONCLUSION Exposure to multiple phthalates was positively associated with periodontitis in US adults between 30 and 80 years old. And DEHP aggravated inflammation in periodontitis by activating NFκB pathway.
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Affiliation(s)
- Wei Wu
- Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Wenxiu Jiang
- Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China; Department of Orthodontic, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yongmiao Zhou
- Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Zhewei Zhang
- Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Guoqing Li
- Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Chunbo Tang
- Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China.
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Poblano-Pérez LI, Castro-Manrreza ME, González-Alva P, Fajardo-Orduña GR, Montesinos JJ. Mesenchymal Stromal Cells Derived from Dental Tissues: Immunomodulatory Properties and Clinical Potential. Int J Mol Sci 2024; 25:1986. [PMID: 38396665 PMCID: PMC10888494 DOI: 10.3390/ijms25041986] [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: 12/30/2023] [Revised: 01/30/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent cells located in different areas of the human body. The oral cavity is considered a potential source of MSCs because they have been identified in several dental tissues (D-MSCs). Clinical trials in which cells from these sources were used have shown that they are effective and safe as treatments for tissue regeneration. Importantly, immunoregulatory capacity has been observed in all of these populations; however, this function may vary among the different types of MSCs. Since this property is of clinical interest for cell therapy protocols, it is relevant to analyze the differences in immunoregulatory capacity, as well as the mechanisms used by each type of MSC. Interestingly, D-MSCs are the most suitable source for regenerating mineralized tissues in the oral region. Furthermore, the clinical potential of D-MSCs is supported due to their adequate capacity for proliferation, migration, and differentiation. There is also evidence for their potential application in protocols against autoimmune diseases and other inflammatory conditions due to their immunosuppressive capacity. Therefore, in this review, the immunoregulatory mechanisms identified at the preclinical level in combination with the different types of MSCs found in dental tissues are described, in addition to a description of the clinical trials in which MSCs from these sources have been applied.
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Affiliation(s)
- Luis Ignacio Poblano-Pérez
- Mesenchymal Stem Cell Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center (IMSS), Mexico City 06720, Mexico; (L.I.P.-P.); (G.R.F.-O.)
| | - Marta Elena Castro-Manrreza
- Immunology and Stem Cells Laboratory, FES Zaragoza, National Autonomous University of Mexico (UNAM), Mexico City 09230, Mexico;
| | - Patricia González-Alva
- Tissue Bioengineering Laboratory, Postgraduate Studies, Research Division, Faculty of Dentistry, National Autonomous University of Mexico (UNAM), Mexico City 04510, Mexico;
| | - Guadalupe R. Fajardo-Orduña
- Mesenchymal Stem Cell Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center (IMSS), Mexico City 06720, Mexico; (L.I.P.-P.); (G.R.F.-O.)
| | - Juan José Montesinos
- Mesenchymal Stem Cell Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center (IMSS), Mexico City 06720, Mexico; (L.I.P.-P.); (G.R.F.-O.)
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Kadkhoda Z, Motie P, Rad MR, Mohaghegh S, Kouhestani F, Motamedian SR. Comparison of Periodontal Ligament Stem Cells with Mesenchymal Stem Cells from Other Sources: A Scoping Systematic Review of In vitro and In vivo Studies. Curr Stem Cell Res Ther 2024; 19:497-522. [PMID: 36397622 DOI: 10.2174/1574888x17666220429123319] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 12/31/2021] [Accepted: 03/11/2022] [Indexed: 11/22/2022]
Abstract
OBJECTIVE The application of stem cells in regenerative medicine depends on their biological properties. This scoping review aimed to compare the features of periodontal ligament stem cells (PDLSSCs) with stem cells derived from other sources. DESIGN An electronic search in PubMed/Medline, Embase, Scopus, Google Scholar and Science Direct was conducted to identify in vitro and in vivo studies limited to English language. RESULTS Overall, 65 articles were included. Most comparisons were made between bone marrow stem cells (BMSCs) and PDLSCs. BMSCs were found to have lower proliferation and higher osteogenesis potential in vitro and in vivo than PDLSCs; on the contrary, dental follicle stem cells and umbilical cord mesenchymal stem cells (UCMSCs) had a higher proliferative ability and lower osteogenesis than PDLSCs. Moreover, UCMSCs exhibited a higher apoptotic rate, hTERT expression, and relative telomerase length. The immunomodulatory function of adipose-derived stem cells and BMSCs was comparable to PDLSCs. Gingival mesenchymal stem cells showed less sensitivity to long-term culture. Both pure and mixed gingival cells had lower osteogenic ability compared to PDLSCs. Comparison of dental pulp stem cells (DPSCs) with PDLSCs regarding proliferation rate, osteo/adipogenesis, and immunomodulatory properties was contradictory; however, in vivo bone formation of DPSCs seemed to be lower than PDLSCs. CONCLUSION In light of the performed comparative studies, PDLSCs showed comparable results to stem cells derived from other sources; however, further in vivo studies are needed to determine the actual pros and cons of stem cells in comparison to each other.
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Affiliation(s)
- Zeinab Kadkhoda
- Department of Periodontology, School of Dentistry, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Parisa Motie
- Student Research Committee, School of Dentistry, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Maryam Rezaei Rad
- Dental Research Center, Research Institute of Dental Sciences, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sadra Mohaghegh
- Student Research Committee, School of Dentistry, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Farnaz Kouhestani
- Department of Periodontics, School of Dentistry, Bushehr University of Medical Sciences, Tehran, Iran
| | - Saeed Reza Motamedian
- Dentofacial Deformities Research Center, Research Institute of Dental Sciences, Department of Orthodontics, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Ivan A, Cristea MI, Telea A, Oprean C, Galuscan A, Tatu CA, Paunescu V. Stem Cells Derived from Human Exfoliated Deciduous Teeth Functional Assessment: Exploring the Changes of Free Fatty Acids Composition during Cultivation. Int J Mol Sci 2023; 24:17249. [PMID: 38139076 PMCID: PMC10743411 DOI: 10.3390/ijms242417249] [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: 11/05/2023] [Revised: 12/05/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
The metabolic regulation of stemness is widely recognized as a crucial factor in determining the fate of stem cells. When transferred to a stimulating and nutrient-rich environment, mesenchymal stem cells (MSCs) undergo rapid proliferation, accompanied by a change in protein expression and a significant reconfiguration of central energy metabolism. This metabolic shift, from quiescence to metabolically active cells, can lead to an increase in the proportion of senescent cells and limit their regenerative potential. In this study, MSCs from human exfoliated deciduous teeth (SHEDs) were isolated and expanded in vitro for up to 10 passages. Immunophenotypic analysis, growth kinetics, in vitro plasticity, fatty acid content, and autophagic capacity were assessed throughout cultivation to evaluate the functional characteristics of SHEDs. Our findings revealed that SHEDs exhibit distinctive patterns of cell surface marker expression, possess high self-renewal capacity, and have a unique potential for neurogenic differentiation. Aged SHEDs exhibited lower proliferation rates, reduced potential for chondrogenic and osteogenic differentiation, an increasing capacity for adipogenic differentiation, and decreased autophagic potential. Prolonged cultivation of SHEDs resulted in changes in fatty acid composition, signaling a transition from anti-inflammatory to proinflammatory pathways. This underscores the intricate connection between metabolic regulation, stemness, and aging, crucial for optimizing therapeutic applications.
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Affiliation(s)
- Alexandra Ivan
- Department of Immunology and Allergology, Biology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (C.A.T.); (V.P.)
- Center for Gene and Cellular Therapies in the Treatment of Cancer—Oncogen Center, Clinical County Hospital “Pius Brînzeu”, 300723 Timisoara, Romania; (M.I.C.); (A.T.); (C.O.)
| | - Mirabela I. Cristea
- Center for Gene and Cellular Therapies in the Treatment of Cancer—Oncogen Center, Clinical County Hospital “Pius Brînzeu”, 300723 Timisoara, Romania; (M.I.C.); (A.T.); (C.O.)
| | - Ada Telea
- Center for Gene and Cellular Therapies in the Treatment of Cancer—Oncogen Center, Clinical County Hospital “Pius Brînzeu”, 300723 Timisoara, Romania; (M.I.C.); (A.T.); (C.O.)
| | - Camelia Oprean
- Center for Gene and Cellular Therapies in the Treatment of Cancer—Oncogen Center, Clinical County Hospital “Pius Brînzeu”, 300723 Timisoara, Romania; (M.I.C.); (A.T.); (C.O.)
- Department of Drug analysis, Chemistry of the Environment and Food, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Atena Galuscan
- Translational and Experimental Clinical Research Centre in Oral Health, Department of Preventive, Community Dentistry and Oral Health, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Calin A. Tatu
- Department of Immunology and Allergology, Biology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (C.A.T.); (V.P.)
- Center for Gene and Cellular Therapies in the Treatment of Cancer—Oncogen Center, Clinical County Hospital “Pius Brînzeu”, 300723 Timisoara, Romania; (M.I.C.); (A.T.); (C.O.)
| | - Virgil Paunescu
- Department of Immunology and Allergology, Biology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (C.A.T.); (V.P.)
- Center for Gene and Cellular Therapies in the Treatment of Cancer—Oncogen Center, Clinical County Hospital “Pius Brînzeu”, 300723 Timisoara, Romania; (M.I.C.); (A.T.); (C.O.)
