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1
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Davidson CL, Smit C, Nel S. Supernumerary teeth: A pictorial review and revised classification. J Oral Biol Craniofac Res 2025; 15:454-462. [PMID: 40144646 PMCID: PMC11938152 DOI: 10.1016/j.jobcr.2025.03.005] [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: 01/31/2025] [Revised: 03/04/2025] [Accepted: 03/05/2025] [Indexed: 03/28/2025] Open
Abstract
Current literature regarding supernumerary teeth poses the risk of confusion as ambiguity in the terminology and classification of supernumerary teeth permits differing interpretations. Uncertainty in this regard distorts data on the true incidence and prevalence of supernumerary teeth. This pictorial review provides an overview of the current understanding regarding the development of supernumerary teeth, their positional and morphological classification, and eruptive alterations. We highlight the ambiguity in defining supernumerary teeth and propose an updated classification for the description of these teeth.
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Affiliation(s)
- Christy Lana Davidson
- Oral Biology, Department of Oral and Maxillofacial Pathology, School of Dentistry, University of Pretoria, South Africa
| | - Chané Smit
- Diagnostic Imaging, Department of Oral and Maxillofacial Pathology, School of Dentistry, University of Pretoria, South Africa
| | - Sulette Nel
- Oral Biology, Department of Oral and Maxillofacial Pathology, School of Dentistry, University of Pretoria, South Africa
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2
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Li Y, Sun M, Ding Y, Li A. Mandible-derived extracellular vesicles regulate early tooth development in miniature swine via targeting KDM2B. Int J Oral Sci 2025; 17:36. [PMID: 40289114 PMCID: PMC12034755 DOI: 10.1038/s41368-025-00348-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 01/10/2025] [Accepted: 01/13/2025] [Indexed: 04/30/2025] Open
Abstract
Tissue interactions play a crucial role in tooth development. Notably, extracellular vesicle-mediated interactions between the mandible and tooth germ are considered essential. Here, we revealed that mandible extracellular vesicles could modulate the proliferation and differentiation of dental mesenchymal cells by regulating the histone demethylase KDM2B. Further investigation showed that mandible derived extracellular vesicles could deliver miR-206 to KDM2B, thereby regulating tooth development. An animal study demonstrated that the miR-206/KDM2B pathway affected tooth morphogenesis and mineralization after eight weeks of subcutaneous transplantation in nude mice. In conclusion, this study suggested that the mandible played a critical role in tooth morphogenesis and mineralization, which could be a potential therapeutic target for abnormal tooth development and an alternative model for tooth regeneration.
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Affiliation(s)
- Ye Li
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
| | - Meng Sun
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Department of Periodontology, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
| | - Yi Ding
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Department of Periodontology, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
| | - Ang Li
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
- Department of Periodontology, College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
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3
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Morita K, Wang J, Okamoto K, Iwata T. The next generation of regenerative dentistry: From tooth development biology to periodontal tissue, dental pulp, and whole tooth reconstruction in the clinical setting. Regen Ther 2025; 28:333-344. [PMID: 39885872 PMCID: PMC11780712 DOI: 10.1016/j.reth.2025.01.002] [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: 09/29/2024] [Revised: 12/08/2024] [Accepted: 01/04/2025] [Indexed: 02/01/2025] Open
Abstract
In modern dentistry, prosthetic approaches such as implants and dentures have been developed as symptomatic solutions for tooth loss. However, the complete regeneration of teeth and periodontal tissue, an ultimate aspiration of humanity, remains unachieved. Recent advancements in fundamental scientific technologies, including single-cell RNA sequencing and spatial transcriptomics, have significantly advanced our molecular understanding of tooth development, paving the way toward achieving this goal. This review summarizes the fundamental processes of tooth development in humans and mice, recent findings from basic research, and current clinical applications in dental regenerative medicine, including periodontal, alveolar bone, and dental pulp regeneration using cellular approaches. Building on accumulated scientific knowledge, the complete regeneration of teeth and periodontal tissues may be achievable in the near future. We discuss the potential of emerging approaches, such as organoids derived from pluripotent stem cells and xenotransplantation using genetically modified animals, to transform dental medicine. These innovative concepts and integrated technologies hold the promise of enabling the regeneration of fully functional teeth and periodontal tissues.
