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Wahba NKO, Bahnasy SSEL, ElMakawi YM, Dummer PMH, Nagendrababu V, Rossi-Fedele G, Sans FA, Pasqualini D, Alovisi M, Turky M, Ahmed EF, Elheeny AAH. Change in the size of apical radiolucencies in adolescent's mature maxillary incisors following retreatment with two regenerative endodontic techniques: a 12-month randomised clinical trial using volume-based cone-beam computed tomography. Clin Oral Investig 2025; 29:283. [PMID: 40319119 PMCID: PMC12049306 DOI: 10.1007/s00784-025-06344-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 04/14/2025] [Indexed: 05/07/2025]
Abstract
OBJECTIVES The primary aim of this randomised clinical trial was to compare the one year clinical and radiographic outcome of mature permanent central incisors with periapical radiolucencies in adolescents after root canal retreatment using two regenerative endodontic procedures (REPs) with revitalization using induced blood clot formation (BC) or platelet-rich fibrin (PRF) evaluated with cone-beam computed tomography (CBCT). The secondary aim was to assess the responses of the teeth to thermal and electric pulp tests. MATERIALS AND METHODS Fifty-four root filled maxillary central incisors with post-treatment endodontic disease and periapical radiolucencies in 48 adolescents were allocated into two groups (n = 27) using permuted block randomisation. The teeth in one group were root canal retreated with induced BC formation and teeth in the other with PRF. At baseline and at one year, teeth were evaluated clinically and radiographically using periapical radiographs and CBCT scans. Changes in the maximum diameter and volume of the periapical lesions were assessed and pulp sensibility was assessed at one year using thermal and electrical tests. Differences in lesion diameter and volume between the two groups were tested using the Mann-Whitney U test. A linear regression model explored the relationship between independent variables and lesion size. The significant level was set at 5%. RESULTS Reduction in periapical lesion size in the BC and PRF techniques occurred in 85% and 100% of teeth, respectively, with no significant difference. In the BC group, the mean lesion volume diminished from 0.33 ± 0.18 cm3 to 0.13 ± 0.20 cm3, while the mean volume of lesions in the PRF group decreased from 0.27 ± 0.16 cm3 to 0.04 ± 0.06 cm3 with no significant difference between the groups (P > 0.05). Significantly more teeth responded positively to thermal (P = 0.028) and electric (P = 0.032) tests in the PRF group compared to the BC group. CONCLUSIONS REPs using BC or PRF techniques when retreating root canal-treated mature permanent central incisors in adolescents with apical radiolucencies had comparable clinical and radiographic outcomes one year following treatment associated with significantly more positive responses to thermal and electric pulp tests in the PRF group. CLINICAL RELEVANCE Retreatment of mature permanent teeth with apical periodontitis using regenerative endodontic procedures (REPs) is a new and promising approach. REPs with platelet-rich fibrin (PRF) and revascularization techniques provided high and comparable clinical and radiographic success rates.
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Affiliation(s)
- Norhan Khaled Omar Wahba
- Demonstrator of Paediatric and Community Dentistry, Faculty of Oral and Dental Medicine, Nahda University, New Bani Suef, Egypt
| | - Sherif Shafik E L Bahnasy
- Lecturer of Oral Radiology, Faculty of Dentistry, The British University in Egypt, Al Shorouk City, Egypt
| | - Yassmin Mohamed ElMakawi
- Lecturer of Paediatric and Community Dentistry, Faculty of Oral and Dental Medicine, Nahda University, New Bani Suef, Egypt
| | - Paul M H Dummer
- School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK
| | - Venkateshbabu Nagendrababu
- Department of Preventive and Restorative Dentistry, College of Dental Medicine, University of Sharjah, Sharjah, UAE
| | | | - Francesc Abella Sans
- Department of Endodontics, School of Dentistry, Universitat International de Catalunya, Sant Cugat del Valles, Barcelona, Spain
| | - Damiano Pasqualini
- Department of Surgical Sciences, Dental School, University of Turin, Turin, Italy
| | - Mario Alovisi
- Department of Surgical Sciences, Dental School, University of Turin, Turin, Italy
| | - Mohammed Turky
- Department of Endodontics, Faculty of Dentistry, Minia University, Minia, Egypt
- Department of Endodontics, Faculty of Dentistry, Sphinx University, Assiut, Egypt
| | - Eman Farouk Ahmed
- Microbiology and Immunology Department, Faculty of Pharmacy, Sohag University, Sohag, 82524, Province, Egypt
| | - Ahmad Abdel Hamid Elheeny
- Paediatric and Community Dentistry, Faculty of Dentistry, Minia University, Province, 61519, Minya, Egypt.
- Paediatric and Community Dentistry, Faculty of Dentistry, Sphinx University, Asyut Al Gadida City, Egypt.
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Iohara K, Nagumo A, Tominaga M, Ziauddin SM, Shibata H. Dental Pulp Regeneration in Dogs Using a Chemokine Receptor 3 Antagonist Without Transplantation of Dental Pulp Stem Cells. J Endod 2025; 51:316-324. [PMID: 39725372 DOI: 10.1016/j.joen.2024.12.010] [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: 09/05/2024] [Revised: 12/16/2024] [Accepted: 12/16/2024] [Indexed: 12/28/2024]
Abstract
INTRODUCTION Our previous study showed that transplantation of dental pulp stem cells in combination with a chemokine receptor 3 (CCR3) antagonist into the root canals of aged dogs promoted dental pulp regeneration. In this study, we attempted to regenerate dental pulp in young dogs using a CCR3 antagonist without dental pulp stem cell transplantation. METHODS The teeth of dogs were histologically evaluated 4 weeks after extraction of the pulp and administration of scaffold materials and CCR3 antagonist (KDH-136) into the root canal. The effects of KDH-136 on the inflammatory response of RAW264.7 cells were investigated in vitro. In addition, we also examined whether KDH-136 affected neurite outgrowth of PC12 cells. RESULTS Application of KDH-136 resulted in the formation of dental pulp-like tissue. Furthermore, nerve and blood vessel regeneration were observed. KDH-136 suppressed chemokine production from RAW264.7 cells and promoted nerve growth factor-stimulated neurite outgrowth of PC12 cells. CONCLUSIONS CCR3 antagonists may be useful for developing novel methods of dental pulp regeneration that do not require transplantation of dental pulp stem cells.
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Affiliation(s)
- Koichiro Iohara
- Section of Regenerative Dental Medicine, National Center for Geriatrics and Gerontology, Research Institute, Obu, Aichi, Japan.
| | - Akiho Nagumo
- Department of Research and Deveropment, Kowa Dental Health Company, Ltd., Tokyo, Japan
| | - Michiyo Tominaga
- Section of Regenerative Dental Medicine, National Center for Geriatrics and Gerontology, Research Institute, Obu, Aichi, Japan
| | - S M Ziauddin
- Section of Regenerative Dental Medicine, National Center for Geriatrics and Gerontology, Research Institute, Obu, Aichi, Japan
| | - Haruki Shibata
- Tokyo New Drug Research Laboratories, Pharmaceutical Business Unit, Kowa Company, Ltd., Tokyo, Japan
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Su W, Liao C, Liu X. Angiogenic and neurogenic potential of dental-derived stem cells for functional pulp regeneration: A narrative review. Int Endod J 2025; 58:391-410. [PMID: 39660369 DOI: 10.1111/iej.14180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 10/26/2024] [Accepted: 11/22/2024] [Indexed: 12/12/2024]
Abstract
BACKGROUND Dental pulp tissue engineering is expected to become an ideal treatment for irreversible pulpitis and apical periodontitis. However, angiogenesis and neurogenesis for functional pulp regeneration have not yet met the standard for large-scale clinical application, and need further research. OBJECTIVE This review focused on the potential mechanisms of angiogenesis and neurogenesis in pulp regeneration, including stem cell types, upstream and downstream regulatory molecules and cascade signalling pathways, thereby providing a theoretical basis and inspiring new ideas to improve the effectiveness of dental pulp tissue engineering. METHODS An electronic literature search was carried out using the keywords of 'pulp regeneration', 'stem cell transplantation', 'dental pulp stem cells', 'angiogenesis' and 'neurogenesis'. The resulting literature was screened and reviewed. RESULTS Stem cells used in dental pulp tissue engineering can be classified as dental-derived and non-dental-derived stem cells, amongst which dental pulp stem cells (DPSC) have achieved promising results in animal experiments and clinical trials. Multiple molecules and signalling pathways are involved in the process of DPSC-mediated angiogenic and neurogenetic regeneration. In order to promote angiogenesis and neurogenesis in pulp regeneration, feasible measures include the addition of growth factors, the modulation of transcription factors and signalling pathways, the use of extracellular vesicles and the modification of bioscaffold materials. CONCLUSION Dental pulp tissue engineering has had breakthroughs in preclinical and clinical studies in vivo. Overcoming difficulties in pulpal angiogenesis and neurogenesis, and achieving functional pulp regeneration will lead to a significant impact in endodontics.
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Affiliation(s)
- Wanting Su
- School of Stomatology, Jinan University, Guangzhou, China
| | - Chufang Liao
- School of Stomatology, Jinan University, Guangzhou, China
- Clinical Research Platform for Interdiscipline of Stomatology, Jinan University, Guangzhou, China
- Hospital of stomatology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xiangning Liu
- School of Stomatology, Jinan University, Guangzhou, China
- Clinical Research Platform for Interdiscipline of Stomatology, Jinan University, Guangzhou, China
- Hospital of stomatology, The First Affiliated Hospital of Jinan University, Guangzhou, China
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Quigley RM, Kearney M, Kennedy OD, Duncan HF. Tissue engineering approaches for dental pulp regeneration: The development of novel bioactive materials using pharmacological epigenetic inhibitors. Bioact Mater 2024; 40:182-211. [PMID: 38966600 PMCID: PMC11223092 DOI: 10.1016/j.bioactmat.2024.06.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 06/05/2024] [Accepted: 06/06/2024] [Indexed: 07/06/2024] Open
Abstract
The drive for minimally invasive endodontic treatment strategies has shifted focus from technically complex and destructive root canal treatments towards more conservative vital pulp treatment. However, novel approaches to maintaining dental pulp vitality after disease or trauma will require the development of innovative, biologically-driven regenerative medicine strategies. For example, cell-homing and cell-based therapies have recently been developed in vitro and trialled in preclinical models to study dental pulp regeneration. These approaches utilise natural and synthetic scaffolds that can deliver a range of bioactive pharmacological epigenetic modulators (HDACis, DNMTis, and ncRNAs), which are cost-effective and easily applied to stimulate pulp tissue regrowth. Unfortunately, many biological factors hinder the clinical development of regenerative therapies, including a lack of blood supply and poor infection control in the necrotic root canal system. Additional challenges include a need for clinically relevant models and manufacturing challenges such as scalability, cost concerns, and regulatory issues. This review will describe the current state of bioactive-biomaterial/scaffold-based engineering strategies to stimulate dentine-pulp regeneration, explicitly focusing on epigenetic modulators and therapeutic pharmacological inhibition. It will highlight the components of dental pulp regenerative approaches, describe their current limitations, and offer suggestions for the effective translation of novel epigenetic-laden bioactive materials for innovative therapeutics.
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Affiliation(s)
- Ross M. Quigley
- Division of Restorative Dentistry & Periodontology, Dublin Dental University Hospital, Trinity College Dublin (TCD), University of Dublin, Lincoln Place, Dublin, Ireland
- Department of Anatomy and Regenerative Medicine, and Tissue Engineering Research Group, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, Ireland
| | - Michaela Kearney
- Division of Restorative Dentistry & Periodontology, Dublin Dental University Hospital, Trinity College Dublin (TCD), University of Dublin, Lincoln Place, Dublin, Ireland
| | - Oran D. Kennedy
- Department of Anatomy and Regenerative Medicine, and Tissue Engineering Research Group, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, Ireland
- The Trinity Centre for Biomedical Engineering (TCBE) and the Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland (RCSI) and Trinity College Dublin (TCD), Dublin, Ireland
| | - Henry F. Duncan
- Division of Restorative Dentistry & Periodontology, Dublin Dental University Hospital, Trinity College Dublin (TCD), University of Dublin, Lincoln Place, Dublin, Ireland
- The Trinity Centre for Biomedical Engineering (TCBE) and the Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland (RCSI) and Trinity College Dublin (TCD), Dublin, Ireland
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Shah P, Aghazadeh M, Rajasingh S, Dixon D, Jain V, Rajasingh J. Stem cells in regenerative dentistry: Current understanding and future directions. J Oral Biosci 2024; 66:288-299. [PMID: 38403241 DOI: 10.1016/j.job.2024.02.006] [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: 02/15/2024] [Accepted: 02/18/2024] [Indexed: 02/27/2024]
Abstract
BACKGROUND Regenerative dentistry aims to enhance the structure and function of oral tissues and organs. Modern tissue engineering harnesses cell and gene-based therapies to advance traditional treatment approaches. Studies have demonstrated the potential of mesenchymal stem cells (MSCs) in regenerative dentistry, with some progressing to clinical trials. This review comprehensively examines animal studies that have utilized MSCs for various therapeutic applications. Additionally, it seeks to bridge the gap between related findings and the practical implementation of MSC therapies, offering insights into the challenges and translational aspects involved in transitioning from preclinical research to clinical applications. HIGHLIGHTS To achieve this objective, we have focused on the protocols and achievements related to pulp-dentin, alveolar bone, and periodontal regeneration using dental-derived MSCs in both animal and clinical studies. Various types of MSCs, including dental-derived cells, bone-marrow stem cells, and umbilical cord stem cells, have been employed in root canals, periodontal defects, socket preservation, and sinus lift procedures. Results of such include significant hard tissue reconstruction, functional pulp regeneration, root elongation, periodontal ligament formation, and cementum deposition. However, cell-based treatments for tooth and periodontium regeneration are still in early stages. The increasing demand for stem cell therapies in personalized medicine underscores the need for scientists and responsible organizations to develop standardized treatment protocols that adhere to good manufacturing practices, ensuring high reproducibility, safety, and cost-efficiency. CONCLUSION Cell therapy in regenerative dentistry represents a growing industry with substantial benefits and unique challenges as it strives to establish sustainable, long-term, and effective oral tissue regeneration solutions.
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Affiliation(s)
- Pooja Shah
- Department of Bioscience Research, College of Dentistry, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Marziyeh Aghazadeh
- Department of Bioscience Research, College of Dentistry, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Sheeja Rajasingh
- Department of Bioscience Research, College of Dentistry, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Douglas Dixon
- Department of Bioscience Research, College of Dentistry, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Periodontology, College of Dentistry, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Vinay Jain
- Department of Prosthodontics, College of Dentistry, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Johnson Rajasingh
- Department of Bioscience Research, College of Dentistry, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Medicine-Cardiology, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA.