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Cabaña-Muñoz ME, Pelaz Fernández MJ, Parmigiani-Cabaña JM, Parmigiani-Izquierdo JM, Merino JJ. Adult Mesenchymal Stem Cells from Oral Cavity and Surrounding Areas: Types and Biomedical Applications. Pharmaceutics 2023; 15:2109. [PMID: 37631323 PMCID: PMC10459416 DOI: 10.3390/pharmaceutics15082109] [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] [Received: 07/02/2023] [Revised: 07/28/2023] [Accepted: 08/02/2023] [Indexed: 08/27/2023] Open
Abstract
Adult mesenchymal stem cells are those obtained from the conformation of dental structures (DMSC), such as deciduous and permanent teeth and other surrounding tissues. Background: The self-renewal and differentiation capacities of these adult stem cells allow for great clinical potential. Because DMSC are cells of ectomesenchymal origin, they reveal a high capacity for complete regeneration of dental pulp, periodontal tissue, and other biomedical applications; their differentiation into other types of cells promotes repair in muscle tissue, cardiac, pancreatic, nervous, bone, cartilage, skin, and corneal tissues, among others, with a high predictability of success. Therefore, stem and progenitor cells, with their exosomes of dental origin and surrounding areas in the oral cavity due to their plasticity, are considered a fundamental pillar in medicine and regenerative dentistry. Tissue engineering (MSCs, scaffolds, and bioactive molecules) sustains and induces its multipotent and immunomodulatory effects. It is of vital importance to guarantee the safety and efficacy of the procedures designed for patients, and for this purpose, more clinical trials are needed to increase the efficacy of several pathologies. Conclusion: From a bioethical and transcendental anthropological point of view, the human person as a unique being facilitates better clinical and personalized therapy, given the higher prevalence of dental and chronic systemic diseases.
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Affiliation(s)
- María Eugenia Cabaña-Muñoz
- CIROM—Centro de Rehabilitación Oral Multidisciplinaria, 30001 Murcia, Spain; (M.E.C.-M.); (J.M.P.-C.); (J.M.P.-I.)
| | | | - José María Parmigiani-Cabaña
- CIROM—Centro de Rehabilitación Oral Multidisciplinaria, 30001 Murcia, Spain; (M.E.C.-M.); (J.M.P.-C.); (J.M.P.-I.)
| | | | - José Joaquín Merino
- Departamento de Farmacología, Farmacognosia y Botánica, Facultad de Farmacia, Universidad Complutense de Madrid (U.C.M), 28040 Madrid, Spain
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Hardin LT, Vang D, Thor D, Han X, Mashkoor F, Alpagot T, Ojcius DM, Xiao N. Cigarette smoking exposure disrupts the regenerative potential of dental pulp stem cells. Tob Induc Dis 2023; 21:101. [PMID: 37533959 PMCID: PMC10392041 DOI: 10.18332/tid/168125] [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: 01/31/2023] [Revised: 04/04/2023] [Accepted: 06/12/2023] [Indexed: 08/04/2023] Open
Abstract
INTRODUCTION Smoking is known to alter the regenerative and immunomodulatory properties of many types of mesenchymal stem cells (MSCs). This study investigates the impact of cigarette smoke exposure on the regenerative potential of dental pulp stem cells (DPSCs). METHODS DPSCs were treated with various doses of cigarette smoke condensate (CSC) or nicotine. Cell proliferation and survival were evaluated by a water-soluble tetrazolium salt (WST-1) and a survival assay. DPSC migration, cytokine expression, mutagenesis, and the signaling pathway were also measured during CSC and nicotine treatment. RESULTS Low concentrations of CSC and nicotine did not impair cell proliferation, but higher concentrations reduced cell proliferation. CSC and nicotine could impede DPSC survival and migration in a dose-dependent manner. In addition, the cytokine secretion expression profile was altered with CSC or nicotine treatments. In particular, secretion of IL-6, TNF-α, and IL-10 significantly increased, while TGF-β1 levels showed different patterns after exposure to CSC or nicotine, as shown by ELISA and quantitative PCR. Nicotine treatment increased AKT (also known as protein kinase B) and extracellular signal-regulated kinase (ERK) phosphorylation. Finally, CSC induced higher levels of mutagenicity than nicotine, as shown by the Ames test. CONCLUSIONS These findings suggest that cigarette smoke exposure alters the regenerative abilities of DPSCs in various ways. Future studies are warranted to further characterize the underlying molecular mechanisms of smoking-mediated damage to DPSCs, which will guide the personalized stem cell treatment plan for smoking patients.
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Affiliation(s)
- Leyla Tahrani Hardin
- Department of Biomedical Sciences, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, United States
| | - David Vang
- Department of Biomedical Sciences, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, United States
| | - Der Thor
- Department of Biomedical Sciences, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, United States
| | - Xiaoyuan Han
- Department of Biomedical Sciences, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, United States
| | - Fatima Mashkoor
- Department of Oral and Maxillofacial Surgery, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, United States
| | - Tamer Alpagot
- Department of Periodontics, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, United States
| | - David M. Ojcius
- Department of Biomedical Sciences, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, United States
| | - Nan Xiao
- Department of Biomedical Sciences, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, United States
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Mert S, Malyaran H, Craveiro RB, Wolf M, Modabber A, Jahnen-Dechent W, Neuss S. Comparative analysis of proliferative and multilineage differentiation potential of human periodontal ligament stem cells from maxillary and mandibular molars. J Periodontol 2023; 94:882-895. [PMID: 36547974 DOI: 10.1002/jper.22-0706] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 12/02/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Clinical experience indicates that wounds in alveolar bone and periodontal tissue heal faster and more efficiently in the maxilla compared with the mandible. Since stem cells are known to have a decisive influence on wound healing and tissue regeneration, the aim of this study was to determine whether differences in proliferation and differentiation of periodontal ligament stem cells (PDLSC) from upper (u-PDLSC) and lower jaw (l-PDLSC) contribute to the enhanced wound healing in the maxilla. METHODS u-PDLSC and l-PDLSC from the same donor were harvested from the periodontal ligament of extracted human maxillary and mandibular third molars. Cell differentiation potential was assessed by analyzing stem cell markers, proliferation rate, and multilineage differentiation among each other and bone marrow-derived mesenchymal stem cells (MSC). Successful differentiation of PDLSC and MSC toward osteoblasts, adipocytes, and chondrocytes was analyzed via reverse transcriptase-quantitative polymerase chain reaction and histochemical staining (Alizarin Red, Oil Red O, Toluidine Blue). RESULTS u-PDLSC and l-PDLSC expressed the MSC-markers CD73+ , CD90+ , and CD105+ and lacked expression of CD34- and CD45- . Proliferation was significantly higher in u-PDLSC than in l-PDLSC, regardless of the culture conditions. Osteogenic (ALP, RunX2, and osteocalcin) and chondrogenic (SOX9 and ACAN) related gene expression as well as staining intensities were significantly higher in u-PDLSC than in l-PDLSC. No difference in adipogenic differentiation was observed. CONCLUSION u-PDLSC showed a significantly higher proliferative and differentiation potential than l-PDLSC, offering a possible cell-based explanation for the differences in periodontal wound healing efficacy between maxilla and mandible.
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Affiliation(s)
- Sinan Mert
- Helmholtz Institute for Biomedical Engineering, BioInterface Group, RWTH Aachen University Hospital, Aachen, Germany
- Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany
| | - Hanna Malyaran
- Helmholtz Institute for Biomedical Engineering, BioInterface Group, RWTH Aachen University Hospital, Aachen, Germany
- Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany
- Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University Hospital, Aachen, Germany
| | - Rogerio B Craveiro
- Department of Orthodontics, Dental Clinic, RWTH Aachen University Hospital, Aachen, Germany
| | - Michael Wolf
- Department of Orthodontics, Dental Clinic, RWTH Aachen University Hospital, Aachen, Germany
| | - Ali Modabber
- Department of Oral and Maxillofacial Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Willi Jahnen-Dechent
- Helmholtz Institute for Biomedical Engineering, BioInterface Group, RWTH Aachen University Hospital, Aachen, Germany
| | - Sabine Neuss
- Helmholtz Institute for Biomedical Engineering, BioInterface Group, RWTH Aachen University Hospital, Aachen, Germany
- Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany
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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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11
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Subba TA, Varma S, Thomas B, Rao S, Kumar M, Talwar A, Shashidhar K. Comparison of Cellular and Differentiation Characteristics of Mesenchymal Stem Cells Derived from Human Gingiva and Periodontal Ligament. J Int Soc Prev Community Dent 2022; 12:235-244. [PMID: 35462740 PMCID: PMC9022390 DOI: 10.4103/jispcd.jispcd_259_21] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 12/01/2021] [Accepted: 12/15/2021] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVES Dental tissues possess multipotent stem cells with varying biological properties. The present study was aimed to establish a primary culture of human gingiva-derived mesenchymal stem cells (GMSCs) and periodontal ligament-derived stem cells (PDLSCs) from periodontally healthy subjects and compare their biological characteristics. MATERIALS AND METHODS Gingival and periodontal ligament (PDL) tissues were collected from extracted premolar teeth of five healthy subjects and primary cultures were established. Basic biological characteristics, such as cell morphology, viability, proliferation capacity, and colony-forming units, and in vitro osteogenic and adipogenic differentiation potential were performed at passage 3 of GMSCs and PDLSCs. This was followed by immuno-phenotyping and flow cytometric analysis for identification of positive mesenchymal stem cell (MSC) markers, such as CD73, CD90, and CD105, and negative markers CD45 and CD34. STATISTICAL ANALYSIS USED One-way analysis of variance (ANOVA). RESULTS Primary cultures of GMSCs and PDLSCs were successfully established. Cells exhibited a fibroblast-like morphology with a homogeneous population at passage 3. Cells derived from both tissues were highly viable (>95%), proliferative, and capable of forming colonies. Both cells did not exhibit any noticeable differences in cellular properties. Immunofluorescence and flow cytometric analyses showed positivity for MSC markers, CD73, CD90, and CD105, and negativity for CD34 and CD45. Furthermore, GMSCs and PDLSCs were capable of differentiating in vitro into osteocytes as evidenced by Alizarin red-S staining, and adipocytes as demonstrated by oil red O staining. CONCLUSIONS The results of the present study indicate that both GMSCs and PDLSCs have similar cellular characteristics and mesenchymal differentiation potential. Therefore, they may serve as an equally potent source of stem cells for use in cell-based periodontal therapies.