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Affiliation(s)
- Kazuki Morita
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo (Science Tokyo), 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Jiacheng Wang
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo (Science Tokyo), 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Keisuke Okamoto
- Health Science Research and Development Center (HeRD), Institute of Science Tokyo (Science Tokyo), 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Takanori Iwata
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo (Science Tokyo), 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
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4
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Chu X, Zhou Z, Qian X, Shen H, Cheng H, Zhang J. Functional regeneration strategies of hair follicles: advances and challenges. Stem Cell Res Ther 2025; 16:77. [PMID: 39985119 PMCID: PMC11846195 DOI: 10.1186/s13287-025-04210-y] [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: 11/23/2024] [Accepted: 01/29/2025] [Indexed: 02/24/2025] Open
Abstract
Hair follicles are essential appendages of human skin that function in protection, sensation, thermoregulation and social interactions. The multicellular components, particularly the dermal papilla, matrix and bulge housing stem cells, enable cyclic hair growth postnatally. However, miniaturization and loss of hair follicles can occur in the context of ageing, trauma and various alopecia-related diseases. Conventional treatments involve the redistribution of existing follicles, which may not be viable in patients lacking follicular resources. Recent progress in the comprehension of morphogenesis and the development of biomaterials has significantly advanced follicle reconstruction, incorporating organ germ assembling, stem cell induction and bioprinting techniques. Despite these advancements, fully restoring hair follicles remains challenging due to the complexities of replicating embryonic signals and sustaining growth cycles. Identifying suitable cell sources for clinical applications also presents a hurdle. Here, we retrospect the progress made in the field of hair follicle regeneration, aiming to offer an exhaustive analysis on the benefits and limitations of these methods, and to foster the development of innovative solutions.
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Affiliation(s)
- Xi Chu
- Department of Plastic and Cosmetic Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, 261 Huansha Road, Hangzhou, 310000, Zhejiang, China
| | - Zhentao Zhou
- Department of Plastic and Cosmetic Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, 261 Huansha Road, Hangzhou, 310000, Zhejiang, China
| | - Xifei Qian
- School of Medicine, Zhejiang Chinese Medical University, Hangzhou, 310000, Zhejiang, China
| | - Haiyan Shen
- Department of Plastic and Cosmetic Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, 261 Huansha Road, Hangzhou, 310000, Zhejiang, China
| | - Hanxiao Cheng
- Department of Plastic and Cosmetic Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, 261 Huansha Road, Hangzhou, 310000, Zhejiang, China
| | - Jufang Zhang
- Department of Plastic and Cosmetic Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, 261 Huansha Road, Hangzhou, 310000, Zhejiang, China.
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5
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Han J, Leeuwenburgh SCG, Jansen JA, Yang F, van Oirschot BAJA. Biological Processes in Gingival Tissue Integration Around Dental Implants. TISSUE ENGINEERING. PART B, REVIEWS 2025; 31:1-19. [PMID: 38526353 DOI: 10.1089/ten.teb.2023.0371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/26/2024]
Abstract
Peri-implant gingival tissue integration (GTI) is pivotal in determining the long-term success and functionality of dental implants. To enhance GTI, researchers have increasingly focused during the past decade on unraveling the response of gingival tissues to implant surfaces. This increased focus on soft instead of hard tissue integration has led to the development of various models, including in vitro cell culture systems and in vivo animal models, designed to predict and assess GTI around dental implants. However, inconsistent study outcomes between the different models have created confusion, highlighting the need for a comprehensive review. Therefore, the main objective of this review is to present a comprehensive overview of existing in vitro models, ranging from 2D to 3D, specifically designed to investigate cellular behavior relevant to peri-implant GTI. To facilitate a better comprehension of the utility of these models, the review initiates an elucidation of the histological characteristics of gingival tissues surrounding natural dentition, offering insights into the healing dynamics and histological adaptation processes occurring in gingival tissues adjacent to dental implants. In addition, through a critical evaluation of the strengths and limitations inherent in each model, our aim is to contribute to a more profound understanding of their applicability and effectiveness in GTI research.