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Guo X, Li J, Wu Y, Xu L. Recent advancements in hydrogels as novel tissue engineering scaffolds for dental pulp regeneration. Int J Biol Macromol 2024; 264:130708. [PMID: 38460622 DOI: 10.1016/j.ijbiomac.2024.130708] [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: 12/07/2023] [Revised: 02/22/2024] [Accepted: 03/05/2024] [Indexed: 03/11/2024]
Abstract
Although conventional root canal treatment offers an effective therapeutic solution, it negatively affects the viability of the affected tooth. In recent years, pulp regeneration technology has emerged as a novel method for treating irreversible pulpitis due to its ability to maintain tooth vitality. The successful implementation of this technique depends on scaffolds and transplantation of exogenous stem cells or recruitment of endogenous stem cells. Accordingly, the three-dimensional structure and viscoelastic characteristics of hydrogel scaffolds, which parallel those of the extracellular matrix, have generated considerable interest. Furthermore, hydrogels support the controlled release of regenerative drugs and to load a wide variety of bioactive molecules. By integrating antibacterial agents into the hydrogel matrix and stimulating an immune response, root canal disinfection can be significantly improved and the rate of pulp regeneration can be accelerated. This review aims to provide an overview of the clinical applications of hydrogels that have been reported in the last 5 years, and offer a comprehensive summary of the different approaches that have been utilized for the optimization of hydrogel scaffolds for pulp regeneration. Advancements and challenges in pulp regeneration using hydrogels treating aged teeth are discussed.
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Affiliation(s)
- Xiaofei Guo
- Xiangya Shool of Stomatology, Central South University, Changsha, Hunan, China
| | - Jiaxuan Li
- Xiangya School of Medicine, Central South University, Changsha, Hunan 410083, China
| | - Yong Wu
- Department of Nephrology, The Second Xiangya Hospital, Key Laboratory of Kidney Disease and Blood Purification, Central South University, Changsha, Hunan, China
| | - Laijun Xu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, China; School of Stomatology, Changsha Medical University, Changsha, Hunan 410219, China.
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Montenegro Raudales JL, Okuwa Y, Honda M. Dental Pulp Cell Transplantation Combined with Regenerative Endodontic Procedures Promotes Dentin Matrix Formation in Mature Mouse Molars. Cells 2024; 13:348. [PMID: 38391961 PMCID: PMC10886544 DOI: 10.3390/cells13040348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/06/2024] [Accepted: 02/11/2024] [Indexed: 02/24/2024] Open
Abstract
Regenerative endodontic procedures (REPs) are promising for dental pulp tissue regeneration; however, their application in permanent teeth remains challenging. We assessed the potential combination of an REP and local dental pulp cell (DPC) transplantation in the mature molars of C57BL/6 mice with (REP + DPC group) or without (REP group) transplantation of DPCs from green fluorescent protein (GFP) transgenic mice. After 4 weeks, the regenerated tissue was evaluated by micro-computed tomography and histological analyses to detect odontoblasts, vasculogenesis, and neurogenesis. DPCs were assessed for mesenchymal and pluripotency markers. Four weeks after the REP, the molars showed no signs of periapical lesions, and both the REP and REP + DPC groups exhibited a pulp-like tissue composed of a cellular matrix with vessels surrounded by an eosin-stained acellular matrix that resembled hard tissue. However, the REP + DPC group had a broader cellular matrix and uniquely contained odontoblast-like cells co-expressing GFP. Vasculogenesis and neurogenesis were detected in both groups, with the former being more prominent in the REP + DPC group. Overall, the REP was achieved in mature mouse molars and DPC transplantation improved the outcomes by inducing the formation of odontoblast-like cells and greater vasculogenesis.
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Affiliation(s)
- Jorge Luis Montenegro Raudales
- Department of Oral Anatomy, School of Dentistry, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Aichi, Japan; (Y.O.); (M.H.)
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Duncan HF, Kobayashi Y, Kearney M, Shimizu E. Epigenetic therapeutics in dental pulp treatment: Hopes, challenges and concerns for the development of next-generation biomaterials. Bioact Mater 2023; 27:574-593. [PMID: 37213443 PMCID: PMC10199232 DOI: 10.1016/j.bioactmat.2023.04.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/11/2023] [Accepted: 04/11/2023] [Indexed: 05/23/2023] Open
Abstract
This opinion-led review paper highlights the need for novel translational research in vital-pulp-treatment (VPT), but also discusses the challenges in translating evidence to clinics. Traditional dentistry is expensive, invasive and relies on an outmoded mechanical understanding of dental disease, rather than employing a biological perspective that harnesses cell activity and the regenerative-capacity. Recent research has focussed on developing minimally-invasive biologically-based 'fillings' that preserve the dental pulp; research that is shifting the paradigm from expensive high-technology dentistry, with high failure rates, to smart restorations targeted at biological processes. Current VPTs promote repair by recruiting odontoblast-like cells in a material-dependent process. Therefore, exciting opportunities exist for development of next-generation biomaterials targeted at regenerative processes in the dentin-pulp complex. This article analyses recent research using pharmacological-inhibitors to therapeutically-target histone-deacetylase (HDAC) enzymes in dental-pulp-cells (DPCs) that stimulate pro-regenerative effects with limited loss of viability. Consequently, HDAC-inhibitors have the potential to enhance biomaterial-driven tissue responses at low concentration by influencing the cellular processes with minimal side-effects, providing an opportunity to develop a topically-placed, inexpensive bio-inductive pulp-capping material. Despite positive results, clinical translation of these innovations requires enterprise to counteract regulatory obstacles, dental-industry priorities and to develop strong academic/industry partnerships. The aim of this opinion-led review paper is to discuss the potential role of therapeutically-targeting epigenetic modifications as part of a topical VPT strategy in the treatment of the damaged dental pulp, while considering the next steps, material considerations, challenges and future for the clinical development of epigenetic therapeutics or other 'smart' restorations in VPT.
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Affiliation(s)
- Henry F. Duncan
- Division of Restorative Dentistry & Periodontology, Dublin Dental University Hospital, Trinity College Dublin, University of Dublin, Lincoln Place, Dublin, Ireland
| | - Yoshifumi Kobayashi
- Department of Oral Biology, Rutgers School of Dental Medicine, Newark, NJ, USA
| | - Michaela Kearney
- Division of Restorative Dentistry & Periodontology, Dublin Dental University Hospital, Trinity College Dublin, University of Dublin, Lincoln Place, Dublin, Ireland
| | - Emi Shimizu
- Department of Oral Biology, Rutgers School of Dental Medicine, Newark, NJ, USA
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Hanson-Drury S, Patni AP, Lee DL, Alghadeer A, Zhao YT, Ehnes DD, Vo VN, Kim SY, Jithendra D, Phal A, Edman NI, Schlichthaerle T, Baker D, Young JE, Mathieu J, Ruohola-Baker H. Single Cell RNA Sequencing Reveals Human Tooth Type Identity and Guides In Vitro hiPSC Derived Odontoblast Differentiation (iOB). FRONTIERS IN DENTAL MEDICINE 2023; 4:1209503. [PMID: 38259324 PMCID: PMC10802932 DOI: 10.3389/fdmed.2023.1209503] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 05/29/2023] [Indexed: 01/24/2024] Open
Abstract
Over 90% of the U.S. adult population suffers from tooth structure loss due to caries. Most of the mineralized tooth structure is composed of dentin, a material produced and mineralized by ectomesenchyme derived cells known as odontoblasts. Clinicians, scientists, and the general public share the desire to regenerate this missing tooth structure. To bioengineer missing dentin, increased understanding of human tooth development is required. Here we interrogate at the single cell level the signaling interactions that guide human odontoblast and ameloblast development and which determine incisor or molar tooth germ type identity. During human odontoblast development, computational analysis predicts that early FGF and BMP activation followed by later HH signaling is crucial. Application of this sci-RNA-seq analysis generates a differentiation protocol to produce mature hiPSC derived odontoblasts in vitro (iOB). Further, we elucidate the critical role of FGF signaling in odontoblast maturation and its biomineralization capacity using the de novo designed FGFR1/2c isoform specific minibinder scaffolded as a C6 oligomer that acts as a pathway agonist. We find that FGFR1c is upregulated in functional odontoblasts and specifically plays a crucial role in driving odontoblast maturity. Using computational tools, we show on a molecular level how human molar development is delayed compared to incisors. We reveal that enamel knot development is guided by FGF and WNT in incisors and BMP and ROBO in the molars, and that incisor and molar ameloblast development is guided by FGF, EGF and BMP signaling, with tooth type specific intensity of signaling interactions. Dental ectomesenchyme derived cells are the primary source of signaling ligands responsible for both enamel knot and ameloblast development.
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Affiliation(s)
- Sesha Hanson-Drury
- Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, United States
- Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA, United States
| | - Anjali P. Patni
- Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, United States
- Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA, United States
- Department of Genetic Engineering, SRM Institute of Science and Technology, Chennai, India
| | - Deborah L. Lee
- Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, United States
- Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA, United States
| | - Ammar Alghadeer
- Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, United States
- Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA, United States
- Department of Biomedical Dental Sciences, College of Dentistry, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia
| | - Yan Ting Zhao
- Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, United States
- Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA, United States
| | - Devon Duron Ehnes
- Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, United States
- Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA, United States
| | - Vivian N. Vo
- Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA, United States
- Department of Biology, University of Washington, Seattle, WA, United States
| | - Sydney Y. Kim
- Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA, United States
| | - Druthi Jithendra
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA, United States
- Department of Biotechnology, SRM Institute of Science and Technology, Chennai, India
| | - Ashish Phal
- Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA, United States
- Department of Bioengineering, University of Washington, Seattle, WA, United States
| | - Natasha I. Edman
- Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA, United States
- Institute for Protein Design, University of Washington, Seattle, WA, United States
- Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, United States
- Medical Scientist Training Program, University of Washington, Seattle, WA, United States
| | - Thomas Schlichthaerle
- Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA, United States
- Institute for Protein Design, University of Washington, Seattle, WA, United States
| | - David Baker
- Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA, United States
- Institute for Protein Design, University of Washington, Seattle, WA, United States
| | - Jessica E. Young
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA, United States
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States
| | - Julie Mathieu
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA, United States
- Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, WA, United States
| | - Hannele Ruohola-Baker
- Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, United States
- Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA, United States
- Department of Biology, University of Washington, Seattle, WA, United States
- Department of Bioengineering, University of Washington, Seattle, WA, United States
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Piglionico SS, Pons C, Romieu O, Cuisinier F, Levallois B, Panayotov IV. In vitro, ex vivo, and in vivo models for dental pulp regeneration. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2023; 34:15. [PMID: 37004591 PMCID: PMC10067643 DOI: 10.1007/s10856-023-06718-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 03/13/2023] [Indexed: 05/03/2023]
Abstract
Based on the concept of tissue engineering (Cells-Scaffold-Bioactive molecules), regenerative endodontics appeared as a new notion for dental endodontic treatment. Its approaches aim to preserve dental pulp vitality (pulp capping) or to regenerate a vascularized pulp-like tissue inside necrotic root canals by cell homing. To improve the methods of tissue engineering for pulp regeneration, numerous studies using in vitro, ex vivo, and in vivo models have been performed. This review explores the evolution of laboratory models used in such studies and classifies them according to different criteria. It starts from the initial two-dimensional in vitro models that allowed characterization of stem cell behavior, through 3D culture matrices combined with dental tissue and finally arrives at the more challenging ex vivo and in vivo models. The travel which follows the elaboration of such models reveals the difficulty in establishing reproducible laboratory models for dental pulp regeneration. The development of well-established protocols and new laboratory ex vivo and in vivo models in the field of pulp regeneration would lead to consistent results, reduction of animal experimentation, and facilitation of the translation to clinical practice.
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Affiliation(s)
- Sofia Silvia Piglionico
- LBN, Univ. Montpellier, Montpellier, France.
- Centro de Investigaciones Odontológicas, National University of Cuyo, Mendoza, Argentina.
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11
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Queiroz A, Pelissari C, Paris AFC, Rodrigues MFSD, Trierveiler M. Periodontal ligament cells mobilized by transforming growth factor-beta 1 and migrated without stimuli showed enhanced osteogenic differentiation. Arch Oral Biol 2023; 147:105636. [PMID: 36738489 DOI: 10.1016/j.archoralbio.2023.105636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 12/29/2022] [Accepted: 01/29/2023] [Indexed: 02/03/2023]
Abstract
OBJECTIVE This study aimed to analyze the ability of G-CSF and TGF-β1 to mobilize periodontal ligament stem cells to obtain populations with better potential for proliferation and osteogenic differentiation. DESIGN Primary cultures were established from the periodontal ligament of Wistar rats. After a cell migration assay, four experimental groups were obtained: PDLSC, composed of the primary culture, non-mobilized cells; MPDLSC, the spontaneously migrated cells; MPDLSC-GCSF, the cells mobilized with G-CSF; and MPDLSC-TGF-β1, the cells mobilized with TGF-β1. The expression of mesenchymal stem cell markers was assessed by flow cytometry. Clonogenicity, viability, proliferative potential, and osteogenic differentiation capacity were also analyzed. RESULTS All the study groups expressed well-known mesenchymal stem cell markers and exhibited clonogenic capacity. The higher proliferation potential was seen in the PDLSC and MPDLSC groups, while the MPDLSC and MPDLSC-TGFβ1 groups showed a higher number of mineralized deposits in vitro and higher ALP activity after osteogenic differentiation induction. Cells of all the groups also expressed mRNA of genes associated with osteogenic differentiation without previous induction. CONCLUSIONS Both agents were able to mobilize stem cells from the periodontal ligament, but G-CSF did not show an advantage, whereas TGF-β1 appears to direct the cells towards a state of increased osteogenic differentiation. Furthermore, spontaneous cell migration through a membrane was sufficient to enrich the cell population.
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Affiliation(s)
- Aline Queiroz
- Laboratory of Stem Cell Biology in Dentistry - LABITRON, Oral and Maxillofacial Pathology Division, School of Dentistry, University of São Paulo, São Paulo, SP, Brazil.
| | - Cibele Pelissari
- Laboratory of Stem Cell Biology in Dentistry - LABITRON, Oral and Maxillofacial Pathology Division, School of Dentistry, University of São Paulo, São Paulo, SP, Brazil.
| | - Adriana Fraga Costa Paris
- Laboratory of Stem Cell Biology in Dentistry - LABITRON, Oral and Maxillofacial Pathology Division, School of Dentistry, University of São Paulo, São Paulo, SP, Brazil.
| | | | - Marília Trierveiler
- Laboratory of Stem Cell Biology in Dentistry - LABITRON, Oral and Maxillofacial Pathology Division, School of Dentistry, University of São Paulo, São Paulo, SP, Brazil.