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Affiliation(s)
- Tarona A. Subba
- Department of Periodontics, Nitte (Deemed-to-be-University), AB Shetty Memorial Institute of Dental Sciences (ABSMIDS), Mangalore, Karnataka, India
| | - Sudhir Varma
- Department of Clinical Sciences, Ajman University, Ajman, UAE
| | - Biju Thomas
- Department of Periodontics, Nitte (Deemed-to-be-University), AB Shetty Memorial Institute of Dental Sciences (ABSMIDS), Mangalore, Karnataka, India
| | - Shama Rao
- Nitte (Deemed-to-be-University), KS Hegde Medical Academy (KSHEMA), Nitte University Centre for Stem Cell Research and Regenerative Medicine (NUCSReM), Mangalore, Karnataka, India
| | - Mohana Kumar
- Nitte (Deemed-to-be-University), KS Hegde Medical Academy (KSHEMA), Nitte University Centre for Stem Cell Research and Regenerative Medicine (NUCSReM), Mangalore, Karnataka, India
| | - Avaneendra Talwar
- Department of Periodontics, Nitte (Deemed-to-be-University), AB Shetty Memorial Institute of Dental Sciences (ABSMIDS), Mangalore, Karnataka, India
| | - Keerthan Shashidhar
- Department of Orthodontics, Nitte (Deemed-to-be-University), AB Shetty Memorial Institute of Dental Sciences (ABSMIDS), Mangalore, Karnataka, India
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12
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Kim M, Go J, Kwon JH, Jin HJ, Bae YK, Kim EY, Chang EJ, Choi SJ, Kim SW. CD26 Inhibition Potentiates the Therapeutic Effects of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells by Delaying Cellular Senescence. Front Cell Dev Biol 2022; 9:803645. [PMID: 35178399 PMCID: PMC8846329 DOI: 10.3389/fcell.2021.803645] [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: 10/28/2021] [Accepted: 12/23/2021] [Indexed: 12/27/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are recognized as potential treatments for multiple degenerative and inflammatory disorders as a number of animal and human studies have indicated their therapeutic effects. There are also several clinically approved medicinal products that are manufactured using these cells. For such large-scale manufacturing requirements, the in vitro expansion of harvested MSCs is essential. Multiple subculturing of MSCs, however, provokes cellular senescence processes which is known to deteriorate the therapeutic efficacy of the cells. Strategies to rejuvenate or selectively remove senescent MSCs are therefore highly desirable for fostering future clinical applications of these cells. In this present study, we investigated gene expression changes related to cellular senescence of MSCs derived from umbilical cord blood and found that CD26, also known as DPP4, is significantly upregulated upon cellular aging. We further observed that the inhibition of CD26 by genetic or pharmacologic means delayed the cellular aging of MSCs with their multiple passaging in culture. Moreover, the sorting and exclusion of CD26-positive MSCs from heterogenous cell population enhanced in vitro cell attachment and reduced senescence-associated cytokine secretion. CD26-negative MSCs also showed superior therapeutic efficacy in mouse lung emphysema model. Our present results collectively suggest CD26 is a potential novel target for the rejuvenation of senescent MSCs for their use in manufacturing MSC-based applications.
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Affiliation(s)
- Miyeon Kim
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam, South Korea
| | - Jinyoung Go
- Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Ji Hye Kwon
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam, South Korea
| | - Hye Jin Jin
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam, South Korea
| | - Yun Kyung Bae
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam, South Korea
| | - Eun-Young Kim
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Eun-Ju Chang
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Soo Jin Choi
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam, South Korea
| | - Seong Who Kim
- Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
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13
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Gousopoulou E, Bakopoulou A, Apatzidou DA, Leyhausen G, Volk J, Staufenbiel I, Geurtsen W, Adam K. Evaluation of stemness properties of cells derived from granulation tissue of peri-implantitis lesions. Clin Exp Dent Res 2021; 7:739-753. [PMID: 33605088 PMCID: PMC8543464 DOI: 10.1002/cre2.406] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 12/31/2020] [Accepted: 01/29/2021] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Peri-implantitis (PI) is an inflammatory disease associated with peri-implant bone loss and impaired healing potential. There is limited evidence about the presence of mesenchymal stromal cells (MSCs) and their regenerative properties within the granulation tissue (GT) of infrabony peri-implantitis defects. The aim of the present study was to characterize the cells derived from the GT of infrabony PI lesions (peri-implantitis derived mesenchymal stromal cells-PIMSCs). MATERIAL AND METHODS PIMSC cultures were established from GT harvested from PI lesions with a pocket probing depth ≥6 mm, bleeding on probing/suppuration, and radiographic evidence of an infrabony component from four systemically healthy individuals. Cultures were analyzed for embryonic (SSEA4, NANOG, SOX2, OCT4A), mesenchymal (CD90, CD73, CD105, CD146, STRO1) and hematopoietic (CD34, CD45) stem cell markers using flow cytometry. PIMSC cultures were induced for neurogenic, angiogenic and osteogenic differentiation by respective media. Cultures were analyzed for morphological changes and mineralization potential (Alizarin Red S method). Gene expression of neurogenic (NEFL, NCAM1, TUBB3, ENO2), angiogenic (VEGFR1, VEGFR2, PECAM1) and osteogenic (ALPL, BGLAP, BMP2, RUNX2) markers was determined by quantitative RT-PCR. RESULTS PIMSC cultures demonstrated high expression of embryonic and mesenchymal stem cell markers with inter-individual variability. After exposure to neurogenic, angiogenic and osteogenic conditions, PIMSCs showed pronounced tri-lineage differentiation potential, as evidenced by their morphology and expression of respective markers. High mineralization potential was observed. CONCLUSIONS This study provides evidence that MSC-like populations reside within the GT of PI lesions and exhibit a multilineage differentiation potential. Further studies are needed to specify the biological role of these cells in the healing processes of inflamed PI tissues and to provide indications for their potential use in regenerative therapies.
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Affiliation(s)
- Evangelia Gousopoulou
- Department of Preventive Dentistry, Periodontology & Implant Biology, School of Dentistry, Faculty of Health SciencesAristotle University of Thessaloniki (AUTh)ThessalonikiGreece
- Department of Conservative Dentistry, Periodontology & Preventive Dentistry, School of DentistryHannover Medical School (MHH)HannoverGermany
| | - Athina Bakopoulou
- Department of Conservative Dentistry, Periodontology & Preventive Dentistry, School of DentistryHannover Medical School (MHH)HannoverGermany
- Department of Prosthodontics, School of Dentistry, Faculty of Health SciencesAristotle University of Thessaloniki (AUTh)ThessalonikiGreece
| | - Danae Anastasia Apatzidou
- Department of Preventive Dentistry, Periodontology & Implant Biology, School of Dentistry, Faculty of Health SciencesAristotle University of Thessaloniki (AUTh)ThessalonikiGreece
| | - Gabriele Leyhausen
- Department of Conservative Dentistry, Periodontology & Preventive Dentistry, School of DentistryHannover Medical School (MHH)HannoverGermany
| | - Joachim Volk
- Department of Conservative Dentistry, Periodontology & Preventive Dentistry, School of DentistryHannover Medical School (MHH)HannoverGermany
| | - Ingmar Staufenbiel
- Department of Conservative Dentistry, Periodontology & Preventive Dentistry, School of DentistryHannover Medical School (MHH)HannoverGermany
| | - Werner Geurtsen
- Department of Conservative Dentistry, Periodontology & Preventive Dentistry, School of DentistryHannover Medical School (MHH)HannoverGermany
| | - Knut Adam
- Department of Conservative Dentistry, Periodontology & Preventive Dentistry, School of DentistryHannover Medical School (MHH)HannoverGermany
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14
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Wang J, Liu X, Wang Y, Xin B, Wang W. The role of long noncoding RNA THAP9-AS1 in the osteogenic differentiation of dental pulp stem cells via the miR-652-3p/VEGFA axis. Eur J Oral Sci 2021; 129:e12790. [PMID: 34288157 DOI: 10.1111/eos.12790] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 03/15/2021] [Accepted: 03/25/2021] [Indexed: 12/18/2022]
Abstract
Dental pulp stem cells (DPSCs) are multipotent and may play crucial roles in dentin-pulp regeneration. Recent studies have revealed that long noncoding RNAs (lncRNAs) are implicated in the osteogenic differentiation of DPSCs. However, the specific role and potential mechanisms of the lncRNA trihydroxyacetophenone domain containing nine antisense RNA 1 (THAP9-AS1) during osteogenic differentiation of DPSCs remain unknown. In the present study, we determined that THAP9-AS1 expression was upregulated during osteogenic differentiation of DPSCs. Moreover, we investigated the biological functions of THAP9-AS1 during osteogenic differentiation of DPSCs by loss-of-function assays. THAP9-AS1 knockdown inhibited osteogenic differentiation of DPSCs by decreasing alkaline phosphatase activity, alkaline phosphatase-positive cell ratio, mineralizing matrix and mRNA, and protein levels of early osteogenic-markers. We also found that THAP9-AS1 interacted with miR-652-3p, whose downstream gene target is vascular endothelial growth factor A (VEGFA). In addition, rescue assays indicated that VEGFA rescued the effects of THAP9-AS1 knockdown during osteogenic differentiation of DPSCs. In summary, we verified that knockdown of THAP9-AS1 inhibits osteogenic differentiation of DPSCs via the miR-652-3p/VEGFA axis. Our findings may be helpful to extend research on the mechanisms underlying osteogenic differentiation of DPSCs.