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Affiliation(s)
- Jing Han
- Department of Dentistry-Regenerative Biomaterials, Research Institute for Medical Innovation, Radboudumc, Nijmegen, The Netherlands
| | - Sander C G Leeuwenburgh
- Department of Dentistry-Regenerative Biomaterials, Research Institute for Medical Innovation, Radboudumc, Nijmegen, The Netherlands
| | - John A Jansen
- Department of Dentistry-Regenerative Biomaterials, Research Institute for Medical Innovation, Radboudumc, Nijmegen, The Netherlands
| | - Fang Yang
- Department of Dentistry-Regenerative Biomaterials, Research Institute for Medical Innovation, Radboudumc, Nijmegen, The Netherlands
| | - Bart A J A van Oirschot
- Department of Dentistry-Regenerative Biomaterials, Research Institute for Medical Innovation, Radboudumc, Nijmegen, The Netherlands
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6
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Zhang Z, Hu H, Xu Z, Shan C, Chen H, Xie K, Wang K, Wang Y, Zhu Q, Yin Y, Cai H, Zhang Y, Li Z. A Chemically Defined Culture for Tooth Reconstitution. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2404345. [PMID: 39601338 PMCID: PMC11744639 DOI: 10.1002/advs.202404345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 11/10/2024] [Indexed: 11/29/2024]
Abstract
It is known for decades that dental epithelium and mesenchyme can reconstitute and regenerate a functional tooth. However, the mechanism of tooth reconstitution remains largely unknown due to the lack of an efficient in vitro model. Here, a chemically defined culture system is established that supports tooth reconstitution, further development with normal anatomy, and prompt response to chemical interference in key developmental signaling pathways, termed as toothoids. By using such a system, it is discovered that, during reconstitution, instead of resetting the developmental clock, dental cells reorganized and restarted from the respective developmental stage where they are originally isolated. Moreover, co-stimulation of Activin A and Hedgehog/Smoothened agonist (SAG) sustained the initial induction of tooth fate from the first branchial arch, which would be otherwise quickly lost in culture. Furthermore, activation of Bone Morphogenetic Protein (BMP) signaling triggered efficient enamel formation in the late-stage toothoids, without affecting the normal development of ameloblasts. Together, these data highlight the toothoid culture as a powerful tool to dissect the molecular mechanisms of tooth reconstitution and regeneration.
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Affiliation(s)
- Ziwei Zhang
- Center of Growth Metabolism and AgingKey Laboratory of Bio‐Resource and Eco‐Environment of Ministry of EducationAnimal Disease Prevention and Food Safety Key Laboratory of Sichuan ProvinceCollege of Life SciencesSichuan University24 South Section 1, 1st Ring RoadChengdu610065China
| | - Hong Hu
- Center of Growth Metabolism and AgingKey Laboratory of Bio‐Resource and Eco‐Environment of Ministry of EducationAnimal Disease Prevention and Food Safety Key Laboratory of Sichuan ProvinceCollege of Life SciencesSichuan University24 South Section 1, 1st Ring RoadChengdu610065China
| | - Zhiheng Xu
- Center of Growth Metabolism and AgingKey Laboratory of Bio‐Resource and Eco‐Environment of Ministry of EducationAnimal Disease Prevention and Food Safety Key Laboratory of Sichuan ProvinceCollege of Life SciencesSichuan University24 South Section 1, 1st Ring RoadChengdu610065China
| | - Ce Shan
- Center of Growth Metabolism and AgingKey Laboratory of Bio‐Resource and Eco‐Environment of Ministry of EducationAnimal Disease Prevention and Food Safety Key Laboratory of Sichuan ProvinceCollege of Life SciencesSichuan University24 South Section 1, 1st Ring RoadChengdu610065China
| | - Hanyi Chen
- Center of Growth Metabolism and AgingKey Laboratory of Bio‐Resource and Eco‐Environment of Ministry of EducationAnimal Disease Prevention and Food Safety Key Laboratory of Sichuan ProvinceCollege of Life SciencesSichuan University24 South Section 1, 1st Ring RoadChengdu610065China
| | - Kun Xie
- Center of Growth Metabolism and AgingKey Laboratory of Bio‐Resource and Eco‐Environment of Ministry of EducationAnimal Disease Prevention and Food Safety Key Laboratory of Sichuan ProvinceCollege of Life SciencesSichuan University24 South Section 1, 1st Ring RoadChengdu610065China
| | - Kun Wang
- Center of Growth Metabolism and AgingKey Laboratory of Bio‐Resource and Eco‐Environment of Ministry of EducationAnimal Disease Prevention and Food Safety Key Laboratory of Sichuan ProvinceCollege of Life SciencesSichuan University24 South Section 1, 1st Ring RoadChengdu610065China
| | - Yifu Wang
- Center of Growth Metabolism and AgingKey Laboratory of Bio‐Resource and Eco‐Environment of Ministry of EducationAnimal Disease Prevention and Food Safety Key Laboratory of Sichuan ProvinceCollege of Life SciencesSichuan University24 South Section 1, 1st Ring RoadChengdu610065China