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12
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Ngai P, Lee AHC, Xu J, Chang JWW, Liu J, Hu M, Sun Z, Neelakantan P, Li X, Zhang C. Effects of L-Chg 10-Teixobactin on Viability, Proliferation, and Osteo/Odontogenic Differentiation of Stem Cells from Apical Papilla. J Endod 2023; 49:162-168. [PMID: 36592717 DOI: 10.1016/j.joen.2022.11.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 11/04/2022] [Accepted: 11/09/2022] [Indexed: 01/01/2023]
Abstract
INTRODUCTION Intracanal medicament is one of the essential steps for ensuring success in regenerative endodontic procedures. L-Chg10-teixobactin is a novel antimicrobial agent that exhibited potent antibacterial and antibiofilm effects against Enterococcusfaecalis at low concentrations compared with ampicillin. At the same time, its cytotoxicity on dental stem cells has not been studied. This study aimed to investigate the effects of L-Chg10-teixobactin on the viability, proliferation, migration, and osteo/odontogenic differentiation of stem cells from apical papilla (SCAPs). MATERIALS AND METHODS SCAPs isolated from immature human third molars were treated with various concentrations of L-Chg10-teixobactin, calcium hydroxide, and dimethyl sulfoxide. The viability and proliferation of SCAPs were assessed using the LIVE/DEAD Viability/Cytotoxicity Kit and Cell Counting Kit-8. A scratch wound healing test was used to evaluate the lateral migration capacity of SCAPs. Alkaline phosphatase (ALP) activity, calcium mineralization ability tests -ie, ALP staining and alizarin red S staining, and quantitative real-time polymerase chain reaction were performed to assess the osteo /odontogenic differentiation of SCAPs. RESULTS The tested concentrations of L-Chg10-teixobactin (0.01, 0.02, and 0.03 mg/mL), 1 mg/mL calcium hydroxide, and 0.03% dimethyl sulfoxide had no significant cytotoxic effect on SCAPs at any time point (P > .05). Besides, there were no significant differences between the control and experimental groups in SCAPs' viability, proliferation, and migration. L-Chg10-teixobactin upregulated the gene expression of osteo/odontogenic markers in SCAPs, while no significant difference was found in the ALP activity and alizarin red S staining. CONCLUSIONS L-Chg10-teixobactin demonstrated excellent biocompatibility on SCAPs at concentrations from 0.01 to 0.03 mg/mL and potentially enhance the osteo/odontogenic differentiation of SCAPs; suggesting its promising role as root canal medicament for regenerative endodontic procedures.
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Affiliation(s)
- Ping Ngai
- Restorative Dental Sciences, Endodontics, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR, P. R. China
| | - Angeline Hui Cheng Lee
- Restorative Dental Sciences, Endodontics, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR, P. R. China
| | - Jian Xu
- Department of Dentistry, Longgang ENT Hospital, Shenzhen Longgang Institute of Stomatology, Shenzhen, P. R. China
| | - Jeffrey Wen Wei Chang
- Restorative Dental Sciences, Endodontics, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR, P. R. China
| | - Junqing Liu
- Restorative Dental Sciences, Endodontics, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR, P. R. China
| | - Mingxin Hu
- Restorative Dental Sciences, Endodontics, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR, P. R. China
| | - Zhenquan Sun
- Department of Chemistry, State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong, SAR, P. R. China
| | - Prasanna Neelakantan
- Restorative Dental Sciences, Endodontics, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR, P. R. China
| | - Xuechen Li
- Department of Chemistry, State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong, SAR, P. R. China.
| | - Chengfei Zhang
- Restorative Dental Sciences, Endodontics, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR, P. R. China.
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13
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Liu G, Li X, Yang F, Qi J, Shang L, Zhang H, Li S, Xu F, Li L, Yu H, Li Y, Dong X, Song Q, Zhu F, Chen G, Cao C, Jiang L, Su J, Yang L, Xu X, Zhang Z, Zhao RC, Li B. C-Phycocyanin Ameliorates the Senescence of Mesenchymal Stem Cells through ZDHHC5-Mediated Autophagy via PI3K/AKT/mTOR Pathway. Aging Dis 2023:AD.2023.0121. [PMID: 37163424 PMCID: PMC10389819 DOI: 10.14336/ad.2023.0121] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 01/15/2023] [Indexed: 05/12/2023] Open
Abstract
The senescence of mesenchymal stem cells (MSCs) impairs their regenerative capacity to maintain tissue homeostasis. Numerous studies are focusing on the interventions and mechanisms to attenuate the senescence of MSCs. C-phycocyanin (C-PC) is reported to have multiple functions such as antitumor, antioxidation, anti-inflammation and anti-aging roles, but there is little research about the effects of C-PC on the senescence of MSCs. Here we investigated the roles and mechanism of C-PC on MSCs senescence. In vitro results showed that C-PC could reduce senescence, enhance proliferation, promote the adipogenic and osteogenic differentiation in senescent MSCs induced by oxidative stress. In vivo D-Galactose (D-Gal) induced rats aging models showed C-PC also increased the viability and differentiation of intrinsic senescent bone marrow derived MSCs (BMSCs). Furthermore, C-PC also decreased the levels of oxidative stress markers ROS or MDA, elevated the SOD activity, and increased the anti-inflammatory factors. Proteomic chip analysis showed that C-PC interacted with ZDHHC5, and their interaction was verified by pull down assay. Overexpression of ZDHHC5 aggravated the senescence of MSCs and greatly lessened the beneficial effects of C-PC on senescence. In addition, we found ZDHHC5 regulated autophagy by altering LC3, Beclin1 and PI3K/AKT/mTOR pathway. In summary, our data indicated that C-PC ameliorates the senescence of MSCs through zinc finger Asp-His-His-Cys (DHHC) domain-containing protein 5 (ZDHHC5) mediated autophagy via PI3K/AKT/mTOR pathway. The present study uncovered the key role of autophagy in MSCs senescence and PI3K/AKT/mTOR pathway may be a potential target for anti-senescence studies of MSCs.
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Affiliation(s)
- Guoxiang Liu
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Xiaoxia Li
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Fanghao Yang
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Jingyu Qi
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Lipeng Shang
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Huhu Zhang
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Shuang Li
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Fenghua Xu
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Lingne Li
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Huaxin Yu
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Yang Li
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Xiaolei Dong
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Qinghang Song
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Feng Zhu
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Guang Chen
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Can Cao
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Liangqian Jiang
- Department of Medical Genetics, Linyi People's Hospital, Linyi, China
| | - Junzhe Su
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Lina Yang
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Xiaohui Xu
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Zhe Zhang
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Robert Chunhua Zhao
- College of Basic Medicine, Institute of Stem Cell and Regenerative Medicine, Qingdao University, Qingdao, China
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Bing Li
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
- Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Potent bystander effect and tumor tropism in suicide gene therapy using stem cells from human exfoliated deciduous teeth. Cancer Gene Ther 2023; 30:85-95. [PMID: 36076062 DOI: 10.1038/s41417-022-00527-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 08/01/2022] [Accepted: 08/24/2022] [Indexed: 01/20/2023]
Abstract
Herpes simplex virus thymidine kinase (HSVTK)/ganciclovir (GCV) suicide gene therapy has a long history of treating malignant gliomas. Recently, stem cells from human exfoliated deciduous teeth (SHED), which are collected from deciduous teeth and have excellent harvestability, ethical aspects, and self-renewal, have been attracting attention mainly in the field of gene therapy. In the present study, we assessed SHED as a novel cellular vehicle for suicide gene therapy in malignant gliomas, as we have previously demonstrated with various cell types. SHED was transduced with the HSVTK gene (SHEDTK). In vitro experiments showed a significant bystander effect between SHEDTK and glioma cell lines in coculture. Furthermore, apoptotic changes caused by caspase 3/7 activation were simultaneously observed in SHEDTK and glioma cells. Mice implanted with a mixture of U87 and SHEDTK and treated with intraperitoneal GCV survived for longer than 100 days. Additionally, tumors in treatment model mice were significantly reduced in size during the treatment period. SHEDTK implanted at the contralateral hemisphere migrated toward the tumor crossing the corpus callosum. These results suggested that SHEDTK-based suicide gene therapy has potent tumor tropism and a bystander-killing effect, potentially offering a new promising therapeutic modality for malignant gliomas.
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15
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Towards a New Concept of Regenerative Endodontics Based on Mesenchymal Stem Cell-Derived Secretomes Products. BIOENGINEERING (BASEL, SWITZERLAND) 2022; 10:bioengineering10010004. [PMID: 36671576 PMCID: PMC9854964 DOI: 10.3390/bioengineering10010004] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/09/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022]
Abstract
The teeth, made up of hard and soft tissues, represent complex functioning structures of the oral cavity, which are frequently affected by processes that cause structural damage that can lead to their loss. Currently, replacement therapy such as endodontics or implants, restore structural defects but do not perform any biological function, such as restoring blood and nerve supplies. In the search for alternatives to regenerate the dental pulp, two alternative regenerative endodontic procedures (REP) have been proposed: (I) cell-free REP (based in revascularization and homing induction to remaining dental pulp stem cells (DPSC) and even stem cells from apical papilla (SCAP) and (II) cell-based REP (with exogenous cell transplantation). Regarding the last topic, we show several limitations with these procedures and therefore, we propose a novel regenerative approach in order to revitalize the pulp and thus restore homeostatic functions to the dentin-pulp complex. Due to their multifactorial biological effects, the use of mesenchymal stem cells (MSC)-derived secretome from non-dental sources could be considered as inducers of DPSC and SCAP to completely regenerate the dental pulp. In partial pulp damage, appropriate stimulate DPSC by MSC-derived secretome could contribute to formation and also to restore the vasculature and nerves of the dental pulp.
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16
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Neural Regeneration in Regenerative Endodontic Treatment: An Overview and Current Trends. Int J Mol Sci 2022; 23:ijms232415492. [PMID: 36555133 PMCID: PMC9779866 DOI: 10.3390/ijms232415492] [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: 10/28/2022] [Revised: 11/24/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
Pulpal and periapical diseases are the most common dental diseases. The traditional treatment is root canal therapy, which achieves satisfactory therapeutic outcomes-especially for mature permanent teeth. Apexification, pulpotomy, and pulp revascularization are common techniques used for immature permanent teeth to accelerate the development of the root. However, there are obstacles to achieving functional pulp regeneration. Recently, two methods have been proposed based on tissue engineering: stem cell transplantation, and cell homing. One of the goals of functional pulp regeneration is to achieve innervation. Nerves play a vital role in dentin formation, nutrition, sensation, and defense in the pulp. Successful neural regeneration faces tough challenges in both animal studies and clinical trials. Investigation of the regeneration and repair of the nerves in the pulp has become a serious undertaking. In this review, we summarize the current understanding of the key stem cells, signaling molecules, and biomaterials that could promote neural regeneration as part of pulp regeneration. We also discuss the challenges in preclinical or clinical neural regeneration applications to guide deep research in the future.
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17
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Sugiaman VK, Djuanda R, Pranata N, Naliani S, Demolsky WL. Tissue Engineering with Stem Cell from Human Exfoliated Deciduous Teeth (SHED) and Collagen Matrix, Regulated by Growth Factor in Regenerating the Dental Pulp. Polymers (Basel) 2022; 14:polym14183712. [PMID: 36145860 PMCID: PMC9503223 DOI: 10.3390/polym14183712] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 08/25/2022] [Accepted: 09/02/2022] [Indexed: 11/16/2022] Open
Abstract
Maintaining dental pulp vitality and preventing tooth loss are two challenges in endodontic treatment. A tooth lacking a viable pulp loses its defense mechanism and regenerative ability, making it more vulnerable to severe damage and eventually necessitating extraction. The tissue engineering approach has drawn attention as an alternative therapy as it can regenerate dentin-pulp complex structures and functions. Stem cells or progenitor cells, extracellular matrix, and signaling molecules are triad components of this approach. Stem cells from human exfoliated deciduous teeth (SHED) are a promising, noninvasive source of stem cells for tissue regeneration. Not only can SHEDs regenerate dentin-pulp tissues (comprised of fibroblasts, odontoblasts, endothelial cells, and nerve cells), but SHEDs also possess immunomodulatory and immunosuppressive properties. The collagen matrix is a material of choice to provide structural and microenvironmental support for SHED-to-dentin pulp tissue differentiation. Growth factors regulate cell proliferation, migration, and differentiation into specific phenotypes via signal-transduction pathways. This review provides current concepts and applications of the tissue engineering approach, especially SHEDs, in endodontic treatment.
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Affiliation(s)
- Vinna K Sugiaman
- Department of Oral Biology, Faculty of Dentistry, Maranatha Christian University, Bandung 40164, Indonesia
| | - Rudy Djuanda
- Department of Conservative Dentistry and Endodontic, Faculty of Dentistry, Maranatha Christian University, Bandung 40164, Indonesia
| | - Natallia Pranata
- Department of Oral Biology, Faculty of Dentistry, Maranatha Christian University, Bandung 40164, Indonesia
| | - Silvia Naliani
- Department of Prosthodontics, Faculty of Dentistry, Maranatha Christian University, Bandung 40164, Indonesia
| | - Wayan L Demolsky
- Department of Oral Biology, Faculty of Dentistry, Maranatha Christian University, Bandung 40164, Indonesia
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18
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Zeng Q, Zhang J, Guo J, Liu S, Yang M, Lin J. Preoperative factors analysis on root development after regenerative endodontic procedures: a retrospective study. BMC Oral Health 2022; 22:374. [PMID: 36058906 PMCID: PMC9442966 DOI: 10.1186/s12903-022-02412-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/26/2022] [Indexed: 12/22/2022] Open
Abstract
Background Regenerative endodontic procedures (REPs) have achieved clinical success on the immature permanent teeth with pulp necrosis, and can promote root development. However, preoperative factors and their effects on root development of REPs have not been definitely concluded. The aim of this study was to investigate the preoperative factors that may influence the root development of REPs. Methods A total of 116 teeth in 110 patients treated with REPs in the Paediatric Dentistry Department and Endodontics Department from 2013 to 2017 were included in this study. Preoperative factors including aetiology, age, diagnosis and initial root morphology were collected retrospectively, and the associations between these factors and root development after REPs were analysed by Fisher's exact test and multivariate logistic regression model. Results The overall rate of root development after REPs was 89.7%. The dens evaginatus group showed a higher rate (98.8%) in root development than the trauma group (67.6%) (P < 0.01). There was no significant difference among the different age groups (7–13 years old) or among different diagnoses groups (P > 0.05). And it showed in the trauma group that the teeth with apical foramen sizes larger than 3 mm significantly promoted root development than those smaller than 3 mm (P < 0.01). Multivariate logistic regression indicated that aetiology was significantly correlated with root development of REPs (OR: 0.07, 95% CI 0.007, 0.627, P < 0.05). Conclusions The REPs promoted more root developments in the dens evaginatus group than the trauma group, indicating that aetiology may be correlated with the root development of REPs. Supplementary Information The online version contains supplementary material available at 10.1186/s12903-022-02412-x.