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Affiliation(s)
- Jia Wang
- Department of Cariology and Endodontology, Qingdao Stomatological Hospital Affiliated to Qingdao University, Qingdao, Shandong, China
| | - Xueyu Liu
- Department of Cariology and Endodontology, Qingdao Stomatological Hospital Affiliated to Qingdao University, Qingdao, Shandong, China
| | - Yue Wang
- Department of Stomatology, Qingdao Eighth People's Hospital, Qingdao, Shandong, China
| | - Bingchang Xin
- Department of Cariology and Endodontology, Qingdao Stomatological Hospital Affiliated to Qingdao University, Qingdao, Shandong, China
| | - Wei Wang
- Department of Prosthodontics, Qingdao Stomatological Hospital Affiliated to Qingdao University, Qingdao, Shandong, China
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15
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Queiroz A, Albuquerque-Souza E, Gasparoni LM, França BND, Pelissari C, Trierveiler M, Holzhausen M. Therapeutic potential of periodontal ligament stem cells. World J Stem Cells 2021; 13:605-618. [PMID: 34249230 PMCID: PMC8246246 DOI: 10.4252/wjsc.v13.i6.605] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/24/2021] [Accepted: 04/22/2021] [Indexed: 02/07/2023] Open
Abstract
Inflammatory periodontal disease known as periodontitis is one of the most common conditions that affect human teeth and often leads to tooth loss. Due to the complexity of the periodontium, which is composed of several tissues, its regeneration and subsequent return to a homeostatic state is challenging with the therapies currently available. Cellular therapy is increasingly becoming an alternative in regenerative medicine/dentistry, especially therapies using mesenchymal stem cells, as they can be isolated from a myriad of tissues. Periodontal ligament stem cells (PDLSCs) are probably the most adequate to be used as a cell source with the aim of regenerating the periodontium. Biological insights have also highlighted PDLSCs as promising immunomodulator agents. In this review, we explore the state of knowledge regarding the properties of PDLSCs, as well as their therapeutic potential, describing current and future clinical applications based on tissue engineering techniques.
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Affiliation(s)
- Aline Queiroz
- Laboratory of Stem Cell Biology in Dentistry-LABITRON, Department of Oral and Maxillofacial Pathology, School of Dentistry, University of São Paulo, São Paulo 05508-000, Brazil
| | - Emmanuel Albuquerque-Souza
- Department of Stomatology, Division of Periodontics, School of Dentistry, University of São Paulo, São Paulo 05508-000, Brazil
| | - Leticia Miquelitto Gasparoni
- Department of Stomatology, Division of Periodontics, School of Dentistry, University of São Paulo, São Paulo 05508-000, Brazil
| | - Bruno Nunes de França
- Department of Stomatology, Division of Periodontics, School of Dentistry, University of São Paulo, São Paulo 05508-000, Brazil
| | - Cibele Pelissari
- Laboratory of Stem Cell Biology in Dentistry-LABITRON, Department of Oral and Maxillofacial Pathology, School of Dentistry, University of São Paulo, São Paulo 05508-000, Brazil
| | - Marília Trierveiler
- Laboratory of Stem Cell Biology in Dentistry-LABITRON, Department of Oral and Maxillofacial Pathology, School of Dentistry, University of São Paulo, São Paulo 05508-000, Brazil
| | - Marinella Holzhausen
- Department of Stomatology, Division of Periodontics, School of Dentistry, University of São Paulo, São Paulo 05508-000, Brazil
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16
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Zha K, Li X, Yang Z, Tian G, Sun Z, Sui X, Dai Y, Liu S, Guo Q. Heterogeneity of mesenchymal stem cells in cartilage regeneration: from characterization to application. NPJ Regen Med 2021; 6:14. [PMID: 33741999 PMCID: PMC7979687 DOI: 10.1038/s41536-021-00122-6] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 02/01/2021] [Indexed: 01/31/2023] Open
Abstract
Articular cartilage is susceptible to damage but hard to self-repair due to its avascular nature. Traditional treatment methods are not able to produce satisfactory effects. Mesenchymal stem cells (MSCs) have shown great promise in cartilage repair. However, the therapeutic effect of MSCs is often unstable partly due to their heterogeneity. Understanding the heterogeneity of MSCs and the potential of different types of MSCs for cartilage regeneration will facilitate the selection of superior MSCs for treating cartilage damage. This review provides an overview of the heterogeneity of MSCs at the donor, tissue source and cell immunophenotype levels, including their cytological properties, such as their ability for proliferation, chondrogenic differentiation and immunoregulation, as well as their current applications in cartilage regeneration. This information will improve the precision of MSC-based therapeutic strategies, thus maximizing the efficiency of articular cartilage repair.
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Affiliation(s)
- Kangkang Zha
- Medical School of Chinese PLA, Beijing, China
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Xu Li
- Musculoskeletal Research Laboratory, Department of Orthopedics and Traumatology, Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Zhen Yang
- Medical School of Chinese PLA, Beijing, China
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Guangzhao Tian
- Medical School of Chinese PLA, Beijing, China
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Zhiqiang Sun
- Medical School of Chinese PLA, Beijing, China
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Xiang Sui
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
| | - Yongjing Dai
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
| | - Shuyun Liu
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China.
| | - Quanyi Guo
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China.
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17
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Bashir NZ. The role of insulin-like growth factors in modulating the activity of dental mesenchymal stem cells. Arch Oral Biol 2020; 122:104993. [PMID: 33259987 DOI: 10.1016/j.archoralbio.2020.104993] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 11/14/2020] [Accepted: 11/19/2020] [Indexed: 12/27/2022]
Abstract
Regenerative treatment protocols are an exciting prospect in the management of oral pathology, as they allow for tissues to be restored to their original form and function, as compared to the reparative healing mechanisms which currently govern the outcomes of the majority of dental treatment. Stem cell therapy presents with a great deal of untapped potential in this pursuit of tissue regeneration, and, in particular, mesenchymal stem cells (MSCs) derived from dental tissues are of specific relevance with regards to their applications in engineering craniofacial tissues. A number of mediatory factors are involved in modulating the actions of dental MSCs, and, of these, insulin like growth factors (IGFs) are known to have potent effects in governing the behavior of these cells. The IGF family comprises a number of primary ligands, receptors, and binding proteins which are known to modulate the key properties of dental MSCs, such as their proliferation rates, differentiation potential, and mineralisation. The aims of this review are three-fold: (i) to present an overview of dental MSCs and the role of growth factors in modulating their characteristics, (ii) to discuss in greater detail the specific role of IGFs and the benefits they may convey for tissue engineering, and (iii) to provide a summary of potential for in vivo clinical translation of the current in vitro body of evidence.
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18
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Ng TK, Chen CB, Xu C, Xu Y, Yao X, Huang L, Liang JJ, Cheung HS, Pang CP, Huang Y. Attenuated regenerative properties in human periodontal ligament-derived stem cells of older donor ages with shorter telomere length and lower SSEA4 expression. Cell Tissue Res 2020; 381:71-81. [PMID: 32043210 DOI: 10.1007/s00441-020-03176-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 01/22/2020] [Indexed: 02/05/2023]
Abstract
Periodontal ligament (PDL) stem cell properties are critical in the periodontal tissue regeneration for periodontitis. Previously, we have demonstrated that cigarette smoking attenuates PDL-derived stem cell (PDLSC) regenerative properties. Here, we report the findings on the regenerative properties of human PDLSCs with different donor ages and the underlying mechanisms. Human PDLSCs from 18 independent donors were divided into different age groups (≤ 20, 20-40, and > 40 years old). The proliferation of PDLSCs with donor age of ≤ 20 years old was significantly higher than that of the 20-40- and > 40-years-old groups, whereas the migration of PDLSCs with donor age of ≤ 20 and 20-40 years old was significantly higher than that of the > 40-years-old group. Moreover, the mesodermal lineage differentiation capabilities of PDLSCs were also higher in the donor age group of ≤ 20 years old than the donor age of > 40 years old. In addition, shorter telomere length and lower expression of SSEA4 were found in PDLSCs with donor age of > 40 years old, compared with those with donor age of ≤ 20-years-old group. Besides, PDLSCs with donor age of 20-40 and > 40 years old had higher IL6 and CXCL8 gene expressions. In summary, results from this study revealed the attenuated proliferation, migration, and mesodermal lineage differentiation properties in human PDLSCs with older donor ages. Donor age of PDLSCs should be considered as the selection criteria for the periodontal tissue regeneration treatment.
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Affiliation(s)
- Tsz Kin Ng
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, North Dongxia Road, Shantou, 515041, Guangdong, China.
- Shantou University Medical College, Shantou, Guangdong, China.
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Chong-Bo Chen
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, North Dongxia Road, Shantou, 515041, Guangdong, China
| | - Ciyan Xu
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, North Dongxia Road, Shantou, 515041, Guangdong, China
| | - Yanxuan Xu
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, North Dongxia Road, Shantou, 515041, Guangdong, China
| | - Xiaowu Yao
- Dentistry Department, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Li Huang
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Jia-Jian Liang
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, North Dongxia Road, Shantou, 515041, Guangdong, China
| | - Herman S Cheung
- Geriatric Research, Education and Clinical Center, Miami Veterans Affairs Medical Center, Miami, FL, USA
- Department of Biomedical Engineering, College of Engineering, University of Miami, Coral Gables, FL, USA
| | - Chi Pui Pang
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, North Dongxia Road, Shantou, 515041, Guangdong, China
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Yuqiang Huang
- Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, North Dongxia Road, Shantou, 515041, Guangdong, China.