| | - Qing Zhu
- Center of Growth Metabolism and AgingKey Laboratory of Bio‐Resource and Eco‐Environment of Ministry of EducationAnimal Disease Prevention and Food Safety Key Laboratory of Sichuan ProvinceCollege of Life SciencesSichuan University24 South Section 1, 1st Ring RoadChengdu610065China
- Department of AnesthesiologyWest China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of EducationSichuan UniversityNo. 20, Section 3, South Renmin RoadChengdu610041China
| | - Yike Yin
- Center of Growth Metabolism and AgingKey Laboratory of Bio‐Resource and Eco‐Environment of Ministry of EducationAnimal Disease Prevention and Food Safety Key Laboratory of Sichuan ProvinceCollege of Life SciencesSichuan University24 South Section 1, 1st Ring RoadChengdu610065China
| | - Haoyang Cai
- Center of Growth Metabolism and AgingKey Laboratory of Bio‐Resource and Eco‐Environment of Ministry of EducationAnimal Disease Prevention and Food Safety Key Laboratory of Sichuan ProvinceCollege of Life SciencesSichuan University24 South Section 1, 1st Ring RoadChengdu610065China
| | - Yunqiu Zhang
- Center of Growth Metabolism and AgingKey Laboratory of Bio‐Resource and Eco‐Environment of Ministry of EducationAnimal Disease Prevention and Food Safety Key Laboratory of Sichuan ProvinceCollege of Life SciencesSichuan University24 South Section 1, 1st Ring RoadChengdu610065China
| | - Zhonghan Li
- Center of Growth Metabolism and AgingKey Laboratory of Bio‐Resource and Eco‐Environment of Ministry of EducationAnimal Disease Prevention and Food Safety Key Laboratory of Sichuan ProvinceCollege of Life SciencesSichuan University24 South Section 1, 1st Ring RoadChengdu610065China
- Department of AnesthesiologyWest China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of EducationSichuan UniversityNo. 20, Section 3, South Renmin RoadChengdu610041China
- State Key Laboratory of Oral DiseaseWest China Hospital of StomatologySichuan UniversityNo. 14, Section 3, South Renmin RoadChengdu610041China
- Yunnan Key Laboratory of StomatologyDepartment of Pediatric DentistryThe Affiliated Stomatology Hospital of Kunming Medical UniversityKunming Medical UniversityNo. 1088, Mid‐Haiyuan RoadKunming650500China
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7
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Zhang X, Contessi Negrini N, Correia R, Sharpe PT, Celiz AD, Angelova Volponi A. Generating Tooth Organoids Using Defined Bioorthogonally Cross-Linked Hydrogels. ACS Macro Lett 2024; 13:1620-1626. [PMID: 39532305 PMCID: PMC11656705 DOI: 10.1021/acsmacrolett.4c00520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 11/06/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024]
Abstract
Generating teeth in vitro requires mimicking tooth developmental processes. Biomaterials are essential to support 3D tooth organoid formation, but their properties must be finely tuned to achieve the required biomimicry for tooth development. For the first time, we used bioorthogonally cross-linked hydrogels as defined 3D matrixes for tooth developmental engineering, and we highlighted how their properties play a pivotal role in enabling 3D tooth organoid formation in vitro. We prepared hydrogels by mixing gelatin precursors modified either with tetrazine (Tz) or norbornene (Nb) moieties. We tuned the hydrogel properties (E = 2-7 kPa; G' = 500-1500 Pa) by varying the gelatin concentration (8% vs 12% w/V) and stoichiometric ratio (Tz:Nb = 1 vs 0.5). We encapsulated dental epithelial-mesenchymal cell pellets in a library of hydrogels and identified a hydrogel formulation that enabled successful growth kinetics and morphogenesis of tooth germs, introducing a defined tunable platform for tooth organoid engineering and modeling.
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Affiliation(s)
- Xuechen Zhang
- Centre
for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral
& Craniofacial Sciences, King’s
College London, Guy’s Hospital, SE1 9RT London, U.K.
| | - Nicola Contessi Negrini
- Department
of Bioengineering, Imperial College London, W12 0BZ London, U.K.
- The
Francis Crick Institute, NW1 1AT London, U.K.
| | - Rita Correia
- Department
of Bioengineering, Imperial College London, W12 0BZ London, U.K.
- The
Francis Crick Institute, NW1 1AT London, U.K.
| | - Paul T. Sharpe
- Centre
for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral
& Craniofacial Sciences, King’s
College London, Guy’s Hospital, SE1 9RT London, U.K.
| | - Adam D. Celiz
- Department
of Bioengineering, Imperial College London, W12 0BZ London, U.K.
- The
Francis Crick Institute, NW1 1AT London, U.K.
| | - Ana Angelova Volponi
- Centre
for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral
& Craniofacial Sciences, King’s
College London, Guy’s Hospital, SE1 9RT London, U.K.