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Affiliation(s)
- Qian Zeng
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
| | - Jianying Zhang
- Xiangya Stomatological Hospital, Xiangya School of Stomatology, Central South University, Hunan Key Laboratory of Oral Health Research, Changsha, Hunan, China
| | - Jiang Guo
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
| | - Shuya Liu
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
| | - Maobin Yang
- Department of Endodontology, Kornberg School of Dentistry, Temple University, Philadelphia, PA, USA.
| | - Jiacheng Lin
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China.
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Dave JR, Chandekar SS, Behera S, Desai KU, Salve PM, Sapkal NB, Mhaske ST, Dewle AM, Pokare PS, Page M, Jog A, Chivte PA, Srivastava RK, Tomar GB. Human gingival mesenchymal stem cells retain their growth and immunomodulatory characteristics independent of donor age. SCIENCE ADVANCES 2022; 8:eabm6504. [PMID: 35749495 PMCID: PMC9232118 DOI: 10.1126/sciadv.abm6504] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 05/06/2022] [Indexed: 05/28/2023]
Abstract
Aging has been reported to deteriorate the quantity and quality of mesenchymal stem cells (MSCs), which affect their therapeutic use in regenerative medicine. A dearth of age-related stem cell research further restricts their clinical applications. The present study explores the possibility of using MSCs derived from human gingival tissues (GMSCs) for studying their ex vivo growth characteristics and differentiation potential with respect to donor age. GMSCs displayed decreased in vitro adipogenesis and in vitro and in vivo osteogenesis with age, but in vitro neurogenesis remained unaffected. An increased expression of p53 and SIRT1 with donor age was correlated to their ability of eliminating tumorigenic events through apoptosis or autophagy, respectively. Irrespective of donor age, GMSCs displayed effective immunoregulation and regenerative potential in a mouse model of LPS-induced acute lung injury. Thus, we suggest the potential of GMSCs for designing cell-based immunomodulatory therapeutic approaches and their further extrapolation for acute inflammatory conditions such as acute respiratory distress syndrome and COVID-19.
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Affiliation(s)
- Jay R. Dave
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Sayali S. Chandekar
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Shubhanath Behera
- National Centre for Cell Science, Savitribai Phule Pune University Campus, Pune, 411007 Maharashtra, India
| | - Kaushik U. Desai
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Pradnya M. Salve
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Neha B. Sapkal
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Suhas T. Mhaske
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Ankush M. Dewle
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Parag S. Pokare
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Megha Page
- Department of Dentistry, Deenanath Mangeshkar Hospital and Research Centre, Pune, 411004 Maharashtra, India
| | - Ajay Jog
- Department of Dentistry, Deenanath Mangeshkar Hospital and Research Centre, Pune, 411004 Maharashtra, India
| | - Pankaj A. Chivte
- Saraswati Danwantri Dental College and Hospital, Parbhani, 431401 Maharashtra, India
| | - Rupesh K. Srivastava
- Department of Biotechnology, All India Institute of Medical Science, New Delhi 110029, India
| | - Geetanjali B. Tomar
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
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Chouaib B, Cuisinier F, Collart-Dutilleul PY. Dental stem cell-conditioned medium for tissue regeneration: Optimization of production and storage. World J Stem Cells 2022; 14:287-302. [PMID: 35662860 PMCID: PMC9136565 DOI: 10.4252/wjsc.v14.i4.287] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 05/19/2021] [Accepted: 04/21/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSC) effects on tissue regeneration are mainly mediated by their secreted substances (secretome), inducing their paracrine activity. This Conditioned medium (CM), including soluble factors (proteins, nucleic acids, lipids) and extracellular vesicles is emerging as a potential alternative to cell therapy. However, the manufacturing of CM suffers from variable procedures and protocols leading to varying results between studies. Besides, there is no well-defined optimized procedure targeting specific applications in regenerative medicine. AIM To focus on conditioned medium produced from dental MSC (DMSC-CM), we reviewed the current parameters and manufacturing protocols, in order to propose a standardization and optimization of these manufacturing procedures. METHODS We have selected all publications investigating the effects of dental MSC secretome in in vitro and in vivo models of tissue regeneration, in accordance with the PRISMA guidelines. RESULTS A total of 351 results were identified. And based on the inclusion criteria described above, 118 unique articles were included in the systematic review. DMSC-CM production was considered at three stages: before CM recovery (cell sources for CM), during CM production (culture conditions) and after production (CM treatment). CONCLUSION No clear consensus could be recovered as evidence-based methods, but we were able to describe the most commonly used protocols: donors under 30 years of age, dental pulp stem cells and exfoliated deciduous tooth stem cells with cell passage between 1 and 5, at a confluence of 70% to 80%. CM were often collected during 48 h, and stored at -80 °C. It is important to point out that the preconditioning environment had a significant impact on DMSC-CM content and efficiency.
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Affiliation(s)
- Batoul Chouaib
- Laboratory Bioengineering and Nanosciences UR_UM104, University of Montpellier, Montpellier 34000, France
| | - Frédéric Cuisinier
- Laboratory Bioengineering and Nanosciences UR_UM104, University of Montpellier, Montpellier 34000, France
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21
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Vu HT, Han MR, Lee JH, Kim JS, Shin JS, Yoon JY, Park JH, Dashnyam K, Knowles JC, Lee HH, Kim JB, Lee JH. Investigating the Effects of Conditioned Media from Stem Cells of Human Exfoliated Deciduous Teeth on Dental Pulp Stem Cells. Biomedicines 2022; 10:biomedicines10040906. [PMID: 35453661 PMCID: PMC9027398 DOI: 10.3390/biomedicines10040906] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/07/2022] [Accepted: 04/08/2022] [Indexed: 12/24/2022] Open
Abstract
Pulp regeneration has recently attracted interest in modern dentistry. However, the success ratio of pulp regeneration is low due to the compromising potential of stem cells, such as their survival, migration, and odontoblastic differentiation. Stem cells from human exfoliated deciduous teeth (SHED) have been considered a promising tool for regenerative therapy due to their ability to secrete multiple factors that are essential for tissue regeneration, which is achieved by minimally invasive procedures with fewer ethical or legal concerns than those of other procedures. The aim of this study is to investigate the potency of SHED-derived conditioned media (SHED CM) on dental pulp stem cells (DPSCs), a major type of mesenchymal stem cells for dental pulp regeneration. Our results show the promotive efficiency of SHED CM on the proliferation, survival rate, and migration of DPSCs in a dose-dependent manner. Upregulation of odontoblast/osteogenic-related marker genes, such as ALP, DSPP, DMP1, OCN, and RUNX2, and enhanced mineral deposition of impaired DPSCs are also observed in the presence of SHED CM. The analysis of SHED CM found that a variety of cytokines and growth factors have positive effects on cell proliferation, migration, anti-apoptosis, and odontoblast/osteogenic differentiation. These findings suggest that SHED CM could provide some benefits to DPSCs in pulp regeneration.
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Affiliation(s)
- Huong Thu Vu
- Department of Pediatric Dentistry, College of Dentistry, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea; (H.T.V.); (M.-R.H.); (J.-H.L.); (J.-S.K.); (J.-S.S.)
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, 119 Dandae-ro, Cheonan 31116, Korea; (J.-Y.Y.); (J.-H.P.); (K.D.); (J.C.K.); (H.-H.L.)
| | - Mi-Ran Han
- Department of Pediatric Dentistry, College of Dentistry, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea; (H.T.V.); (M.-R.H.); (J.-H.L.); (J.-S.K.); (J.-S.S.)
| | - Jun-Haeng Lee
- Department of Pediatric Dentistry, College of Dentistry, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea; (H.T.V.); (M.-R.H.); (J.-H.L.); (J.-S.K.); (J.-S.S.)
| | - Jong-Soo Kim
- Department of Pediatric Dentistry, College of Dentistry, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea; (H.T.V.); (M.-R.H.); (J.-H.L.); (J.-S.K.); (J.-S.S.)
| | - Ji-Sun Shin
- Department of Pediatric Dentistry, College of Dentistry, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea; (H.T.V.); (M.-R.H.); (J.-H.L.); (J.-S.K.); (J.-S.S.)
| | - Ji-Young Yoon
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, 119 Dandae-ro, Cheonan 31116, Korea; (J.-Y.Y.); (J.-H.P.); (K.D.); (J.C.K.); (H.-H.L.)
- Department of Biomaterials science, College of Dentistry, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea
| | - Jeong-Hui Park
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, 119 Dandae-ro, Cheonan 31116, Korea; (J.-Y.Y.); (J.-H.P.); (K.D.); (J.C.K.); (H.-H.L.)
- Department of Biomaterials science, College of Dentistry, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea
| | - Khandmaa Dashnyam
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, 119 Dandae-ro, Cheonan 31116, Korea; (J.-Y.Y.); (J.-H.P.); (K.D.); (J.C.K.); (H.-H.L.)
- Department of Biomaterials science, College of Dentistry, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea
- Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea
| | - Jonathan Campbell Knowles
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, 119 Dandae-ro, Cheonan 31116, Korea; (J.-Y.Y.); (J.-H.P.); (K.D.); (J.C.K.); (H.-H.L.)
- Department of Biomaterials science, College of Dentistry, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea
- UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea
- Mechanobiology Dental Medicine Research Centre, Cheonan 31116, Korea
- Cell & Matter Institue, Dankook University, Cheonan 31116, Korea
- Division of Biomaterials and Tissue Engineering, Eastman Dental Institute, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK
| | - Hae-Hyoung Lee
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, 119 Dandae-ro, Cheonan 31116, Korea; (J.-Y.Y.); (J.-H.P.); (K.D.); (J.C.K.); (H.-H.L.)
- UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea
- The Discoveries Centre for Regenerative and Precision Medicine, Eastman Dental Institute, University College, London WC1E 6BT, UK
| | - Jong-Bin Kim
- Department of Pediatric Dentistry, College of Dentistry, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea; (H.T.V.); (M.-R.H.); (J.-H.L.); (J.-S.K.); (J.-S.S.)
- Correspondence: (J.-B.K.); (J.-H.L.); Tel.: +82-41-550-3081 (J.-B.K. & J.-H.L.); Fax: +82-41-559-7839 (J.-B.K. & J.-H.L.)
| | - Jung-Hwan Lee
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, 119 Dandae-ro, Cheonan 31116, Korea; (J.-Y.Y.); (J.-H.P.); (K.D.); (J.C.K.); (H.-H.L.)
- Department of Biomaterials science, College of Dentistry, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea
- UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea
- Mechanobiology Dental Medicine Research Centre, Cheonan 31116, Korea
- The Discoveries Centre for Regenerative and Precision Medicine, Eastman Dental Institute, University College, London WC1E 6BT, UK
- Drug Research Institute, Mongolian Pharmaceutical University & Monos Group, Ulaanbaatar 14250, Mongolia
- Correspondence: (J.-B.K.); (J.-H.L.); Tel.: +82-41-550-3081 (J.-B.K. & J.-H.L.); Fax: +82-41-559-7839 (J.-B.K. & J.-H.L.)
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22
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Cui Y, Ji W, Gao Y, Xiao Y, Liu H, Chen Z. Single-cell characterization of monolayer cultured human dental pulp stem cells with enhanced differentiation capacity. Int J Oral Sci 2021; 13:44. [PMID: 34911932 PMCID: PMC8674359 DOI: 10.1038/s41368-021-00140-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/14/2021] [Accepted: 10/18/2021] [Indexed: 12/12/2022] Open
Abstract
Human dental pulp stem cells (hDPSCs) are easily obtained multipotent cells, however, their potential value in regenerative medicine is hindered by the phenotypic and functional changes after conventional monolayer expansion. Here, we employed single-cell RNA sequencing (scRNA-seq) to comprehensively study the transcriptional difference between the freshly isolated and monolayer cultured DPSCs. The cell cluster analysis based on our scRNA-seq data showed that monolayer culture resulted in a significant cellular composition switch compared to the freshly isolated DPSCs. However, one subpopulation, characterized as MCAM(+)JAG(+)PDGFRA(-), maintained the most transcriptional characteristics compared to their freshly isolated counterparts. Notably, immunofluorescent staining revealed that the MCAM(+)JAG(+)PDGFRA(-) hDPSCs uniquely located in the perivascular region of human dental pulp tissue. Flow-cytometry analysis confirmed that their proportion remained relatively stable (~2%) regardless of physiological senescence or dental caries. Consistent with the annotation of scRNA-seq data, MCAM(+)JAG(+)PDGFRA(-) hDPSCs showed higher proliferation capacity and enhanced in vitro multilineage differentiation potentials (osteogenic, chondrogenic and adipogenic) compared with their counterparts PDGFRA(+) subpopulation. Furthermore, the MCAM(+)JAG(+)PDGFRA(-) hDPSCs showed enhanced bone tissue formation and adipose tissue formation after 4-week subcutaneous implantation in nude mice. Taken together, our study for the first time revealed the cellular composition switch of monolayer cultured hDPSCs compared to the freshly isolated hDPSCs. After in vitro expansion, the MCAM(+)JAG(+)PDGFRA(-) subpopulation resembled the most transcriptional characteristics of fresh hDPSCs which may be beneficial for further tissue regeneration applications.
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Affiliation(s)
- Yu Cui
- The State Key Laboratory Breeding Base of Basic Sciences of Stomatology, Key Laboratory of Oral Biomedicine, Ministry of Education (Hubei-MOST KLOS & KLOBM), School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Wei Ji
- The State Key Laboratory Breeding Base of Basic Sciences of Stomatology, Key Laboratory of Oral Biomedicine, Ministry of Education (Hubei-MOST KLOS & KLOBM), School and Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Oral Implantology, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yongyan Gao
- The State Key Laboratory Breeding Base of Basic Sciences of Stomatology, Key Laboratory of Oral Biomedicine, Ministry of Education (Hubei-MOST KLOS & KLOBM), School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yao Xiao
- The State Key Laboratory Breeding Base of Basic Sciences of Stomatology, Key Laboratory of Oral Biomedicine, Ministry of Education (Hubei-MOST KLOS & KLOBM), School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Huan Liu
- The State Key Laboratory Breeding Base of Basic Sciences of Stomatology, Key Laboratory of Oral Biomedicine, Ministry of Education (Hubei-MOST KLOS & KLOBM), School and Hospital of Stomatology, Wuhan University, Wuhan, China.
- Department of Periodontology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
| | - Zhi Chen
- The State Key Laboratory Breeding Base of Basic Sciences of Stomatology, Key Laboratory of Oral Biomedicine, Ministry of Education (Hubei-MOST KLOS & KLOBM), School and Hospital of Stomatology, Wuhan University, Wuhan, China.