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19
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Fan XL, Zhang Y, Li X, Fu QL. Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cell Mol Life Sci 2020; 77:2771-2794. [PMID: 31965214 PMCID: PMC7223321 DOI: 10.1007/s00018-020-03454-6] [Citation(s) in RCA: 327] [Impact Index Per Article: 65.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 01/02/2020] [Accepted: 01/03/2020] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) have been extensively investigated for the treatment of various diseases. The therapeutic potential of MSCs is attributed to complex cellular and molecular mechanisms of action including differentiation into multiple cell lineages and regulation of immune responses via immunomodulation. The plasticity of MSCs in immunomodulation allow these cells to exert different immune effects depending on different diseases. Understanding the biology of MSCs and their role in treatment is critical to determine their potential for various therapeutic applications and for the development of MSC-based regenerative medicine. This review summarizes the recent progress of particular mechanisms underlying the tissue regenerative properties and immunomodulatory effects of MSCs. We focused on discussing the functional roles of paracrine activities, direct cell-cell contact, mitochondrial transfer, and extracellular vesicles related to MSC-mediated effects on immune cell responses, cell survival, and regeneration. This will provide an overview of the current research on the rapid development of MSC-based therapies.
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Affiliation(s)
- Xing-Liang Fan
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road II, Guangzhou, 510080, People's Republic of China
| | - Yuelin Zhang
- Department of Emergency, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Road II, Guangzhou, 510080, People's Republic of China
| | - Xin Li
- Department of Emergency, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Road II, Guangzhou, 510080, People's Republic of China
| | - Qing-Ling Fu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road II, Guangzhou, 510080, People's Republic of China.
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.
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20
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Ayoub S, Berbéri A, Fayyad-Kazan M. An update on human periapical cyst-mesenchymal stem cells and their potential applications in regenerative medicine. Mol Biol Rep 2020; 47:2381-2389. [PMID: 32026284 DOI: 10.1007/s11033-020-05298-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 01/31/2020] [Indexed: 12/16/2022]
Abstract
The broad clinical applications of Mesenchymal Stem Cells (MSCs) in the regenerative medicine field is attributed to their ability to self-renew and differentiate into multiple cellular lineages. Nowadays, MSCs can be derived from a variety of adult and fetal tissues including bone marrow, adipose tissue, umbilical cord and placenta. The difficulties associated with the isolation of MSCs from certain tissues such as bone marrow promoted the search for alternative tissues which are easily accessible. Oral derived MSCs include dental pulp stem cells (DPSCs), dental follicle progenitor cells (DFPC), and periodontal ligament stem cells (PDLSC). Being abundant and easily accessible, oral derived MSCs represent an interesting alternative MSC type to be employed in regenerative medicine. Human periapical cyst-mesenchymal stem cells (hPCy-MSCs) correspond to a newly discovered and characterized MSC subtype. Interestingly, hPCy-MSCs are collected from periapical cysts, which are a biological waste, without any influence on the other healthy tissues in oral cavity. hPCy-MSCs exhibit cell surface marker profile similar to that of other oral derived MSCs, show high proliferative potency, and possess the potential to differentiate into different cell types such as osteoblasts, adipocytes and neurons-like cells. hPCy-MSCs, therefore, represent a novel promising MSCs type to be applied in regenerative medicine domain. In this review, we will compare the different types of dental derived MSCs, we will highlight the isolation technique, the characteristics, and the therapeutic potential of hPCy-MSCs.
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Affiliation(s)
- Sara Ayoub
- Department of Prosthodontics, Faculty of Dental Medicine, Lebanese University, Beirut, Lebanon
| | - Antoine Berbéri
- Department of Oral and Maxillofacial Surgery, Faculty of Dental Medicine, Lebanese University, Beirut, Lebanon
| | - Mohammad Fayyad-Kazan
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon. .,Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Lebanon.
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21
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Mesenchymal Stem/Stromal Cells Derived from Dental Tissues: A Comparative In Vitro Evaluation of Their Immunoregulatory Properties Against T cells. Cells 2019; 8:cells8121491. [PMID: 31766697 PMCID: PMC6953107 DOI: 10.3390/cells8121491] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 11/19/2019] [Accepted: 11/20/2019] [Indexed: 12/13/2022] Open
Abstract
Bone marrow mesenchymal stem/stromal cells (BM-MSCs) have immunoregulatory properties and have been used as immune regulators for the treatment of graft-versus-host disease (GVHD). Human dental tissue mesenchymal stem cells (DT-MSCs) constitute an attractive alternative to BM-MSCs for potential clinical applications because of their accessibility and easy preparation. The aim of this in vitro study was to compare MSCs from dental pulp (DP-MSCs), gingival tissue (G-MSCs), and periodontal ligament (PDL-MSCs) in terms of their immunosuppressive properties against lymphoid cell populations enriched for CD3+ T cells to determine which MSCs would be the most appropriate for in vivo immunoregulatory applications. BM-MSCs were included as the gold standard. Our results demonstrated, in vitro, that MSCs from DP, G, and PDL showed immunoregulatory properties similar to those from BM, in terms of the cellular proliferation inhibition of both CD4+- and CD8+-activated T-cells. This reduced proliferation in cell co-cultures correlated with the production of interferon-γ and tumor necrosis factor alpha (TNF-α) and the upregulation of programmed death ligand 1 (PD-L1) in MSCs and cytotoxic T-cell-associated Ag-4 (CTLA-4) in T-cells and increased interleukin-10 and prostaglandin E2 production. Interestingly, we observed differences in the production of cytokines and surface and secreted molecules that may participate in T-cell immunosuppression in co-cultures in the presence of DT-MSCs compared with BM-MSCs. Importantly, MSCs from four sources favored the generation of T-cell subsets displaying the regulatory phenotypes CD4+CD25+Foxp3+ and CD4+CD25+CTLA-4+. Our results in vitro indicate that, in addition to BM-MSCs, MSCs from all of the dental sources analyzed in this study might be candidates for future therapeutic applications.
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22
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Takizawa S, Yamamoto T, Honjo KI, Sato Y, Nakamura K, Yamamoto K, Adachi T, Uenishi T, Oseko F, Amemiya T, Yamamoto Y, Kumagai W, Kita M, Kanamura N. Transplantation of dental pulp-derived cell sheets cultured on human amniotic membrane induced to differentiate into bone. Oral Dis 2019; 25:1352-1362. [PMID: 30912198 DOI: 10.1111/odi.13096] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 02/19/2019] [Accepted: 02/25/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The usefulness of the amniotic membrane as a cell culture substrate has led to its use in the development of dental pulp-derived cell sheets. We induced osteoblastic differentiation of dental pulp-derived cell sheets and conducted histological and immunological examinations in addition to imaging assessments for regeneration of bone defects. METHODS Dental pulp cells were obtained by primary culture of the dental pulp tissue harvested from extracted wisdom teeth. These cells were maintained for three to four passages. Subsequently, the dental pulp cells were seeded onto an amniotic membrane to produce dental pulp-derived cell sheets. Following the induction of osteoblastic differentiation, the sheets were grafted into the subcutaneous tissue of the lower back and maxillary bone defect of a nude mouse. Histological and immunological examinations of both grafts were performed. RESULTS Dental pulp-derived cell sheets cultured on an osteoblast differentiation-inducing medium demonstrated resemblance to dental pulp tissue and produced calcified tissue. Mineralization was maintained following grafting of the sheets. Regeneration of the maxillary bone defect was observed. CONCLUSION Induction of osteoblastic differentiation of the dental pulp-derived cell sheets may be indicated for the regeneration of periodontal tissue.
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Affiliation(s)
- Shigeta Takizawa
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toshiro Yamamoto
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Ken-Ichi Honjo
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshiki Sato
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Koya Nakamura
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kenta Yamamoto
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tetsuya Adachi
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toshihiro Uenishi
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Fumishige Oseko
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takeshi Amemiya
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshiaki Yamamoto
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Wataru Kumagai
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masakazu Kita
- Department of Laboratory Animal Center, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Narisato Kanamura
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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23
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Durand N, Russell A, Zubair AC. Effect of Comedications and Endotoxins on Mesenchymal Stem Cell Secretomes, Migratory and Immunomodulatory Capacity. J Clin Med 2019; 8:jcm8040497. [PMID: 30979082 PMCID: PMC6517980 DOI: 10.3390/jcm8040497] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/04/2019] [Accepted: 04/08/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are becoming an increasingly popular therapeutic option among patients with a broad range of ailments to modulate immunity and induce regeneration. The majority of patients receiving these MSC therapies are on concurrent medication or have ongoing infection. In the present study, we examined the effect of immunosuppressive drugs and lipopolysaccharides (LPS)/endotoxins on the secretory profile, migration towards site of injury, and suppression of lymphocyte proliferation of bone marrow-derived MSCs (BMSCs). Generally, LPS coculture augmented the secretory capacity of BMSCs while exposure to immunosuppressive drugs resulted primarily in no change or attenuated secretion, with some cases of increased secretion, dependent on the cytokine assayed. Among the immunosuppressants evaluated, Hydrocortisone had the most widespread inhibitory effect, while LPS from E. coli O111:B4 had the most potent stimulatory effect. In addition, we also showed that Hydrocortisone or LPS from E. coli O111:B4 affected the migratory and immunosuppressive capacity of BMSCs. Following simulation with Hydrocortisone, BMSC migration was attenuated, and immunosuppressive capacity against T cell proliferation was enhanced, however, the opposite effects were seen with LPS from E. coli O111:B4. Our data suggests that the clinical outcomes of MSC-based therapy are affected by the use of immunosuppressive medication or the presence of endotoxemia in patients.
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Affiliation(s)
- Nisha Durand
- Transfusion Medicine, Department of Laboratory Medicine and Pathology and Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL 32224, USA.