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8
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Nakazato H, Onodera S, Aida N, Furusawa M, Azuma T. Comprehensive analysis of transcription factors involved in odontoblast differentiation mechanism. Med Mol Morphol 2024; 57:253-267. [PMID: 38987402 DOI: 10.1007/s00795-024-00389-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 04/18/2024] [Indexed: 07/12/2024]
Abstract
Primary cultured odontoblasts rapidly lose their tissue-specific phenotype. To identify transcription factors (TF) that are important for the maintenance of the odontoblast phenotype, primary cultures of C57BL/6 J mouse dental mesenchymal cells (DMC) were isolated, and expression of TF and odontoblast marker genes in cells immediately after isolation and 2 days after culture were comprehensively evaluated and compared using RNA-sequencing (RNA-seq). The expression of odontoblast markers in mouse dental mesenchymal cells decreased rapidly after isolation. In addition, the expression of Hedgehog-related, Notch-related, and immediate- early gene (IEG)-related transcription factors significantly decreased. Forced expression of these genes in lentiviral vectors, together with fibroblast growth factor 4 (FGF4), fibroblast growth factor 9 (FGF9), and the Wnt pathway activator CHIR99021, significantly induced the expression of odontogenic marker genes. These results indicate, for the first time, that Notch signaling and early genes may be important for maintaining odontoblast cultures. Furthermore, simultaneous stimulation of FGF, Wnt, Hedgehog, Notch pathways, and IEG transcription factors cooperatively promoted the maintenance of the odontoblast phenotype. These results suggest that the Hedgehog and Notch signaling pathways may play an important role in maintaining odontoblast phenotypes, in addition to FGF and Wnt signaling.
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Affiliation(s)
- Haruka Nakazato
- Department of Endodontics, Tokyo Dental College, 2-9-18 Kanda-Misaki-Chou, Chiyoda, Tokyo, 101-0061, Japan
| | - Shoko Onodera
- Department of Biochemistry, Tokyo Dental College, 2-9-18 Kanda-Misaki-Chou, Chiyoda, Tokyo, 101-0061, Japan
| | - Natsuko Aida
- Department of Biochemistry, Tokyo Dental College, 2-9-18 Kanda-Misaki-Chou, Chiyoda, Tokyo, 101-0061, Japan
| | - Masahiro Furusawa
- Department of Endodontics, Tokyo Dental College, 2-9-18 Kanda-Misaki-Chou, Chiyoda, Tokyo, 101-0061, Japan
| | - Toshifumi Azuma
- Department of Biochemistry, Tokyo Dental College, 2-9-18 Kanda-Misaki-Chou, Chiyoda, Tokyo, 101-0061, Japan.
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9
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Eldeeb D, Ikeda Y, Hojo H, Ohba S. Unraveling the hidden complexity: Exploring dental tissues through single-cell transcriptional profiling. Regen Ther 2024; 27:218-229. [PMID: 38596822 PMCID: PMC11002530 DOI: 10.1016/j.reth.2024.03.023] [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: 02/09/2024] [Revised: 03/21/2024] [Accepted: 03/24/2024] [Indexed: 04/11/2024] Open
Abstract
Understanding the composition and function of cells constituting tissues and organs is vital for unraveling biological processes. Single-cell analysis has allowed us to move beyond traditional methods of categorizing cell types. This innovative technology allows the transcriptional and epigenetic profiling of numerous individual cells, leading to significant insights into the development, homeostasis, and pathology of various organs and tissues in both animal models and human samples. In this review, we delve into the outcomes of major investigations using single-cell transcriptomics to decipher the cellular composition of mammalian teeth and periodontal tissues. The recent single-cell transcriptome-based studies have traced in detail the dental epithelium-ameloblast lineage and dental mesenchyme lineages in the mouse incisors and the tooth germ of both mice and humans; unraveled the microenvironment, the identity of niche cells, and cellular intricacies in the dental pulp; shed light on the molecular mechanisms orchestrating root formation; and characterized cellular dynamics of the periodontal ligament. Additionally, cellular components in dental pulps were compared between healthy and carious teeth at a single-cell level. Each section of this review contributes to a comprehensive understanding of tooth biology, offering valuable insights into developmental processes, niche cell identification, and the molecular secrets of the dental environment.