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23
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Mai Z, Chen H, Ye Y, Hu Z, Sun W, Cui L, Zhao X. Translational and Clinical Applications of Dental Stem Cell-Derived Exosomes. Front Genet 2021; 12:750990. [PMID: 34764982 PMCID: PMC8576041 DOI: 10.3389/fgene.2021.750990] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 10/07/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are promising seed cells in tissue repair and regeneration due to their featured properties of self-renewal and multipotency. However, a growing body of evidence has demonstrated that MSCs exert biological functions mainly through secreting exosomes. Exosomes, which contain RNA, proteins, lipids, and metabolites, are new players in regulating many fundamental processes and play important roles in regenerative medicine. Exosomes not only mimic the effects of their parent cells but also possess many advantages such as high drug loading capacity, low immunogenicity, excellent biocompatibility, and low side effects. Currently, a total of 6 different dental stem cells (DSCs) including dental pulp stem cells (DPSCs), stem cells from exfoliated deciduous teeth (SHEDs), periodontal ligament stem cells (PDLSCs), dental follicle progenitor cells (DFPCs), stem cells from apical papilla (SCAPs) and gingival mesenchymal stem cells (GMSCs) have been isolated and identified. DSC-derived exosomes (DSC-Exos) are actively involved in intercellular communication, anti-inflammation, osteogenesis, angiogenesis, immunomodulation, nurturing neurons, and promoting tumor cell apoptosis. In this review, we will critically review the emerging role and clinical application potential of DSC-Exos.
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Affiliation(s)
- Zizhao Mai
- Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Huan Chen
- Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Yu Ye
- Institute of Stomatology, Nanjing Medical University, Nanjing, China.,Key Laboratory of Oral Diseases of Jiangsu Province, Stomatological Institute, Nanjing Medical University, Nanjing, China
| | - Ziyu Hu
- Department of Pediatrics, Nanjing Jinling Stomatology Hospital, Nanjing, China
| | - Wenjuan Sun
- Department of Stomatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li Cui
- Stomatological Hospital, Southern Medical University, Guangzhou, China.,UCLA School of Dentistry, Los Angeles, CA, United States
| | - Xinyuan Zhao
- Stomatological Hospital, Southern Medical University, Guangzhou, China
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24
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Lee HN, Liang C, Liao L, Tian WD. Advances in Research on Stem Cell-Based Pulp Regeneration. Tissue Eng Regen Med 2021; 18:931-940. [PMID: 34536210 DOI: 10.1007/s13770-021-00389-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 07/17/2021] [Accepted: 08/18/2021] [Indexed: 02/05/2023] Open
Abstract
Although root canal therapy is the most common and widely used treatment at clinical presentation, there are still some postoperative complications. As cell biology and tissue engineering techniques advance rapidly, the use of biological therapy to regenerate dental pulp has become a new trend; Relevant literatures in recent five years were searched using key words such as "root canal therapy", "Dental pulp stem cells", "Dental pulp regeneration", and "Cell homing" in PubMed, Web of Science, etc; Dental pulp stem cells (DPSCs) have multi-differentiation potential, self-renewal capability, and high proliferative ability. Stem cell-based dental pulp regeneration has emerged as a new research hot spot in clinical therapy. Recently, dental pulp-like structures have been generated by the transplantation of exogenous DPSCs or the induction of homing of endogenous DPSCs. Studies on DPSCs are important and significant for dental pulp regeneration and dental restoration; In this review, the existing clinical treatment methods, dental pulp regeneration, and DPSC research status are revealed, and their application prospects are discussed. The stem cell-based pulp regeneration exerts promising potential in clinical therapy for pulp regeneration.
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Affiliation(s)
- Hua-Nien Lee
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases and Engineering Research Center of Oral Translational Medicine, Ministry of Education and National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610044, China
| | - Cheng Liang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases and Engineering Research Center of Oral Translational Medicine, Ministry of Education and National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610044, China
| | - Li Liao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases and Engineering Research Center of Oral Translational Medicine, Ministry of Education and National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610044, China.
| | - Wei-Dong Tian
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases and Engineering Research Center of Oral Translational Medicine, Ministry of Education and National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610044, China.
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25
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Scelza P, Gonçalves F, Caldas I, Nunes F, Lourenço ES, Tavares S, Magno M, Pintor A, Montemezzi P, Edoardo ED, Mourão CFDAB, Alves G, Scelza MZ. Prognosis of Regenerative Endodontic Procedures in Mature Teeth: A Systematic Review and Meta-Analysis of Clinical and Radiographic Parameters. MATERIALS 2021; 14:ma14164418. [PMID: 34442940 PMCID: PMC8398537 DOI: 10.3390/ma14164418] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 07/20/2021] [Accepted: 08/04/2021] [Indexed: 12/13/2022]
Abstract
This work aimed to investigate the use of Regenerative Endodontic Procedures (REP) on the treatment of pulp necrosis in mature teeth through systematic review and meta-analysis of evidence on clinical and radiographic parameters before and after REP. A search was performed in different databases on 9 September 2020, including seven clinical studies and randomized controlled trials (RCT). The methodological quality was assessed using Revised Cochrane risk-of-bias (RoB 2) and Before-and-After tools. Meta-analyses were performed to evaluate the success incidences regarding the reduction of periapical lesion and recovery of sensitivity. The certainty of the evidence was assessed using GRADE. Meta-analysis showed a high overall success of 0.95 (0.92, 0.98) I2 = 6%, with high periapical lesion reduction at 12 months (0.93 (0.86, 0.96) I2 = 37%) and by the end of follow-up (0.91 (0.83, 0.96) I2 = 13%). Lower incidences of positive sensitivity response were identified for the electrical (0.58 (0.46, 0.70) I2 = 51%) and cold tests (0.70 (0.54, 0.84) I2 = 68%). The calculated levels of REP success were similar to those reported for immature teeth. With a very low certainty of evidence, the meta-analysis showed a high incidence of REP’s success for mature teeth with necrotic pulp evidenced by periapical lesion reduction and moderate positive responses to sensitivity tests.
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Affiliation(s)
- Pantaleo Scelza
- Geriatric Dentistry Department, Universidade Federal Fluminense, Niterói 24020-140, RJ, Brazil; (P.S.); (I.C.); (F.N.)
| | - Fabiano Gonçalves
- Post-Graduate Program in Dentistry, Universidade Federal Fluminense, Niterói 24020-140, RJ, Brazil; (F.G.); (E.S.L.); (S.T.)
| | - Isleine Caldas
- Geriatric Dentistry Department, Universidade Federal Fluminense, Niterói 24020-140, RJ, Brazil; (P.S.); (I.C.); (F.N.)
| | - Fernanda Nunes
- Geriatric Dentistry Department, Universidade Federal Fluminense, Niterói 24020-140, RJ, Brazil; (P.S.); (I.C.); (F.N.)
| | - Emanuelle Stellet Lourenço
- Post-Graduate Program in Dentistry, Universidade Federal Fluminense, Niterói 24020-140, RJ, Brazil; (F.G.); (E.S.L.); (S.T.)
| | - Sandro Tavares
- Post-Graduate Program in Dentistry, Universidade Federal Fluminense, Niterói 24020-140, RJ, Brazil; (F.G.); (E.S.L.); (S.T.)
| | - Marcela Magno
- Department of Pediatric Dentistry and Orthodontics, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (M.M.); (A.P.)
| | - Andrea Pintor
- Department of Pediatric Dentistry and Orthodontics, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (M.M.); (A.P.)
| | | | | | - Carlos Fernando de Almeida Barros Mourão
- Clinical Research Unit of the Antonio Pedro Hospital, Universidade Federal Fluminense, Niterói 24033-900, RJ, Brazil;
- Correspondence: (C.F.d.A.B.M.); (M.Z.S.); Tel.: +1-941-(830)-1302 (C.F.d.A.B.M.); +55-21-99984-0270 (M.Z.S.)
| | - Gutemberg Alves
- Clinical Research Unit of the Antonio Pedro Hospital, Universidade Federal Fluminense, Niterói 24033-900, RJ, Brazil;
| | - Miriam Zaccaro Scelza
- Laboratory of Experimental Culture Cell (LECCel), Department of Endodontics, Faculty of Dentistry, Universidade Federal Fluminense, Niterói 24020-140, RJ, Brazil
- Correspondence: (C.F.d.A.B.M.); (M.Z.S.); Tel.: +1-941-(830)-1302 (C.F.d.A.B.M.); +55-21-99984-0270 (M.Z.S.)
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26
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Khazaei S, Khademi A, Nasr Esfahani MH, Khazaei M, Nekoofar MH, Dummer PMH. Isolation and Differentiation of Adipose-Derived Stem Cells into Odontoblast-Like Cells: A Preliminary In Vitro Study. CELL JOURNAL 2021; 23:288-293. [PMID: 34308571 PMCID: PMC8286457 DOI: 10.22074/cellj.2021.7325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 01/21/2020] [Indexed: 11/04/2022]
Abstract
Objective The aim of present study was to isolate and differentiate human adipose-derived stem cells (ASCs) into odontoblast-like cells. Materials and Methods In this experimental study, human adipose tissues were taken from the buccal fat pad of three individuals (mean age: 24.6 ± 2.1 years). The tissues were transferred to a laboratory in a sterile culture medium, divided into small pieces and digested by collagenase I (2 mg/mL, 60-90 minutes). ASCs were isolated by passing the cell suspension through cell strainers (70 and 40 μm), followed by incubation at 37ºC and 5% CO2 in Dulbecco's modified eagle medium (DMEM) supplemented with fetal bovine serum (FBS 5%) and penicillin/streptomycin (P/S). After three passages, the ASCs were harvested. Subsequently, flow cytometry and reverse transcriptase polymerase chain reaction (RT-PCR) were used to detect expression levels of NANOG and OCT4 to evaluate stemness. Then, a differentiation medium that included high-glucose DMEM supplemented with 10% FBS, dexamethasone (10 nM), sodium β-glycerophosphate (5 mM) and ascorbic acid (100 μM) was added. The cells were cultivated for four weeks, and the odontogenic medium was changed every two days. Cell differentiation was evaluated with Alizarin red staining and expressions of collagen I (COL1A1), dentin sialophosphoprotein (DSPP) and dentin matrix protein-1 (DMP1). Results The ASCs were effectively and easily isolated. They were negative for CD45 and positive for the CD105 and CD73 markers. The ASCs expressed OCT4 and NANOG. Differentiated cells highly expressed DSPP, COL1A1 and DMP1. Alizarin red staining revealed a positive reaction for calcium deposition. Conclusion ASCs were isolated successfully in high numbers from the buccal fat pad of human volunteers and were differentiated into odontoblast-like cells. These ASCs could be considered a new source of cells for use in regenerative endodontic treatments.
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Affiliation(s)
- Saber Khazaei
- Department of Endodontics, School of Dentistry and Dental Research Centre, Dental Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran.,Department of Endodontics, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Abbasali Khademi
- Department of Endodontics, School of Dentistry and Dental Research Centre, Dental Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Mohammad Hossein Nasr Esfahani
- Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Mozafar Khazaei
- Fertility and Infertility Research Centre, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | | | - Paul M H Dummer
- School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK
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27
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Cui D, Yu S, Zhou X, Liu Y, Gan L, Pan Y, Zheng L, Wan M. Roles of Dental Mesenchymal Stem Cells in the Management of Immature Necrotic Permanent Teeth. Front Cell Dev Biol 2021; 9:666186. [PMID: 34095133 PMCID: PMC8170050 DOI: 10.3389/fcell.2021.666186] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/06/2021] [Indexed: 02/05/2023] Open
Abstract
Dental caries and trauma always lead to pulp necrosis and subsequent root development arrest of young permanent teeth. The traditional treatment, apexification, with the absence of further root formation, results in abnormal root morphology and compromises long-term prognosis. Regeneration endodontics procedures (REPs) have been developed and considered as an alternative strategy for management of immature permanent teeth with pulpal necrosis, including cell-free and cell-based REPs. Cell-free REPs, including revascularization and cell homing with molecules recruiting endogenous mesenchymal stem cells (MSCs), have been widely applied in clinical treatment, showing optimistic periapical lesion healing and continued root development. However, the regenerated pulp-dentin complex is still absent in these cases. Dental MSCs, as one of the essentials of tissue engineering, are vital seed cells in regenerative medicine. Dental MSC-based REPs have presented promising potential with pulp-dentin regeneration in large animal studies and clinical trials via cell transplantation. In the present review, we summarize current understanding of the biological basis of clinical treatments for immature necrotic permanent teeth and the roles of dental MSCs during this process and update the progress of MSC-based REPs in the administration of immature necrotic permanent teeth.
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Affiliation(s)
- Dixin Cui
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Sihan Yu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xin Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ying Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lu Gan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yue Pan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Liwei Zheng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Mian Wan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Glia and Orofacial Pain: Progress and Future Directions. Int J Mol Sci 2021; 22:ijms22105345. [PMID: 34069553 PMCID: PMC8160907 DOI: 10.3390/ijms22105345] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/12/2021] [Accepted: 05/14/2021] [Indexed: 12/14/2022] Open
Abstract
Orofacial pain is a universal predicament, afflicting millions of individuals worldwide. Research on the molecular mechanisms of orofacial pain has predominately focused on the role of neurons underlying nociception. However, aside from neural mechanisms, non-neuronal cells, such as Schwann cells and satellite ganglion cells in the peripheral nervous system, and microglia and astrocytes in the central nervous system, are important players in both peripheral and central processing of pain in the orofacial region. This review highlights recent molecular and cellular findings of the glia involvement and glia–neuron interactions in four common orofacial pain conditions such as headache, dental pulp injury, temporomandibular joint dysfunction/inflammation, and head and neck cancer. We will discuss the remaining questions and future directions on glial involvement in these four orofacial pain conditions.
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Huang X, Li Z, Liu A, Liu X, Guo H, Wu M, Yang X, Han B, Xuan K. Microenvironment Influences Odontogenic Mesenchymal Stem Cells Mediated Dental Pulp Regeneration. Front Physiol 2021; 12:656588. [PMID: 33967826 PMCID: PMC8100342 DOI: 10.3389/fphys.2021.656588] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 03/23/2021] [Indexed: 12/21/2022] Open
Abstract
Dental pulp as a source of nutrition for the whole tooth is vulnerable to trauma and bacterial invasion, which causes irreversible pulpitis and pulp necrosis. Dental pulp regeneration is a valuable method of restoring the viability of the dental pulp and even the whole tooth. Odontogenic mesenchymal stem cells (MSCs) residing in the dental pulp environment have been widely used in dental pulp regeneration because of their immense potential to regenerate pulp-like tissue. Furthermore, the regenerative abilities of odontogenic MSCs are easily affected by the microenvironment in which they reside. The natural environment of the dental pulp has been proven to be capable of regulating odontogenic MSC homeostasis, proliferation, and differentiation. Therefore, various approaches have been applied to mimic the natural dental pulp environment to optimize the efficacy of pulp regeneration. In addition, odontogenic MSC aggregates/spheroids similar to the natural dental pulp environment have been shown to regenerate well-organized dental pulp both in preclinical and clinical trials. In this review, we summarize recent progress in odontogenic MSC-mediated pulp regeneration and focus on the effect of the microenvironment surrounding odontogenic MSCs in the achievement of dental pulp regeneration.