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24
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Abstract
In recent years, stem cell therapy has become a very promising and advanced scientific research topic. The development of treatment methods has evoked great expectations. This paper is a review focused on the discovery of different stem cells and the potential therapies based on these cells. The genesis of stem cells is followed by laboratory steps of controlled stem cell culturing and derivation. Quality control and teratoma formation assays are important procedures in assessing the properties of the stem cells tested. Derivation methods and the utilization of culturing media are crucial to set proper environmental conditions for controlled differentiation. Among many types of stem tissue applications, the use of graphene scaffolds and the potential of extracellular vesicle-based therapies require attention due to their versatility. The review is summarized by challenges that stem cell therapy must overcome to be accepted worldwide. A wide variety of possibilities makes this cutting edge therapy a turning point in modern medicine, providing hope for untreatable diseases.
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Affiliation(s)
- Wojciech Zakrzewski
- Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocław, 50-345 Poland
| | - Maciej Dobrzyński
- Department of Conservative Dentistry and Pedodontics, Krakowska 26, Wrocław, 50-425 Poland
| | - Maria Szymonowicz
- Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocław, 50-345 Poland
| | - Zbigniew Rybak
- Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocław, 50-345 Poland
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25
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Berebichez-Fridman R, Montero-Olvera PR. Sources and Clinical Applications of Mesenchymal Stem Cells: State-of-the-art review. Sultan Qaboos Univ Med J 2018; 18:e264-e277. [PMID: 30607265 DOI: 10.18295/squmj.2018.18.03.002] [Citation(s) in RCA: 240] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 04/16/2018] [Accepted: 05/10/2018] [Indexed: 12/15/2022] Open
Abstract
First discovered by Friedenstein in 1976, mesenchymal stem cells (MSCs) are adult stem cells found throughout the body that share a fixed set of characteristics. Discovered initially in the bone marrow, this cell source is considered the gold standard for clinical research, although various other sources-including adipose tissue, dental pulp, mobilised peripheral blood and birth-derived tissues-have since been identified. Although similar, MSCs derived from different sources possess distinct characteristics, advantages and disadvantages, including their differentiation potential and proliferation capacity, which influence their applicability. Hence, they may be used for specific clinical applications in the fields of regenerative medicine and tissue engineering. This review article summarises current knowledge regarding the various sources, characteristics and therapeutic applications of MSCs.
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Affiliation(s)
- Roberto Berebichez-Fridman
- Department of Orthopaedic Surgery, American British Cowdray Medical Center, Mexico City, Mexico.,Tissue Engineering, Cell Therapy & Regenerative Medicine Unit, National Institute of Rehabilitation, Mexico City, Mexico
| | - Pablo R Montero-Olvera
- Tissue Engineering, Cell Therapy & Regenerative Medicine Unit, National Institute of Rehabilitation, Mexico City, Mexico
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26
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Abstract
Adult stem cells are excellent cell resource for cell therapy and regenerative medicine. Dental pulp stem cells (DPSCs) have been discovered and well known in various application. Here, we reviewed the history of dental pulp stem cell study and the detail experimental method including isolation, culture, cryopreservation, and the differentiation strategy to different cell lineage. Moreover, we discussed the future potential application of the combination of tissue engineering and of DPSC differentiation. This review will help the new learner to quickly get into the DPSC filed.
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Affiliation(s)
- Xianrui Yang
- Department of Orthodontics, State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 China
| | - Li Li
- State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan, 430062 Hubei China
| | - Li Xiao
- Department of Stomatology, Sichuan Academy of Medical Science & Sichuan Provincial People’s Hospital, Chengdu, 610072 China
| | - Donghui Zhang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan, 430062 Hubei China
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27
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Detection, Characterization, and Clinical Application of Mesenchymal Stem Cells in Periodontal Ligament Tissue. Stem Cells Int 2018; 2018:5450768. [PMID: 30224921 PMCID: PMC6129323 DOI: 10.1155/2018/5450768] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Accepted: 07/19/2018] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are a kind of somatic stem cells that exert a potential to differentiate into multiple cell types and undergo robust clonal self-renewal; therefore, they are considered as a highly promising stem cell population for tissue engineering. MSCs are identified in various adult organs including dental tissues. Periodontal ligament (PDL) is a highly specialized connective tissue that surrounds the tooth root. PDL also contains MSC population, and many researchers have isolated them and performed their detailed characterization. Here, we review the current understanding of the features and functions of MSC population in PDL tissues and discuss their possibility for the application of PDL regeneration.
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28
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Comparison of Immunological Characteristics of Mesenchymal Stem Cells from the Periodontal Ligament, Umbilical Cord, and Adipose Tissue. Stem Cells Int 2018; 2018:8429042. [PMID: 29760736 PMCID: PMC5901833 DOI: 10.1155/2018/8429042] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 12/16/2017] [Accepted: 12/19/2017] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are of therapeutic importance in the fields of regenerative medicine and immunological diseases. Accordingly, studies evaluating MSCs for clinical applications are increasing. In this study, we characterized MSCs from the periodontal ligament, umbilical cord (UC-MSCs), and adipose tissue, which were relatively easy to obtain with limited ethical concerns regarding their acquisition, and compared their immunological characteristics. Among MSCs isolated from the three different tissues, UC-MSCs grew the fastest in vitro. The three types of MSCs were shown to inhibit proliferation of activated peripheral blood mononuclear cells (PBMCs) to a similar degree, via the indoleamine 2,3-dioxygenase and cyclooxygenase-2 pathways. They were also shown to inhibit the proliferation of PBMCs using HLA-G, which was most prominent in UC-MSCs. Unlike the other two types of MSCs, UC-MSCs showed minimal expression of HLA-DR after activation, suggesting that they pose minimal risk of initiating an allogeneic immune response when administered in vivo. These characteristics, the ease of collection, and the minimal ethical concerns regarding their use suggest UC-MSCs to be suitable MSC therapeutic candidates.
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29
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Otero L, Carrillo N, Calvo-Guirado J, Villamil J, Delgado-Ruíz R. Osteogenic potential of platelet-rich plasma in dental stem-cell cultures. Br J Oral Maxillofac Surg 2017. [DOI: 10.1016/j.bjoms.2017.05.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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30
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Čebatariūnienė A, Jarmalavičiūtė A, Tunaitis V, Pūrienė A, Venalis A, Pivoriūnas A. Microcarrier culture enhances osteogenic potential of human periodontal ligament stromal cells. J Craniomaxillofac Surg 2017; 45:845-854. [DOI: 10.1016/j.jcms.2017.03.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Revised: 02/22/2017] [Accepted: 03/20/2017] [Indexed: 11/15/2022] Open
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TSG-6 secreted by mesenchymal stem cells suppresses immune reactions influenced by BMP-2 through p38 and MEK mitogen-activated protein kinase pathway. Cell Tissue Res 2017; 368:551-561. [PMID: 28247086 DOI: 10.1007/s00441-017-2581-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 12/26/2016] [Indexed: 12/31/2022]
Abstract
Bone morphogenetic protein 2 (BMP-2) has a critical function in bone and cartilage development and in repairing damaged organs and tissue. However, clinical use of BMP-2 at doses of 0.5-1 mg/ml for orthopedics has been associated with severe postoperative swelling requiring emergency surgical intervention. We determined whether a high concentration of BMP-2 induces inflammatory responses in macrophages and the suppression of osteogenesis in hMSCs. We obtained human periodontal ligament stem cells and bone marrow stem cells from the maxilla, i.e., human mesenchymal stem cells (hMSCs), from the periodontal ligament of extracted third molar teeth and from the bone marrow of the maxilla, respectively. Osteogenic differentiation was measured by alkaline phosphatase activity and alizarin red S staining. Proteins were assessed by flow cytometry, enzyme-linked immunosorbent assay, Western blot and immunocytochemistry. Changes of gene expression were measured by reverse transcription plus the polymerase chain reaction (RT-PCR) and real-time PCR. A high BMP-2 concentration inhibited the early stages of osteogenesis in hMSCs. Co-culturing THP-1 cells (human monocytic cells) with hMSCs reduced the late stages of osteogenesis compared with those seen in hMSCs alone. In addition, high-dose BMP-2 induced the expression of inflammatory cytokines in THP-1 cells and the expression of the anti-inflammatory cytokine tumor-necrosis-factor-α-inducible gene 6 protein (TSG-6) in hMSCs. Consistent with the anti-inflammatory effects of hMSCs when co-cultured with THP-1 cells, interleukin-1β expression was downregulated by TSG-6 treatment of THP-1 cells. Our findings suggest that a high BMP-2 concentration triggers inflammation that causes inflammatory cytokine release from THP-1 cells, leading to the suppression of osteogenesis, whereas TSG-6 secreted by hMSCs suppresses inflammatory reactions through p38 and ERK in the mitogen-activated protein kinase pathway.
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32
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Huynh NCN, Everts V, Nifuji A, Pavasant P, Ampornaramveth RS. Histone deacetylase inhibition enhances in-vivo bone regeneration induced by human periodontal ligament cells. Bone 2017; 95:76-84. [PMID: 27871909 DOI: 10.1016/j.bone.2016.11.017] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/16/2016] [Accepted: 11/17/2016] [Indexed: 01/12/2023]
Abstract
UNLABELLED Periodontal ligament cells have the potential to differentiate into bone forming osteoblasts and thus represent a good cellular candidate for bone regeneration. This study aimed to investigate the effect of inhibition of histone deacetylases, using the inhibitor Trichostatin A (TSA), on bone regeneration by human periodontal ligament cells (hPDLCs) in a mouse calvaria bone defect. METHODS RUNX2 protein and its acetylation was analyzed by immunoprecipitation and western blotting. The effect of TSA on osteogenic differentiation of hPDLCs was investigated using in vitro 3D cultures. hPDLCs were pre-incubated with and without TSA and implanted in mouse calvaria defects with polycaprolactone/polyethylene glycol (PCL/PEG) co-polymer scaffold. Micro-CT scanning and bone histomorphometric analysis were used to quantify the amount of bone. Survival of hPDLCs as xenogenic grafts was verified by immunohistochemistry with anti-human β1-integrin. The immunological response of mice against hPDLCs xenografts was evaluated by measuring total IgG and hPDLCs-specific IgG. RESULTS Beside affecting histone protein, TSA also induced hyper-acetylation of RUNX2 which might be a crucial mechanism for enhancing osteogenesis by hPDLCs. TSA enhanced mineral deposition by hPDLCs in in vitro 3D cultures and had no effect on cell viability. In vivo bone regeneration of mouse calvaria defects was significantly enhanced by TSA pre-treated hPDLCs. By using anti-human ß1 integrin hPDLCs were shown to differentiate into osteocyte-like cells that were present in newly formed bone. hPDLCs, as a xenograft, slightly but not significantly induced an immunological response in recipient mice as demonstrated by the level of total IgG and hPDLCs-specific IgG. CONCLUSION Inhibition of histone deacetylases by TSA enhanced in vivo bone regeneration by hPDLCs. The data strongly suggest a novel approach to regenerate bone tissue.