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Affiliation(s)
- Dahlia Eldeeb
- Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Japan
- Department of Physiology, Division of Biomedical Sciences, Nihon University School of Medicine, Japan
- Department of Oral Biology, Faculty of Dentistry, Cairo University, Egypt
| | - Yuki Ikeda
- Department of Tissue and Developmental Biology, Graduate School of Dentistry, Osaka University, Japan
| | - Hironori Hojo
- Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Japan
- Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Japan
| | - Shinsuke Ohba
- Department of Tissue and Developmental Biology, Graduate School of Dentistry, Osaka University, Japan
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10
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Takahashi K, Kiso H, Mihara E, Takagi J, Tokita Y, Murashima-Suginami A. Development of a new antibody drug to treat congenital tooth agenesis. J Oral Biosci 2024; 66:1-9. [PMID: 39389160 DOI: 10.1016/j.job.2024.10.002] [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: 08/17/2024] [Revised: 10/04/2024] [Accepted: 10/07/2024] [Indexed: 10/12/2024]
Abstract
BACKGROUND This study aimed to develop a therapeutic agent promoting teeth regeneration from autologous tissues for congenital tooth agenesis, specifically for hypodontia (≤5 missing congenital teeth, 10% prevalence) and oligodontia (≥6 missing congenital teeth, 0.1% prevalence). HIGHLIGHT We studied mice genetically deficient in the USAG-1 protein, an antagonist of BMP/Wnt which forms excessive teeth. We identified USAG-1 as a target molecule for increasing the number of teeth. Crossing USAG-1-deficient mice with a congenital tooth agenesis model restored tooth formation. We produced anti-USAG-1 neutralizing antibodies as potential therapeutic agents for the treatment of congenital tooth agenesis. Mice anti-USAG-1 neutralizing antibodies can potentially rescue the developmentally arrested tooth germ programmed to a certain tooth type. A humanized anti-USAG-1 antibody was developed as the final candidate. CONCLUSION Targeting USAG-1 shows promise for treating missing congenital tooth. Anti-USAG-1 neutralizing antibodies have been developed and will progress towards clinical trials, which may regenerate missing congenital teeth in conditions, such as hypodontia and oligodontia. The protocol framework for a phase 1 study has been finalized, and preparation for future studies is underway.
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Affiliation(s)
- K Takahashi
- Dentistry & Oral Surgery, Medical Research Institute KITANO HOSPITAL, PIIF Tazuke-kofukai, Osaka, Japan; Toregem Toregem BioPharma, Co.,Ltd, Kyoto, Japan.
| | - H Kiso
- Toregem Toregem BioPharma, Co.,Ltd, Kyoto, Japan
| | - E Mihara
- Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Osaka, Japan
| | - J Takagi
- Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Osaka, Japan
| | - Y Tokita
- Department of Disease Model, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan
| | - A Murashima-Suginami
- Dentistry & Oral Surgery, Medical Research Institute KITANO HOSPITAL, PIIF Tazuke-kofukai, Osaka, Japan; Toregem Toregem BioPharma, Co.,Ltd, Kyoto, Japan
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11
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Wu Y, Li X, Liu H, Yang X, Li R, Zhao H, Shang Z. Organoids in the oral and maxillofacial region: present and future. Int J Oral Sci 2024; 16:61. [PMID: 39482304 PMCID: PMC11528035 DOI: 10.1038/s41368-024-00324-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 06/18/2024] [Accepted: 09/12/2024] [Indexed: 11/03/2024] Open
Abstract
The oral and maxillofacial region comprises a variety of organs made up of multiple soft and hard tissue, which are anatomically vulnerable to the pathogenic factors of trauma, inflammation, and cancer. The studies of this intricate entity have been long-termly challenged by a lack of versatile preclinical models. Recently, the advancements in the organoid industry have provided novel strategies to break through this dilemma. Here, we summarize the existing biological and engineering approaches that were employed to generate oral and maxillofacial organoids. Then, we detail the use of modified co-culture methods, such as cell cluster co-inoculation and air-liquid interface culture technology to reconstitute the vascular network and immune microenvironment in assembled organoids. We further retrospect the existing oral and maxillofacial assembled organoids and their potential to recapitulate the homeostasis in parental tissues such as tooth, salivary gland, and mucosa. Finally, we discuss how the next-generation organoids may benefit to regenerative and precision medicine for treatment of oral-maxillofacial illness.
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Affiliation(s)
- Yufei Wu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Xiang Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Hanzhe Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Xiao Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Rui Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Hui Zhao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
- Department of Oral and Maxillofacial-Head and Neck Oncology, School of Stomatology-Hospital of Stomatology, Wuhan University, Wuhan, China.
| | - Zhengjun Shang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
- Department of Oral and Maxillofacial-Head and Neck Oncology, School of Stomatology-Hospital of Stomatology, Wuhan University, Wuhan, China.