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Affiliation(s)
- Xiaoyao Huang
- State Key Laboratory of Military Stomatology, Fourth Military Medical University, Xi'an, China.,National Clinical Research Center for Oral Diseases, Fourth Military Medical University, Xi'an, China.,Shaanxi Clinical Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Zihan Li
- State Key Laboratory of Military Stomatology, Fourth Military Medical University, Xi'an, China.,National Clinical Research Center for Oral Diseases, Fourth Military Medical University, Xi'an, China.,Shaanxi Clinical Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Anqi Liu
- State Key Laboratory of Military Stomatology, Fourth Military Medical University, Xi'an, China.,National Clinical Research Center for Oral Diseases, Fourth Military Medical University, Xi'an, China.,Shaanxi Clinical Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Xuemei Liu
- State Key Laboratory of Military Stomatology, Fourth Military Medical University, Xi'an, China.,National Clinical Research Center for Oral Diseases, Fourth Military Medical University, Xi'an, China.,Shaanxi Clinical Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Hao Guo
- State Key Laboratory of Military Stomatology, Fourth Military Medical University, Xi'an, China.,National Clinical Research Center for Oral Diseases, Fourth Military Medical University, Xi'an, China.,Shaanxi Clinical Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Meiling Wu
- State Key Laboratory of Military Stomatology, Fourth Military Medical University, Xi'an, China.,National Clinical Research Center for Oral Diseases, Fourth Military Medical University, Xi'an, China.,Shaanxi Clinical Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Xiaoxue Yang
- State Key Laboratory of Military Stomatology, Fourth Military Medical University, Xi'an, China.,National Clinical Research Center for Oral Diseases, Fourth Military Medical University, Xi'an, China.,Shaanxi Clinical Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Bing Han
- State Key Laboratory of Military Stomatology, Fourth Military Medical University, Xi'an, China.,National Clinical Research Center for Oral Diseases, Fourth Military Medical University, Xi'an, China.,Shaanxi Clinical Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Kun Xuan
- State Key Laboratory of Military Stomatology, Fourth Military Medical University, Xi'an, China.,National Clinical Research Center for Oral Diseases, Fourth Military Medical University, Xi'an, China.,Shaanxi Clinical Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi'an, China
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30
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Kim SG. A Cell-Based Approach to Dental Pulp Regeneration Using Mesenchymal Stem Cells: A Scoping Review. Int J Mol Sci 2021; 22:4357. [PMID: 33921924 PMCID: PMC8122243 DOI: 10.3390/ijms22094357] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/18/2021] [Accepted: 04/20/2021] [Indexed: 02/07/2023] Open
Abstract
Despite the recent explosion of investigations on dental pulp regeneration using various tissue engineering strategies, the translation of the findings from such studies into therapeutic applications has not been properly achieved. The purpose of this scoping review was to systematically review the efficacy of mesenchymal stem cell transplantation for dental pulp regeneration. A literature search was conducted using five electronic databases from their inception to January 2021 and supplemented by hand searches. A total of 17 studies, including two clinical trials and 15 animal studies using orthotopic pulp regeneration models, were included for the review. The risk of bias for the individual studies was assessed. This scoping review demonstrated that the regeneration of vascularized pulp-like tissue was achieved using the stem cell transplantation strategy in animal models. Autologous cell transplantation in two clinical studies also successfully regenerated vascularized vital tissue. Dental pulp stem cell subpopulations, such as mobilized dental pulp stem cells, injectable scaffolds such as atelocollagen, and a granulocyte-colony forming factor, were the most commonly used for pulp regeneration. The overall risk of bias was unclear for animal studies and was moderate or judged to raise some concerns for clinical studies. More high-quality clinical studies are needed to further determine the safety and efficacy of the stem cell transplantation strategy for dental pulp regeneration.
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Affiliation(s)
- Sahng G Kim
- Division of Endodontics, Columbia University College of Dental Medicine, New York, NY 10032, USA
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31
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Chansaenroj A, Yodmuang S, Ferreira JN. Trends in Salivary Gland Tissue Engineering: From Stem Cells to Secretome and Organoid Bioprinting. TISSUE ENGINEERING PART B-REVIEWS 2021; 27:155-165. [DOI: 10.1089/ten.teb.2020.0149] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Ajjima Chansaenroj
- Exocrine Gland Biology and Regeneration Research Group, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Supansa Yodmuang
- Exocrine Gland Biology and Regeneration Research Group, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
- Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - João N. Ferreira
- Exocrine Gland Biology and Regeneration Research Group, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
- Faculty of Dentistry, National University of Singapore, Singapore, Singapore
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32
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Comparative analysis of cytokines and growth factors in the conditioned media of stem cells from the pulp of deciduous, young, and old permanent tooth. Saudi J Biol Sci 2021; 28:3559-3565. [PMID: 34121899 PMCID: PMC8176054 DOI: 10.1016/j.sjbs.2021.03.031] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/04/2021] [Accepted: 03/08/2021] [Indexed: 02/08/2023] Open
Abstract
Objectives To compare and analyze the secretome profile of stem cells obtained from the deciduous tooth (SHEDs), young (yDPSCs), and old permanent tooth (oDPSCs). Methods All the stem cells were assessed for mesenchymal stem cell markers. The stem cells were differentiated into osteoblasts and chondrocytes using lineage-specific differentiation media. Conditioned media was collected from growing stem cells, and a cytometric bead array was performed to estimate secreted cytokines and growth factor levels by flow cytometry. Gene expresseion levels were assessed by real-time quantitative polymerase chain reaction. Results Age did not affect the mesenchymal characteristics of dental stem cells from various age groups. The secretomes of SHEDs and young yDPSCs exhibit more growth factors and lesser pro-inflammatory cytokines than oDPSCs. Osteo and chondrogenic differentiation potential were higher in SHEDs and young yDPSCs than in the oDPSCs. TLR1, TLR2, TLR3 show decreased expression levels with age and TLR5, TLR6 show increased expression with age. Conclusion The superior regenerative potential of SHEDs and yDPSCs may be due to the higher growth factors and lower pro-inflammatory cytokine profile.
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33
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Sismanoglu S, Ercal P. Dentin-Pulp Tissue Regeneration Approaches in Dentistry: An Overview and Current Trends. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1298:79-103. [PMID: 32902726 DOI: 10.1007/5584_2020_578] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Conventional treatment approaches in irreversible pulpitis and apical periodontitis include the disinfection of the pulp space followed by filling with various materials, which is commonly known as the root canal treatment. Disadvantages including the loss of tooth vitality and defense mechanism against carious lesions, susceptibility to fractures, discoloration and microleakage led to the development of regenerative therapies for the dentin pulp-complex. The goal of dentin-pulp tissue regeneration is to reestablish the physiological pulp function such as pulp sensibility, pulp repair capability by mineralization and pulp immunity. Recent dentin-pulp tissue regeneration approaches can be divided into cell homing and cell transplantation. Cell based approaches include a suitable scaffold for the delivery of potent stem cells with or without bioactive molecules into the root canal system while cell homing is based on the recruitment of host endogenous stem cells from the resident tissue including periapical region or dental pulp. This review discusses the recent treatment modalities in dentin-pulp tissue regeneration through tissue engineering and current challenges and trends in this field of research.
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Affiliation(s)
- Soner Sismanoglu
- Department of Restorative Dentistry, Faculty of Dentistry, Altinbas University, Istanbul, Turkey
| | - Pınar Ercal
- Department of Oral Surgery, Faculty of Dentistry, Altinbas University, Istanbul, Turkey.
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34
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Nakashima M, Iohara K, Zayed M. Pulp Regeneration: Current Approaches, Challenges, and Novel Rejuvenating Strategies for an Aging Population. J Endod 2020; 46:S135-S142. [PMID: 32950185 DOI: 10.1016/j.joen.2020.06.028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
We showed the safety and efficacy of pulp regenerative therapy by the autologous transplantation of mobilized dental pulp stem cells with granulocyte colony-stimulating factor in a pilot clinical study of young and middle-aged pulpectomized teeth. An experimental study in dogs further demonstrated an age-dependent decline in the amount of regenerated pulp tissue. In our society, in which people will soon live beyond 100 years, this therapy should be efficacious for contributing to the functional survival and endurance of the tooth not only for pulpectomized young teeth but also for aged teeth with periapical disease. However, there are 2 challenges: 1 is enhancing pulp regeneration in aged teeth, and another is complete disinfection before cell transplantation. Thus, this review presents trypsin pretreatment for the former and a novel irrigant, nanobubbles with antibacterial nanopolymers, for the latter, thus demonstrating potential utility for pulp regenerative therapy in aged teeth with periapical disease.
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Affiliation(s)
- Misako Nakashima
- Department of Stem Cell Biology and Regenerative Medicine, National Center for Geriatrics and Gerontology, Research Institute, Obu, Aichi, Japan; Department of Oral Disease Research, National Center for Geriatrics and Gerontology, Research Institute, Obu, Aichi, Japan; Air Water Group, Aeras Bio Inc, Kobe, Hyogo, Japan.
| | - Koichiro Iohara
- Department of Stem Cell Biology and Regenerative Medicine, National Center for Geriatrics and Gerontology, Research Institute, Obu, Aichi, Japan
| | - Mohammed Zayed
- Department of Stem Cell Biology and Regenerative Medicine, National Center for Geriatrics and Gerontology, Research Institute, Obu, Aichi, Japan; Department of Animal Surgery, School of Veterinary Medicine, South Valley University, Qena, Egypt
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35
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Effects of p-Cresol on Senescence, Survival, Inflammation, and Odontoblast Differentiation in Canine Dental Pulp Stem Cells. Int J Mol Sci 2020; 21:ijms21186931. [PMID: 32967298 PMCID: PMC7555360 DOI: 10.3390/ijms21186931] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 09/09/2020] [Accepted: 09/15/2020] [Indexed: 12/12/2022] Open
Abstract
Aging, defined by a decrease in the physical and functional integrity of the tissues, leads to age-associated degenerative diseases. There is a relation between aged dental pulp and the senescence of dental pulp stem cells (DPSCs). Therefore, it is important to investigate the molecular processes underlying the senescence of DPSCs to elucidate the dental pulp aging mechanisms. p-Cresol (PC), a uremic toxin, is strongly related to cellular senescence. Here, age-related phenotypic changes including senescence, apoptosis, inflammation, and declining odontoblast differentiation in PC-treated canine DPSCs were investigated. Under the PC condition, cellular senescence was induced by decreased proliferation capacity and increased cell size, senescence-associated β-galactosidase (SA-β-gal) activity, and senescence markers p21, IL-1β, IL-8, and p53. Exposure to PC could stimulate inflammation by the increased expression of IL-6 and cause the distraction of the cell cycle by the increased level of Bax protein and decreased Bcl-2. The levels of odontoblast differentiation markers, dentin sialophosphoprotein (DSPP), dentin matrix protein 1, and osterix, were decreased. Consistent with those findings, the alizarin red staining, alkaline phosphatase, and DSPP protein level were decreased during the odontoblast differentiation process. Taken together, these findings indicate that PC could induce cellular senescence in DPSCs, which may demonstrate the changes in aging dental pulp.
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36
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Sui B, Wu D, Xiang L, Fu Y, Kou X, Shi S. Dental Pulp Stem Cells: From Discovery to Clinical Application. J Endod 2020; 46:S46-S55. [DOI: 10.1016/j.joen.2020.06.027] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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37
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38
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Iohara K, Zayed M, Takei Y, Watanabe H, Nakashima M. Treatment of Pulpectomized Teeth With Trypsin Prior to Transplantation of Mobilized Dental Pulp Stem Cells Enhances Pulp Regeneration in Aged Dogs. Front Bioeng Biotechnol 2020; 8:983. [PMID: 32923438 PMCID: PMC7456913 DOI: 10.3389/fbioe.2020.00983] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 07/28/2020] [Indexed: 12/20/2022] Open
Abstract
There is an age-dependent decline of pulp regeneration, due to the decline of migration, proliferation, and cell survival of resident stem cells. Trypsin is a proteolytic enzyme clinically used for tissue repair. Here, we investigated the effects of trypsin pretreatment of pulpectomized teeth prior to cell transplantation on pulp regeneration in aged dogs. The amount of regenerated pulp was significantly higher in trypsin-pretreated teeth compared to untreated teeth. Trypsin pretreatment increased the number of cells attached to the dentinal wall that differentiated into odontoblast-like cells. The trypsin receptor, PAR2, was higher in vitro expression in the periodontal ligament cells (PDLCs) from aged dogs compared to those from young. The direct effects of trypsin on aged PDLCs were increased expression of genes related to immunomodulation, cell survival, and extracellular matrix degradation. To examine the indirect effects on microenvironment, highly extracted proteins from aged cementum were identified by proteomic analyses. Western blotting demonstrated that significantly increased fibronectin was released by the trypsin treatment of aged cementum compared to young cementum. The aged cementum extract (CE) and dentin extract (DE) by trypsin treatment increased angiogenesis, neurite extension and migration activities as elicited by fibronectin. Furthermore, the DE significantly increased the mRNA expression of immunomodulatory factors and pulp markers in the aged DPSCs. These results demonstrated the effects of trypsin on the microenvironment in addition to the resident cells including PDLCs in the aged teeth. In conclusion, the potential utility of trypsin pretreatment to stimulate pulp regeneration in aged teeth and the underlying mechanisms were demonstrated.