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Affiliation(s)
- Nam Cong-Nhat Huynh
- Mineralized Tissue Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand; Department of Dental Basic Sciences, Faculty of Odonto-Stomatology, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam; Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Vincent Everts
- Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Research Institute MOVE, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
| | - Akira Nifuji
- Department of Pharmacology, School of Dental Medicine, Tsurumi University, Yokohama, Japan
| | - Prasit Pavasant
- Mineralized Tissue Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand; Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
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Vasandan AB, Jahnavi S, Shashank C, Prasad P, Kumar A, Prasanna SJ. Human Mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE 2-dependent mechanism. Sci Rep 2016; 6:38308. [PMID: 27910911 PMCID: PMC5133610 DOI: 10.1038/srep38308] [Citation(s) in RCA: 285] [Impact Index Per Article: 31.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 11/08/2016] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are speculated to act at macrophage-injury interfaces to mediate efficient repair. To explore this facet in-depth this study evaluates the influence of MSCs on human macrophages existing in distinct functional states. MSCs promoted macrophage differentiation, enhanced respiratory burst and potentiated microbicidal responses in naïve macrophages (Mφ). Functional attenuation of inflammatory M1 macrophages was associated with a concomitant shift towards alternatively activated M2 state in MSC-M1 co-cultures. In contrast, alternate macrophage (M2) activation was enhanced in MSC-M2 co-cultures. Elucidation of key macrophage metabolic programs in Mo/MSC, M1/MSC and M2/MSC co-cultures indicated changes in Glucose transporter1 (GLUT1 expression/glucose uptake, IDO1 protein/activity, SIRTUIN1 and alterations in AMPK and mTOR activity, reflecting MSC-instructed metabolic shifts. Inability of Cox2 knockdown MSCs to attenuate M1 macrophages and their inefficiency in instructing metabolic shifts in polarized macrophages establishes a key role for MSC-secreted PGE2 in manipulating macrophage metabolic status and plasticity. Functional significance of MSC-mediated macrophage activation shifts was further validated on human endothelial cells prone to M1 mediated injury. In conclusion, we propose a novel role for MSC secreted factors induced at the MSC-macrophage interface in re-educating macrophages by manipulating metabolic programs in differentially polarized macrophages.
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Affiliation(s)
- Anoop Babu Vasandan
- School of Regenerative Medicine, Manipal University, Bangalore, 560065, India
| | - Sowmya Jahnavi
- School of Regenerative Medicine, Manipal University, Bangalore, 560065, India
| | - Chandanala Shashank
- School of Regenerative Medicine, Manipal University, Bangalore, 560065, India
| | - Priya Prasad
- School of Regenerative Medicine, Manipal University, Bangalore, 560065, India
| | - Anujith Kumar
- School of Regenerative Medicine, Manipal University, Bangalore, 560065, India
| | - S. Jyothi Prasanna
- School of Regenerative Medicine, Manipal University, Bangalore, 560065, India
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Non-coding RNA as mediators in microenvironment–breast cancer cell communication. Cancer Lett 2016; 380:289-95. [PMID: 26582656 DOI: 10.1016/j.canlet.2015.11.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 11/04/2015] [Accepted: 11/06/2015] [Indexed: 12/18/2022]
Abstract
The tumor microenvironment has a critical role in the survival and decision of the cancer cells. These include support by enhanced angiogenesis, and metastasis or adaptation of dormancy. This article discusses methods by which the microenvironment sustains the tumor. This process is important as it will identify avenues of drug targets. Non-coding RNAs (ncRNAs) are evolving as key mediators in the interaction between the cancer cells and the microenvironment. Thus, the question is how to develop methods to effectively block the effects of the ncRNA and/or to introduce them to prevent metastasis, dormancy or to reverse dormancy. We focused on the advantages of using mesenchymal stem cells (MSCs) for RNA delivery. MSCs can be available as "off-the-shelf" cells. Thus far, MSCs are shown to be safe when transplanted across allogeneic barriers. We discussed the various methods by which MSCs can interact with cancer cells to deliver ncRNA or antagomirs. We also include the advances and possible confounds of using these methods. Overall, this review article provides a potential method by which MSCs can be used for effective delivery of nucleic acid to treat cancer.
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35
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Langhans MT, Yu S, Tuan RS. Stem Cells in Skeletal Tissue Engineering: Technologies and Models. Curr Stem Cell Res Ther 2016; 11:453-474. [PMID: 26423296 DOI: 10.2174/1574888x10666151001115248] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Revised: 04/01/2015] [Accepted: 04/01/2015] [Indexed: 12/14/2022]
Abstract
This review surveys the use of pluripotent and multipotent stem cells in skeletal tissue engineering. Specific emphasis is focused on evaluating the function and activities of these cells in the context of development in vivo, and how technologies and methods of stem cell-based tissue engineering for stem cells must draw inspiration from developmental biology. Information on the embryonic origin and in vivo differentiation of skeletal tissues is first reviewed, to shed light on the persistence and activities of adult stem cells that remain in skeletal tissues after embryogenesis. Next, the development and differentiation of pluripotent stem cells is discussed, and some of their advantages and disadvantages in the context of tissue engineering are presented. The final section highlights current use of multipotent adult mesenchymal stem cells, reviewing their origin, differentiation capacity, and potential applications to tissue engineering.
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Affiliation(s)
| | | | - Rocky S Tuan
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Room 221, Pittsburgh, PA 15219, USA.
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Misawa MYO, Huynh‐Ba G, Villar GM, Villar CC. Efficacy of stem cells on the healing of peri-implant defects: systematic review of preclinical studies. Clin Exp Dent Res 2016; 2:18-34. [PMID: 29744146 PMCID: PMC5839227 DOI: 10.1002/cre2.16] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/23/2015] [Accepted: 11/30/2015] [Indexed: 12/21/2022] Open
Abstract
This systematic review considers the evidence from animal studies evaluating the effectiveness of mesenchymal stem cells (MSC) in the treatment of intraoral peri-implant defects. MEDLINE, EMBASE, and LILACS databases were searched for quantitative preclinical controlled animal model studies that evaluated the effect of MSC on bone healing at intraoral peri-implant bone defects. The primary outcome was the amount of (re-)osseointegration reported as bone-to-implant contact in the defect area. The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines. Ten studies met the inclusion criteria. Only one study induced peri-implant inflammation to produce peri-implant bone defects. In all others, defects were surgically created at implant installation. Differences in defect morphology were identified among the studies. Both xenogenous and autogenous MSC were used to treat peri-implant defects. These included bone marrow-derived MSC, periodontal ligament-derived MSC, umbilical cord MSC, bone marrow-derived mononuclear cells, and peripheral blood mononuclear cells. Meta-analysis was not possible because of heterogeneities in study designs. Nonetheless, in most studies, local MSC implantation was not associated with adverse effects and had a positive effect on bone healing around peri-implant defects. Combination of MSC with membranes and bioactive factors appears to provide improved treatment outcomes. In large animal models, intraoral use of MSC may provide beneficial effects on bone healing within peri-implant defects. The various degrees of success of MSC in peri-implant bone healing are likely to be related to the use of cells from various populations, tissues, and donor species. However, human safety and efficacy must be demonstrated before its clinical use can be considered.
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Affiliation(s)
- Mônica Yuri Orita Misawa
- Division of Periodontics, Department of Stomatology, School of DentistryUniversity of São PauloSão PauloSão PauloBrazil
| | - Guy Huynh‐Ba
- Department of PeriodonticsUniversity of Texas Health Science Center at San Antonio Dental SchoolSan AntonioTexasUSA
| | - Gustavo Machado Villar
- Division of Periodontics, Department of Stomatology, School of DentistryUniversity of São PauloSão PauloSão PauloBrazil
| | - Cristina Cunha Villar
- Division of Periodontics, Department of Stomatology, School of DentistryUniversity of São PauloSão PauloSão PauloBrazil
- Department of PeriodonticsUniversity of Texas Health Science Center at San Antonio Dental SchoolSan AntonioTexasUSA
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Multipotent Differentiation of Human Dental Pulp Stem Cells: a Literature Review. Stem Cell Rev Rep 2016; 12:511-523. [DOI: 10.1007/s12015-016-9661-9] [Citation(s) in RCA: 159] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Liu XX, Fan H, Tang Q, Shou ZX, Tao L, Zhang LJ, Zuo DM. Intravenous administration of mesenchymal stem cells overexpressing CXCR4 protects against experimental colitis in rats. Shijie Huaren Xiaohua Zazhi 2016; 24:1233-1240. [DOI: 10.11569/wcjd.v24.i8.1233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of SDF-1α/CXCR4 axis in the therapeutic effects of lentivirus-preconditioned bone mesenchymal stem cells (BMSCs) for 2,4,6-trinitrobenzene sulfonic acid (TNBS)- induced colitis in rats.