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12
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Kagami H, Li X. Spheroids and organoids: Their implications for oral and craniofacial tissue/organ regeneration. J Oral Biol Craniofac Res 2024; 14:540-546. [PMID: 39092136 PMCID: PMC11292544 DOI: 10.1016/j.jobcr.2024.07.002] [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: 08/19/2023] [Revised: 06/09/2024] [Accepted: 07/01/2024] [Indexed: 08/04/2024] Open
Abstract
Spheroids are spherical aggregates of cells. Normally, most of adherent cells cannot survive in suspension; however, if they adhere to each other and grow to a certain size, they can survive without attaching to the dish surface. Studies have shown that spheroid formation induces dedifferentiation and improves plasticity, proliferative capability, and differentiation capability. In particular, spontaneous spheroids represent a selective and efficient cultivation technique for somatic stem cells. Organoids are considered mini-organs composed of multiple types of cells with extracellular matrices that are maintained in three-dimensional culture. Although their culture environment is similar to that of spheroids, organoids consist of differentiated cells with fundamental tissue/organ structures similar to those of native organs. Organoids have been used for drug development, disease models, and basic biological studies. Spheroid culture has been reported for various cell types in the oral and craniofacial regions, including salivary gland epithelial cells, periodontal ligament cells, dental pulp stem cells, and oral mucosa-derived cells. For broader clinical application, it is crucial to identify treatment targets that can leverage the superior stemness of spheroids. Organoids have been developed from various organs, including taste buds, oral mucosa, teeth, and salivary glands, for basic biological studies and also with the goal to replace damaged or defective organs. The development of novel immune-tolerant cell sources is the key to the widespread clinical application of organoids in regenerative medicine. Further efforts to understand the underlying basic mechanisms of spheroids and organoids will lead to the development of safe and efficient next-generation regenerative therapies.
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Affiliation(s)
- Hideaki Kagami
- Department of Dentistry and Oral Surgery, Aichi Medical University, Aichi, Japan
| | - Xianqi Li
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Matsumoto Dental University, Shiojiri, 399-0781, Japan
- Department of Hard Tissue Research, Graduate School of Oral Medicine, Matsumoto Dental University, Shiojiri, 399-0781, Japan
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13
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Farshbaf A, Mottaghi M, Mohammadi M, Monsef K, Mirhashemi M, Attaran Khorasani A, Mohtasham N. Regenerative application of oral and maxillofacial 3D organoids based on dental pulp stem cell. Tissue Cell 2024; 89:102451. [PMID: 38936200 DOI: 10.1016/j.tice.2024.102451] [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: 01/19/2024] [Revised: 05/30/2024] [Accepted: 06/17/2024] [Indexed: 06/29/2024]
Abstract
Dental pulp stem cells (DPSCs) originate from the neural crest and the present mesenchymal phenotype showed self-renewal capabilities and can differentiate into at least three lineages. DPSCs are easily isolated with minimal harm, no notable ethical constraints, and without general anesthesia to the donor individuals. Furthermore, cryopreservation of DPSCs provides this opportunity for autologous transplantation in future studies without fundamental changes in stemness, viability, proliferation, and differentiating features. Current approaches for pulp tissue regeneration include pulp revascularization, cell-homing-based regenerative endodontic treatment (RET), cell-transplantation-based regenerative endodontic treatment, and allogeneic transplantation. In recent years, a novel technology, organoid, provides a mimic physiological condition and tissue construct that can be applied for tissue engineering, genetic manipulation, disease modeling, single-cell high throughput analysis, living biobank, cryopreserving and maintaining cells, and therapeutic approaches based on personalized medicine. The organoids can be a reliable preclinical prediction model for evaluating cell behavior, monitoring drug response or resistance, and comparing healthy and pathological conditions for therapeutic and prognostic approaches. In the current review, we focused on the promising application of 3D organoid technology based on DPSCs in oral and maxillofacial tissue regeneration. We discussed encountering challenges and limitations, and found promising solutions to overcome obstacles.
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Affiliation(s)
- Alieh Farshbaf
- Dental Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahtab Mottaghi
- School of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehdi Mohammadi
- Medical Informatics Research Center, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran
| | - Kouros Monsef
- Dental Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Mirhashemi
- Department of Oral and Maxillofacial Pathology, and Oral and Maxillofacial Diseases Research Center, School of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Nooshin Mohtasham
- Oral and Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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14
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Hermans F, Hasevoets S, Vankelecom H, Bronckaers A, Lambrichts I. From Pluripotent Stem Cells to Organoids and Bioprinting: Recent Advances in Dental Epithelium and Ameloblast Models to Study Tooth Biology and Regeneration. Stem Cell Rev Rep 2024; 20:1184-1199. [PMID: 38498295 PMCID: PMC11222197 DOI: 10.1007/s12015-024-10702-w] [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] [Accepted: 02/20/2024] [Indexed: 03/20/2024]
Abstract
Ameloblasts are the specialized dental epithelial cell type responsible for enamel formation. Following completion of enamel development in humans, ameloblasts are lost and biological repair or regeneration of enamel is not possible. In the past, in vitro models to study dental epithelium and ameloblast biology were limited to freshly isolated primary cells or immortalized cell lines, both with limited translational potential. In recent years, large strides have been made with the development of induced pluripotent stem cell and organoid models of this essential dental lineage - both enabling modeling of human dental epithelium. Upon induction with several different signaling factors (such as transforming growth factor and bone morphogenetic proteins) these models display elevated expression of ameloblast markers and enamel matrix proteins. The advent of 3D bioprinting, and its potential combination with these advanced cellular tools, is poised to revolutionize the field - and its potential for tissue engineering, regenerative and personalized medicine. As the advancements in these technologies are rapidly evolving, we evaluate the current state-of-the-art regarding in vitro cell culture models of dental epithelium and ameloblast lineage with a particular focus toward their applicability for translational tissue engineering and regenerative/personalized medicine.