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Affiliation(s)
- Koichiro Iohara
- Department of Stem Cell Biology and Regenerative Medicine, National Center for Geriatrics and Gerontology, Research Institute, Obu, Japan
| | - Mohammed Zayed
- Department of Stem Cell Biology and Regenerative Medicine, National Center for Geriatrics and Gerontology, Research Institute, Obu, Japan.,Department of Surgery, College of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Yoshifumi Takei
- Department of Medicinal Biochemistry, School of Pharmacy, Aichi Gakuin University, Nagoya, Japan
| | - Hideto Watanabe
- Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Japan
| | - Misako Nakashima
- Department of Stem Cell Biology and Regenerative Medicine, National Center for Geriatrics and Gerontology, Research Institute, Obu, Japan.,Aeras Bio Inc., Air Water Group, Kobe, Japan
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Jang JH, Moon JH, Kim SG, Kim SY. Pulp regeneration with hemostatic matrices as a scaffold in an immature tooth minipig model. Sci Rep 2020; 10:12536. [PMID: 32719323 PMCID: PMC7385085 DOI: 10.1038/s41598-020-69437-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 07/07/2020] [Indexed: 12/19/2022] Open
Abstract
Control of blood clotting in root canal systems is one of the most critical and difficult concerns for regenerative endodontics therapy (RET). The purpose of this study was to investigate the effects of using gelatin- and fibrin-based hemostatic hydrogels as a scaffold on pulp regeneration in a minipig model. Cell viability of human dental pulp stem cells cultured three-dimensionally in gelatin-based and fibrin-based scaffolds was evaluated by MTT and live/dead assay. RET was performed on 24 immature premolars with an autologous blood clot (PC), gelatin-based and fibrin-based hemostatic matrices (GM and FM), or without the insertion of a scaffold (NC). The follow-up period was 12 weeks. Radiographic and histologic assessments for pulp regeneration were performed. Gelatin-based scaffolds exhibited significantly higher cell viability than fibrin-based scaffolds after 15 days (P < 0.05). The PC and GM groups showed favorable root development without inflammation and newly mineralized tissue deposited in the root canal system, while FM group presented inflammatory changes with the continuation of root development. The NC group exhibited internal root resorption with periapical lesions. The application of GM in RET led to favorable clinical outcomes of root development without inflammatory changes compared to conventional RET. Our results suggest that GM may serve as a viable regenerative scaffold for pulp regeneration.
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Affiliation(s)
- Ji-Hyun Jang
- Department of Conservative Dentistry, School of Dentistry, Kyung Hee University, Seoul, Korea
| | - Joung-Ho Moon
- Department of Conservative Dentistry and Dental Research Institute, School of Dentistry, Seoul National University, 101 Daehakno, Jongno-gu, Seoul, 03080, Korea
| | - Sahng Gyoon Kim
- Division of Endodontics, College of Dental Medicine, Columbia University, New York, NY, USA.
| | - Sun-Young Kim
- Department of Conservative Dentistry and Dental Research Institute, School of Dentistry, Seoul National University, 101 Daehakno, Jongno-gu, Seoul, 03080, Korea.
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40
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Voga M, Adamic N, Vengust M, Majdic G. Stem Cells in Veterinary Medicine-Current State and Treatment Options. Front Vet Sci 2020; 7:278. [PMID: 32656249 PMCID: PMC7326035 DOI: 10.3389/fvets.2020.00278] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 04/27/2020] [Indexed: 12/12/2022] Open
Abstract
Regenerative medicine is a branch of medicine that develops methods to grow, repair, or replace damaged or diseased cells, organs or tissues. It has gained significant momentum in recent years. Stem cells are undifferentiated cells with the capability to self—renew and differentiate into tissue cells with specialized functions. Stem cell therapies are therefore used to overcome the body's inability to regenerate damaged tissues and metabolic processes after acute or chronic insult. The concept of stem cell therapy was first introduced in 1991 by Caplan, who proposed that massive differentiation of cells into the desired tissue could be achieved by isolation, cultivation, and expansion of stem cells in in vitro conditions. Among different stem cell types, mesenchymal stem cells (MSC) currently seem to be the most suitable for therapeutic purposes, based on their simple isolation and culturing techniques, and lack of ethical issues regarding their usage. Because of their remarkable immunomodulatory abilities, MSCs are increasingly gaining recognition in veterinary medicine. Developments are primarily driven by the limitations of current treatment options for various medical problems in different animal species. MSCs represent a possible therapeutic option for many animal diseases, such as orthopedic, orodental and digestive tract diseases, liver, renal, cardiac, respiratory, neuromuscular, dermal, olfactory, and reproductive system diseases. Although we are progressively gaining an understanding of MSC behavior and their mechanisms of action, some of the issues considering their use for therapy are yet to be resolved. The aim of this review is first to summarize the current knowledge and stress out major issues in stem cell based therapies in veterinary medicine and, secondly, to present results of clinical usage of stem cells in veterinary patients.
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Affiliation(s)
- Metka Voga
- Faculty of Veterinary Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Neza Adamic
- Faculty of Veterinary Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Modest Vengust
- Faculty of Veterinary Medicine, University of Ljubljana, Ljubljana, Slovenia
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41
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Zayed M, Iohara K, Watanabe H, Nakashima M. CCR3 antagonist protects against induced cellular senescence and promotes rejuvenation in periodontal ligament cells for stimulating pulp regeneration in the aged dog. Sci Rep 2020; 10:8631. [PMID: 32451381 PMCID: PMC7248074 DOI: 10.1038/s41598-020-65301-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 04/30/2020] [Indexed: 12/31/2022] Open
Abstract
Pulp regeneration after transplantation of mobilized dental pulp stem cells (MDPSCs) declines in the aged dogs due in part to the chronic inflammation and/or cellular senescence. Eotaxin-1/C-C motif chemokine 11 (CCL11) is an inflammation marker via chemokine receptor 3 (CCR3). Moreover, CCR3 antagonist (CCR3A) can inhibit CCL11 binding to CCR3 and prevent CCL11/CCR3 signaling. The study aimed to examine the effect of CCR3A on cellular senescence and anti-inflammation/immunomodulation in human periodontal ligament cells (HPDLCs). The rejuvenating effects of CCR3A on neurite extension and migratory activity to promote pulp regeneration in aged dog teeth were also evaluated. In vivo, the amount of regenerated pulp tissues was significantly increased by transplantation of MDPSCs with CCR3A compared to control without CCR3A. In vitro, senescence of HPDLCs was induced after p-Cresol exposure, as indicated by increased cell size, decreased proliferation and increased senescence markers, p21 and IL-1β. Treatment of HPDLCs with CCR3A prevented the senescence effect of p-Cresol. Furthermore, CCR3A significantly decreased expression of CCL11, increased expression of immunomodulatory factor, IDO, and enhanced neurite extension and migratory activity. In conclusion, CCR3A protects against p-Cresol-induced cellular senescence and enhances rejuvenating effects, suggesting its potential utility to stimulate pulp regeneration in the aged teeth.
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Affiliation(s)
- Mohammed Zayed
- Department of Stem Cell Biology and Regenerative Medicine, National Center for Geriatrics and Gerontology, Research Institute, Obu, Aichi, 474-8511, Japan
- Department of Animal Surgery, College of Veterinary Medicine, South Valley University, Qena, 83523, Egypt
| | - Koichiro Iohara
- Department of Stem Cell Biology and Regenerative Medicine, National Center for Geriatrics and Gerontology, Research Institute, Obu, Aichi, 474-8511, Japan
| | - Hideto Watanabe
- Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi, 480-1195, Japan
| | - Misako Nakashima
- Department of Stem Cell Biology and Regenerative Medicine, National Center for Geriatrics and Gerontology, Research Institute, Obu, Aichi, 474-8511, Japan.
- Aeras Bio Inc., Air Water Group, Kobe, Hyogo, 650-047, Japan.
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42
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Shi X, Mao J, Liu Y. Pulp stem cells derived from human permanent and deciduous teeth: Biological characteristics and therapeutic applications. Stem Cells Transl Med 2020; 9:445-464. [PMID: 31943813 PMCID: PMC7103623 DOI: 10.1002/sctm.19-0398] [Citation(s) in RCA: 137] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 12/27/2019] [Indexed: 12/13/2022] Open
Abstract
Human pulp stem cells (PSCs) include dental pulp stem cells (DPSCs) isolated from dental pulp tissues of human extracted permanent teeth and stem cells from human exfoliated deciduous teeth (SHED). Depending on their multipotency and sensitivity to local paracrine activity, DPSCs and SHED exert therapeutic applications at multiple levels beyond the scope of the stomatognathic system. This review is specifically concentrated on PSC-updated biological characteristics and their promising therapeutic applications in (pre)clinical practice. Biologically, distinguished from conventional mesenchymal stem cell markers in vitro, NG2, Gli1, and Celsr1 have been evidenced as PSC markers in vivo. Both perivascular cells and glial cells account for PSC origin. Therapeutically, endodontic regeneration is where PSCs hold the most promises, attributable of PSCs' robust angiogenic, neurogenic, and odontogenic capabilities. More recently, the interplay between cell homing and liberated growth factors from dentin matrix has endowed a novel approach for pulp-dentin complex regeneration. In addition, PSC transplantation for extraoral tissue repair and regeneration has achieved immense progress, following their multipotential differentiation and paracrine mechanism. Accordingly, PSC banking is undergoing extensively with the intent of advancing tissue engineering, disease remodeling, and (pre)clinical treatments.
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Affiliation(s)
- Xin Shi
- Center of Stomatology, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople's Republic of China
| | - Jing Mao
- Center of Stomatology, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople's Republic of China
| | - Yan Liu
- Laboratory of Biomimetic Nanomaterials, Department of OrthodonticsPeking University School and Hospital of StomatologyBeijingPeople's Republic of China
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Tian S, Liu Y, Dong F, Dou Y, Li W, Wang J. Knockdown of microRNA-584 promotes dental pulp stem cells proliferation by targeting TAZ. Cell Cycle 2020; 19:1048-1058. [PMID: 32208890 DOI: 10.1080/15384101.2020.1744976] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Proliferation of dental pulp stem cells (DPSCs) is crucial in tooth development and damage repairing, also includes its therapy application for tissue engineering. MicroRNAs (miRNAs) are key players in biological processes of DPSCs, and transcriptional co-activator with PDZ-binding motif (TAZ) also plays important roles in cell proliferation and differentiation, however, the roles of miR-584 and TAZ in DPSCs are not known. We found up-regulated miR-584 expression and down-regulated TAZ expression levels in aging dental pulp tissue compare to those in young dental pulp tissue. In proliferating DPSCs we demonstrated the decreased miR-584 expression and increased TAZ expression. miR-584 mimics suppressed DPSCs proliferation and migration, and significantly reduced TAZ production, whereas miR-584 inhibition exerted the converse effects. Knocking down of the TAZ in DPSCs had a similar effect as overexpression of miR-584. Furthermore, luciferase reporter assay demonstrated that miR-584 could directly bind to the TAZ mRNA 3'UTR to repress its translation. Overexpression of TAZ can partly rescue miR-584 mimic-mediated the inhibition of proliferation. Additionally, miR-584 inhibited cell proliferation and downregulated expression of cell cycle proteins by AKT signaling pathway. Together, we identified that miR-584 may be a key regulator in the proliferation of DPSCs by regulating TAZ expression via AKT signaling pathway. It would be a promising biomarker and therapeutic target for pulp disease.
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Affiliation(s)
- Songbo Tian
- Department of Oral Pathology, College of Stomatology, Hebei Medical University, Shijiazhuang, China.,Department of Oral Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yanping Liu
- Physical Examination Center, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Fusheng Dong
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Hebei Medical University, Shijiazhuang, China
| | - Yongqing Dou
- College of Integrated Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Wenjing Li
- Department of Oral Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jie Wang
- Department of Oral Pathology, College of Stomatology, Hebei Medical University, Shijiazhuang, China
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Tissue Engineering Approaches for Enamel, Dentin, and Pulp Regeneration: An Update. Stem Cells Int 2020; 2020:5734539. [PMID: 32184832 PMCID: PMC7060883 DOI: 10.1155/2020/5734539] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 01/07/2020] [Indexed: 12/12/2022] Open
Abstract
Stem/progenitor cells are undifferentiated cells characterized by their exclusive ability for self-renewal and multilineage differentiation potential. In recent years, researchers and investigations explored the prospect of employing stem/progenitor cell therapy in regenerative medicine, especially stem/progenitor cells originating from the oral tissues. In this context, the regeneration of the lost dental tissues including enamel, dentin, and the dental pulp are pivotal targets for stem/progenitor cell therapy. The present review elaborates on the different sources of stem/progenitor cells and their potential clinical applications to regenerate enamel, dentin, and the dental pulpal tissues.
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Shah D, Lynd T, Ho D, Chen J, Vines J, Jung HD, Kim JH, Zhang P, Wu H, Jun HW, Cheon K. Pulp-Dentin Tissue Healing Response: A Discussion of Current Biomedical Approaches. J Clin Med 2020; 9:jcm9020434. [PMID: 32033375 PMCID: PMC7074340 DOI: 10.3390/jcm9020434] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/23/2020] [Accepted: 01/31/2020] [Indexed: 12/12/2022] Open
Abstract
Dental pulp tissue exposed to mechanical trauma or cariogenic process results in root canal and/or periapical infections, and conventionally treated with root canal procedures. The more recent regenerative endodontic procedure intends to achieve effective root canal disinfection and adequate pulp–dentin tissue regeneration; however, numerous limitations are reported. Because tooth is composed of vital soft pulp enclosed by the mineralized hard tissue in a highly organized structure, complete pulp–dentin tissue regeneration has been challenging to achieve. In consideration of the limitations and unique dental anatomy, it is important to understand the healing and repair processes through inflammatory-proliferative-remodeling phase transformations of pulp–dentin tissue. Upon cause by infectious and mechanical stimuli, the innate defense mechanism is initiated by resident pulp cells including immune cells through chemical signaling. After the expansion of infection and damage to resident pulp–dentin cells, consequent chemical signaling induces pluripotent mesenchymal stem cells (MSCs) to migrate to the injury site to perform the tissue regeneration process. Additionally, innovative biomaterials are necessary to facilitate the immune response and pulp–dentin tissue regeneration roles of MSCs. This review highlights current approaches of pulp–dentin tissue healing process and suggests potential biomedical perspective of the pulp–dentin tissue regeneration.
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Affiliation(s)
- Dishant Shah
- Department of Biomedical Engineering, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL 35294, USA; (D.S.); (T.L.); (D.H.); (J.C.); (J.V.); (H.-W.J.)
| | - Tyler Lynd
- Department of Biomedical Engineering, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL 35294, USA; (D.S.); (T.L.); (D.H.); (J.C.); (J.V.); (H.-W.J.)
| | - Donald Ho
- Department of Biomedical Engineering, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL 35294, USA; (D.S.); (T.L.); (D.H.); (J.C.); (J.V.); (H.-W.J.)
| | - Jun Chen
- Department of Biomedical Engineering, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL 35294, USA; (D.S.); (T.L.); (D.H.); (J.C.); (J.V.); (H.-W.J.)
| | - Jeremy Vines
- Department of Biomedical Engineering, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL 35294, USA; (D.S.); (T.L.); (D.H.); (J.C.); (J.V.); (H.-W.J.)
| | - Hwi-Dong Jung
- Department of Oral & Maxillofacial Surgery College of Dentistry, Yonsei University, 50-1 Yonsei-Ro, Seodeamun-Gu, Seoul 03722, Korea;
| | - Ji-Hun Kim
- Department of Dentistry, Wonju College of Medicine, Yonsei University, 20 Il-San-ro, Wonju, Gangwon-Do 26426, Korea;
| | - Ping Zhang
- Department of Pediatric Dentistry, University of Alabama at Birmingham, 1919 7th Avenue S, Birmingham, AL 35294, USA; (P.Z.); (H.W.)
| | - Hui Wu
- Department of Pediatric Dentistry, University of Alabama at Birmingham, 1919 7th Avenue S, Birmingham, AL 35294, USA; (P.Z.); (H.W.)
| | - Ho-Wook Jun
- Department of Biomedical Engineering, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL 35294, USA; (D.S.); (T.L.); (D.H.); (J.C.); (J.V.); (H.-W.J.)
| | - Kyounga Cheon
- Department of Pediatric Dentistry, University of Alabama at Birmingham, 1919 7th Avenue S, Birmingham, AL 35294, USA; (P.Z.); (H.W.)