METHODS: BMSCs were isolated from Sprague-Dawley (SD) rats and identified by flow cytometry. Lentivirus transfection was applied to over-express CXCR4/GFP (Ad-CXCR4-BMSCs) or null/GFP (Ad-GFP-BMSCs) in BMSCs. Thirty-two SD rats were randomly divided into four groups (n = 8): a control group, a model group, an Ad-GFP-BMSCs group and an Ad-CXCR4-BMSCs group. The rats were grouped to receive various treatments by tail vein injections. On day 1, colitis was induced by the TNBS administration. On day 12, animals were anesthetized and submitted to a laparotomy under sterile conditions. The distal colon was then opened longitudinally, slightly cleaned in physiological saline for faecal residue removal, and tissue samples were harvested and analyzed for various studies.
RESULTS: One week after intravenous administration, Ad-GFP-BMSCs failed to colonize in the inflamed colon and had no beneficial effect in TNBS-induced colitis. Instead, Ad-CXCR4-BMSCs signally ameliorated both clinical and microanatomical severity of colitis. Immunofluorescence and Western blot showed that Ad-CXCR4-BMSCs migrated toward inflamed colon was more efficient than Ad-GFP-BMSCs. The therapeutic effect of Ad-CXCR4-BMSCs was mediated by the suppression of pro-inflammatory cytokines and STAT3 phosphorylation in injured colon.
CONCLUSION: Our data indicate that over-expression of CXCR4 promotes the in vivo mobilization and engraftment of BMSCs into inflamed colon where these cells can function as an anti-inflammatory and immunomodulatory component of the immune system in TNBS-induced colitis.
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Mitchell A, Ashton L, Yang XB, Goodacre R, Tomlinson MJ, Smith A, Kirkham J. Aseptic Raman spectroscopy can detect changes associated with the culture of human dental pulp stromal cells in osteoinductive culture. Analyst 2015; 140:7347-54. [PMID: 26374253 PMCID: PMC4621535 DOI: 10.1039/c5an01595b] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 09/10/2015] [Indexed: 12/16/2022]
Abstract
There is an unmet need for the non-invasive characterisation of stem cells to facilitate the translation of cell-based therapies. Raman spectroscopy has proven utility in stem cell characterisation but as yet no method has been reported capable of taking repeated Raman measurements of living cells aseptically over time. The aim of this study was to determine if Raman spectroscopy could be used to monitor changes in a well characterised cell population (human dental pulp stromal cells (DPSCs)) by taking repeated Raman measurements from the same cell populations in osteoinductive culture over time and under aseptic conditions. DPSCs were isolated from extracted premolar teeth from 3 consenting donors. Following in vitro expansion, DPSCs were maintained for 28 days in osteo-inductive medium. Raman spectra were acquired from the cells at days 0, 3, 7, 10, 14 and 28. Principal component analysis (PCA) was carried out to assess if there was any temporal spectral variation. At day 28, osteoinduction was confirmed using alizarin red staining and qRT-PCR for alkaline phosphatase and osteocalcin. Alizarin red staining was positive in all samples at day 28 and significant increases in alkaline phosphatase (p < 0.001) and osteocalcin (p < 0.05) gene expression were also observed compared with day 0. PCA of the Raman data demonstrated trends in PC1 from days 0-10, influenced by protein associated features and PC2 from days 10-28, influenced by DNA/RNA associated features. We conclude that spectroscopy can be used to monitor changes in Raman signature with time associated with the osteoinduction of DPSCs using repeated measurements via an aseptic methodology.
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Affiliation(s)
- Adam Mitchell
- University of Leeds , Department of Oral Biology , Leeds School of Dentistry , Leeds , UK .
| | - Lorna Ashton
- Department of Chemistry , Faraday Building , Lancaster University , Lancaster , UK
| | - Xuebin B. Yang
- University of Leeds , Department of Oral Biology , Leeds School of Dentistry , Leeds , UK .
| | - Royston Goodacre
- School of Chemistry and Manchester Institute of Biotechnology , University of Manchester , Manchester , UK
| | - Matthew J. Tomlinson
- University of Leeds , Department of Oral Biology , Leeds School of Dentistry , Leeds , UK .
| | | | - Jennifer Kirkham
- University of Leeds , Department of Oral Biology , Leeds School of Dentistry , Leeds , UK .
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Grimm WD, Giesenhagen B, Hakki S, Schau I, Sirak S, Sletov A, Varga G, Vukovic MA, Widera D. Translational Research and Therapeutic Applications of Neural Crest-Derived Stem Cells in Regenerative Periodontology. ACTA ACUST UNITED AC 2015. [DOI: 10.1007/s40496-015-0067-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Jayaraman P, Govindasamy V, Gnanasegaran N, Kunasekaran W, Vasanthan P, Musa S, Kasim NHA. Expression patterns of immune genes in long-term cultured dental stem cells. Clin Oral Investig 2015; 20:109-16. [DOI: 10.1007/s00784-015-1497-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 05/20/2015] [Indexed: 01/06/2023]
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Hakki SS, Kayis SA, Hakki EE, Bozkurt SB, Duruksu G, Unal ZS, Turaç G, Karaoz E. Comparison of mesenchymal stem cells isolated from pulp and periodontal ligament. J Periodontol 2014; 86:283-91. [PMID: 25325708 DOI: 10.1902/jop.2014.140257] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Cell-based therapy using mesenchymal stem cells (MSCs) seems promising to obtain regeneration of dental tissues. A comparison of tissue sources, including periodontal ligament (PDL) versus pulp (P), could provide critical information to select an appropriate MSC population for designing predictable regenerative therapies. The purpose of this study is to compare the proliferation and stemness and the MSC-specific and mineralized tissue-specific gene expression of P-MSCs and PDL-MSCs. METHODS MSCs were obtained from PDL and P tissue of premolars (n = 3) extracted for orthodontic reasons. MSC proliferation was evaluated using a real-time cell analyzer for 160 hours. Telomerase activity was evaluated by a telomeric repeat amplification protocol assay based on enzyme-linked immunosorbent assay. Total RNA was isolated from the MSCs on day 3. A polymerase chain reaction (PCR) array was used to compare the expression of MSC-specific genes. The expression of mineralized tissue-associated genes, including Type I collagen (COL I), runt-related transcription factor 2 (RunX2), bone sialoprotein (BSP), and osteocalcin (OCN) messenger RNA (mRNA), was evaluated using quantitative real-time PCR. RESULTS Higher proliferation potential and telomerase activity were observed in the P-MSCs compared to PDL-MSCs of premolar teeth. Fourteen of 84 genes related to MSCs were expressed differently in the PDL-MSCs versus the P-MSCs. The expressions of bone morphogenetic protein 2 (BMP2) and BMP6; sex-determining region Y-box 9 (SOX9); integrin, alpha 6 (ITGA6); melanoma cell adhesion molecule (MCAM); phosphatidylinositol glycan anchor biosynthesis, class S (PIGS); prominin 1 (PROM1); ribosomal protein L13A (RPL13A); and microphthalmia-associated transcription factor (MITF) were higher in the P-MSCs compared to the PDL-MSCs, and higher expression of matrix metalloproteinase 2 (MMP2), interleukin (IL)-6, insulin (INS), alanyl (membrane) aminopeptidase (ANPEP), and IL-10 were observed in the PDL-MSCs. However, there was no statistically significant difference in the expression of mineralized tissue-associated genes, including BSP and RunX2, between the P-MSCs and the PDL-MSCs. Higher expression of COL I and lower expression of OCN mRNA transcripts were noted in the PDL-MSCs compared to the P-MSCs. CONCLUSIONS The results of this study suggest that MSCs isolated from P and PDL tissues show different cellular behavior. To increase the predictability of MSC-based regenerative treatment, differences in dental tissue-derived MSCs and favorable aspects of cell sources should be further clarified.
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Affiliation(s)
- Sema S Hakki
- Department of Periodontology, Faculty of Dentistry, Selçuk University, Konya, Turkey
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Haddad R, Saldanha-Araujo F. Mechanisms of T-cell immunosuppression by mesenchymal stromal cells: what do we know so far? BIOMED RESEARCH INTERNATIONAL 2014; 2014:216806. [PMID: 25025040 PMCID: PMC4082893 DOI: 10.1155/2014/216806] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 05/15/2014] [Accepted: 05/31/2014] [Indexed: 12/12/2022]
Abstract
Mesenchymal stromal cells (MSCs) are multipotent cells, which can give rise to several cell types including osteoblasts, adipocytes, and chondroblasts. These cells can be found in a variety of adult and fetal tissues, such as bone marrow, adipose tissue, cord blood, and placenta. In recent years, the biological properties of MSCs have attracted the attention of researchers worldwide due to their potential application for treating a series of clinical situations. Among these properties, special attention should be given to the immunoregulatory potential of those cells. MSCs are able to act on all cells of the immune system, which includes the capacity to inhibit the proliferation and function of T-cells. This feature renders them natural candidates to treat several diseases in which cellular immune response is exacerbated. In this review, we outline the main mechanisms by which MSCs immunosuppress T-cell response, focusing on cell-cell contact, secretion of soluble factors, and regulatory T-cell generation. The influence of surface markers in the immunosuppression process and features of MSCs isolated from different sources are also discussed. Finally, the influences of toll-like receptors and cytokines on the inflammatory microenvironment are highlighted regarding the activation of MSCs to exert their immunoregulatory function.
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Affiliation(s)
- Rodrigo Haddad
- 1Faculty of Ceilandia, University of Brasilia, 72220-900 Brasilia, DF, Brazil
| | - Felipe Saldanha-Araujo
- 2Faculty of Health Sciences, University of Brasilia, 70910-900 Brasilia, DF, Brazil
- *Felipe Saldanha-Araujo:
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