- Correspondence: ; Tel.: +1-205-975-4303
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Jamali S, Mousavi E, Darvish M, Jabbari G, Nasrabadi N, Ahmadizadeh H. Dental Pulpal Tissue Regeneration, Pulpal Vitality Testing, and Healing of Apical Lesions Following Stem Cell Transplant: A Systematic Review and Meta-Analysis. PESQUISA BRASILEIRA EM ODONTOPEDIATRIA E CLÍNICA INTEGRADA 2020. [DOI: 10.1590/pboci.2020.043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
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47
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Tawfik Tadros MS, El-Baz MAES, Khairy MAEK. Dental stem cells in tooth repair: A systematic review. F1000Res 2019; 8:1955. [DOI: 10.12688/f1000research.21058.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/01/2023] Open
Abstract
Background: Dental stem cells (DSCs) are self-renewable teeth cells, which help maintain or develop oral tissues. These cells can differentiate into odontoblasts, adipocytes, cementoblast-like cells, osteoblasts, or chondroblasts and form dentin/pulp. This systematic review aimed to summarize the current evidence regarding the role of these cells in dental pulp regeneration. Methods: We searched the following databases: PubMed, Cochrane Library, MEDLINE, SCOPUS, ScienceDirect, and Web of Science using relevant keywords. Case reports and non-English studies were excluded. We included all studies using dental stem cells in tooth repair whether in vivo or in vitro studies. Results: Dental pulp stem cell (DPSCs) is the most common type of cell. Most stem cells are incorporated and implanted into the root canals in different scaffold forms. Some experiments combine growth factors such as TDM, BMP, and G-CSF with stem cells to improve the results. The transplant of DPSCs and stem cells from apical papilla (SCAPs) was found to be associated with pulp-like recovery, efficient revascularization, enhanced chondrogenesis, and direct vascular supply of regenerated tissue. Conclusion: The current evidence suggests that DPSCs, stem cells from human exfoliated deciduous teeth, and SCAPs are capable of providing sufficient pulp regeneration and vascularization. For the development of the dental repair field, it is important to screen for more effective stem cells, dentine releasing therapies, good biomimicry scaffolds, and good histological markers.
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48
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Ning T, Shao J, Zhang X, Luo X, Huang X, Wu H, Xu S, Wu B, Ma D. Ageing affects the proliferation and mineralization of rat dental pulp stem cells under inflammatory conditions. Int Endod J 2019; 53:72-83. [PMID: 31419325 DOI: 10.1111/iej.13205] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 08/13/2019] [Indexed: 02/06/2023]
Abstract
AIM To comparatively evaluate changes in the proliferation and mineralization abilities of dental pulp stem cells (DPSCs) from juvenile and adult rats in a lipopolysaccharide (LPS)-induced inflammatory microenvironment to provide a theoretical basis for the age-related differences observed in DPSCs during repair of inflammatory injuries. METHODOLOGY DPSCs were isolated from juvenile (JDPSCs) and adult rats (ADPSCs), and senescence-associated β-galactosidase staining was used to compare senescence between JDPSCs and ADPSCs. Effects of LPS on JDPSCs and ADPSCs proliferation were investigated by cell counting kit-8 assays and flow cytometry. Alizarin red staining, quantitative reverse transcription polymerase chain reaction and Western blot assay were used to examine the effects of LPS on mineralization-related genes and proteins in JDPSCs and ADPSCs. Immunohistochemistry was used to compare interleukin-1β (IL-1β) and osteocalcin (OCN) expression in the pulpitis model. Unpaired Student's t-tests and one-way anova were used for statistical analysis. RESULTS DPSCs were isolated from juvenile and adult rat dental pulp tissues. At low concentrations (0.1-1 μg mL-1 ), LPS significantly promoted the proliferation of JDPSCs (P < 0.01) and ADPSCs (P < 0.01 or P < 0.05), with the effect being stronger in JDPSCs than in ADPSCs. In addition, mineralized nodules and the expression of mineralization-related genes (OCN, DSPP, ALP, BSP) increased significantly after stimulation with LPS (0.5 μg mL-1 ) in JDPSCs and ADPSCs (P < 0.01 or P < 0.05), and JDPSCs displayed a more obvious increase than ADPSCs. Western blots revealed OCN and ALP expression levels in JDPSCs treated with LPS were significantly upregulated (P < 0.05); meanwhile, ALP expression in ADPSCs increased slightly but significantly (P < 0.05), and OCN expression was not affected. Finally, IL-1β expression was significantly higher (P < 0.05) and OCN expression was significantly lower (P < 0.05) in the inflamed dental pulp of adult rats than in juvenile rats. CONCLUSIONS A certain degree of inflammatory stimulation promoted the proliferation and mineralization of DPSCs; however, this effect declined with age. The DPSCs of adult donors in an inflammatory microenvironment have a weaker repair ability than that of juvenile donors, who are better candidates for tissues damage repair.
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Affiliation(s)
- T Ning
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,College of Stomatology, Southern Medical University, Guangzhou, China.,Department of Endodontics, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - J Shao
- Department of Stomatology, Guangzhou Hospital of Integrated Traditional and West Medicine, Guangzhou, China
| | - X Zhang
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,College of Stomatology, Southern Medical University, Guangzhou, China
| | - X Luo
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,College of Stomatology, Southern Medical University, Guangzhou, China
| | - X Huang
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,College of Stomatology, Southern Medical University, Guangzhou, China
| | - H Wu
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,College of Stomatology, Southern Medical University, Guangzhou, China
| | - S Xu
- College of Stomatology, Southern Medical University, Guangzhou, China.,Department of Endodontics, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - B Wu
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,College of Stomatology, Southern Medical University, Guangzhou, China
| | - D Ma
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,College of Stomatology, Southern Medical University, Guangzhou, China
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Fawzy El-Sayed KM, Ahmed GM, Abouauf EA, Schwendicke F. Stem/progenitor cell-mediated pulpal tissue regeneration: a systematic review and meta-analysis. Int Endod J 2019; 52:1573-1585. [PMID: 31232460 DOI: 10.1111/iej.13177] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 06/20/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Stem/progenitor cell-mediated pulpal regeneration could represent a promising therapeutic alternative in the field of clinical endodontics. AIM The present study aimed to systematically assess and meta-analyse dental pulpal tissue regeneration, pulpal vitality and apical healing after the transplantation of stem/progenitor cells versus no transplantation. DATA SOURCES MEDLINE, Cochrane CENTRAL and EMBASE were searched up to January 2019 for animal experiments and human trials evaluating the pulpal transplantation of stem/progenitor cells. Cross-referencing and hand search were additionally performed. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS Based on randomized controlled clinical trials (RCTs) or controlled clinical trials (CCTs), conducted in animals or humans, the effect of the transplantation of stem/progenitor cells compared to no transplantation on pulpal tissue regeneration, pulpal vitality and apical healing was examined. STUDY APPRAISAL AND SYNTHESIS METHODS The primary outcome was histologically determined pulpal tissue regeneration, whilst pulpal vitality and apical healing were secondary outcomes. The SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) guidelines and the revised Cochrane risk of bias tool (RoB 2.0) were used for risk-of-bias assessment. Pooled standardized differences in means (SDM) and 95% confidence intervals (95% CI) were calculated using random-effects meta-analyses. RESULTS From 2834 identified articles, eight animal experiments (82 animals with 336 experimental pulpal defects) and one human trial (40 humans with 40 pulpal defects) were included. Risk of bias of most animal studies was high, whilst the human trial revealed 'some concerns'. Stem/progenitor cell-transplanted pulps demonstrated significantly increased pulpal tissue regeneration compared with controls (SDM [95%CI]: 6.29 [3.78-8.80]). LIMITATIONS Data on pulpal vitality and apical healing were sparse and inconsistent. Heterogeneity across studies was substantial, publication bias was present, and mainly indirect, surrogate outcome measures were applied. The overall strength of evidence was very low. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS The transplanation of stem/progenitor cells shows promise for pulp regeneration, whilst clinical routine application is still not in reach. Further investigations, employing a comprehensive set of outcomes including those demonstrating functional pulp regeneration relevant for patient-centred care, are required.
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Affiliation(s)
- K M Fawzy El-Sayed
- Oral Medicine and Periodontology Department, Faculty of Dentistry, Cairo University, Cairo, Egypt.,Stem Cell and Tissue Engineering Research Group, Faculty of Dentistry, Cairo University, Cairo, Egypt.,Clinic for Conservative Dentistry and Periodontology, Christian-Albrechts-Universität Kiel, Kiel, Germany
| | - G M Ahmed
- Stem Cell and Tissue Engineering Research Group, Faculty of Dentistry, Cairo University, Cairo, Egypt.,Department of Endodontics, Faculty of Dentistry, Cairo University, Cairo, Egypt
| | - E A Abouauf
- Stem Cell and Tissue Engineering Research Group, Faculty of Dentistry, Cairo University, Cairo, Egypt.,Department of Operative and Preventive Dentistry, Faculty of Dentistry, Cairo University, Cairo, Egypt
| | - F Schwendicke
- Department of Operative and Preventive Dentistry, Charité - Universitätsmedizin Berlin, Berlin, Germany
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50
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Zein N, Harmouch E, Lutz JC, Fernandez De Grado G, Kuchler-Bopp S, Clauss F, Offner D, Hua G, Benkirane-Jessel N, Fioretti F. Polymer-Based Instructive Scaffolds for Endodontic Regeneration. MATERIALS 2019; 12:ma12152347. [PMID: 31344822 PMCID: PMC6695966 DOI: 10.3390/ma12152347] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 07/19/2019] [Accepted: 07/22/2019] [Indexed: 12/22/2022]
Abstract
The challenge of endodontic regeneration is modulated by clinical conditions which determine five kinds of tissue requirements: pulp connective-tissue formation, dentin formation, revascularization, reinnervation and radicular edification. Polymer scaffolds constitute keystone of the different endodontic regenerative strategies. Indeed, scaffolds are crucial for carrying active molecules and competent cells which optimize the regeneration. Hydrogels are very beneficial for controlling viscosity and porosity of endodontic scaffolds. The nanofibrous and microporous scaffolds mimicking extracellular matrix are also of great interest for promoting dentin-pulp formation. Two main types of polymer scaffolds are highlighted: collagen and fibrin. Collagen scaffolds which are similar to native pulp tissue, are adequate for pulp connective tissue formation. Functionnalization by active biomolecules as BMP, SDF-1, G-CSF enhances their properties. Fibrin or PRF scaffolds present the advantage of promoting stem cell differentiation and concomitant revascularisation. The choice of the type of polymers (polypeptide, PCL, chitosan) can depend on its ability to deliver the active biomolecule or to build as suitable hydrogel as possible. Since 2010s, proposals to associate different types of polymers in a same scaffold have emerged for adding advantages or for offsetting a disadvantage of a polymer. Further works would study the synergetic effects of different innovative polymers composition.
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Affiliation(s)
- Naimah Zein
- French National Institute of Health and Medical Research (INSERM), Regenerative Nanomedicine, UMR 1260, FMTS, 67085 Strasbourg, France
| | - Ezeddine Harmouch
- French National Institute of Health and Medical Research (INSERM), Regenerative Nanomedicine, UMR 1260, FMTS, 67085 Strasbourg, France
| | - Jean-Christophe Lutz
- Faculté de Médecine de Strasbourg, Strasbourg, Université de Strasbourg, 67000 Strasbourg, France
- Pôle de Chirurgie Maxillo-Faciale et Stomatologie, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
| | - Gabriel Fernandez De Grado
- French National Institute of Health and Medical Research (INSERM), Regenerative Nanomedicine, UMR 1260, FMTS, 67085 Strasbourg, France
- Faculté de Chirurgie Dentaire de Strasbourg, Université de Strasbourg, 67000 Strasbourg, France
- Hôpitaux Universitaires de Strasbourg, Pôle de Médecine et Chirurgie Bucco-Dentaires, 67000 Strasbourg, France
| | - Sabine Kuchler-Bopp
- French National Institute of Health and Medical Research (INSERM), Regenerative Nanomedicine, UMR 1260, FMTS, 67085 Strasbourg, France
| | - François Clauss
- French National Institute of Health and Medical Research (INSERM), Regenerative Nanomedicine, UMR 1260, FMTS, 67085 Strasbourg, France
- Faculté de Chirurgie Dentaire de Strasbourg, Université de Strasbourg, 67000 Strasbourg, France
- Hôpitaux Universitaires de Strasbourg, Pôle de Médecine et Chirurgie Bucco-Dentaires, 67000 Strasbourg, France
| | - Damien Offner
- French National Institute of Health and Medical Research (INSERM), Regenerative Nanomedicine, UMR 1260, FMTS, 67085 Strasbourg, France
- Faculté de Chirurgie Dentaire de Strasbourg, Université de Strasbourg, 67000 Strasbourg, France
- Hôpitaux Universitaires de Strasbourg, Pôle de Médecine et Chirurgie Bucco-Dentaires, 67000 Strasbourg, France
| | - Guoqiang Hua
- French National Institute of Health and Medical Research (INSERM), Regenerative Nanomedicine, UMR 1260, FMTS, 67085 Strasbourg, France
- Faculté de Chirurgie Dentaire de Strasbourg, Université de Strasbourg, 67000 Strasbourg, France
| | - Nadia Benkirane-Jessel
- French National Institute of Health and Medical Research (INSERM), Regenerative Nanomedicine, UMR 1260, FMTS, 67085 Strasbourg, France
- Faculté de Chirurgie Dentaire de Strasbourg, Université de Strasbourg, 67000 Strasbourg, France
| | - Florence Fioretti
- French National Institute of Health and Medical Research (INSERM), Regenerative Nanomedicine, UMR 1260, FMTS, 67085 Strasbourg, France.
- Faculté de Chirurgie Dentaire de Strasbourg, Université de Strasbourg, 67000 Strasbourg, France.
- Hôpitaux Universitaires de Strasbourg, Pôle de Médecine et Chirurgie Bucco-Dentaires, 67000 Strasbourg, France.
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