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Affiliation(s)
- Florian Hermans
- Department of Cardiology and Organ Systems (COS), Biomedical Research Institute (BIOMED), Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, 3590, Belgium.
| | - Steffie Hasevoets
- Department of Cardiology and Organ Systems (COS), Biomedical Research Institute (BIOMED), Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, 3590, Belgium
| | - Hugo Vankelecom
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Leuven, 3000, Belgium
| | - Annelies Bronckaers
- Department of Cardiology and Organ Systems (COS), Biomedical Research Institute (BIOMED), Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, 3590, Belgium
| | - Ivo Lambrichts
- Department of Cardiology and Organ Systems (COS), Biomedical Research Institute (BIOMED), Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, 3590, Belgium.
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15
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Maria OM, Heram A, Tran SD. Bioengineering from the laboratory to clinical translation in oral and maxillofacial reconstruction. Saudi Dent J 2024; 36:955-962. [PMID: 39035556 PMCID: PMC11255950 DOI: 10.1016/j.sdentj.2024.05.004] [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: 11/13/2023] [Revised: 05/07/2024] [Accepted: 05/07/2024] [Indexed: 07/23/2024] Open
Abstract
Background Conventional techniques used in oral and maxillofacial reconstruction focus mainly on utilizing autologous tissues that have unquestionably improved function and esthetics for many patients, worldwide. However, the success depends on countless factors such as: donor and recipient sites conditions, patient's medical history, surgeon's experience, restricted availability of high-quality autogenous tissues or stem cells, and increased surgical cost and time. Materials and Methods Lately, teaming researchers, scientists, surgeons, and engineers, to address these limitations, have allowed tremendous progress in recombinant protein therapy, cell-based therapy, and gene therapy. Results Over the past few years, biomedical engineering has been evolving from the laboratory to clinical applications, for replacement of damaged body tissues due to trauma, cancer, congenital or acquired disorders. Conclusions This review provides an outlook on the content, benefits, recent advances, limitations, and future expectations of biomedical engineering for salivary glands, oral mucosa, dental structures, and maxillofacial reconstruction.
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Affiliation(s)
- Ola M. Maria
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, Quebec, Canada
| | - Ashraf Heram
- Grand Strand Facial and Jaw Surgery, Myrtle Beach, SC, United States
| | - Simon D. Tran
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, Quebec, Canada
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16
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Park S, Cho SW. Bioengineering toolkits for potentiating organoid therapeutics. Adv Drug Deliv Rev 2024; 208:115238. [PMID: 38447933 DOI: 10.1016/j.addr.2024.115238] [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: 09/26/2023] [Revised: 01/28/2024] [Accepted: 02/27/2024] [Indexed: 03/08/2024]
Abstract
Organoids are three-dimensional, multicellular constructs that recapitulate the structural and functional features of specific organs. Because of these characteristics, organoids have been widely applied in biomedical research in recent decades. Remarkable advancements in organoid technology have positioned them as promising candidates for regenerative medicine. However, current organoids still have limitations, such as the absence of internal vasculature, limited functionality, and a small size that is not commensurate with that of actual organs. These limitations hinder their survival and regenerative effects after transplantation. Another significant concern is the reliance on mouse tumor-derived matrix in organoid culture, which is unsuitable for clinical translation due to its tumor origin and safety issues. Therefore, our aim is to describe engineering strategies and alternative biocompatible materials that can facilitate the practical applications of organoids in regenerative medicine. Furthermore, we highlight meaningful progress in organoid transplantation, with a particular emphasis on the functional restoration of various organs.
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Affiliation(s)
- Sewon Park
- Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
| | - Seung-Woo Cho
- Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; Center for Nanomedicine, Institute for Basic Science (IBS), Seoul 03722, Republic of Korea; Graduate Program of Nano Biomedical Engineering (NanoBME), Advanced Science Institute, Yonsei University, Seoul 03722, Republic of Korea.
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17
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Xu X, Gong X, Zhang L, Zhang H, Sun Y. PRX1-positive mesenchymal stem cells drive molar morphogenesis. Int J Oral Sci 2024; 16:15. [PMID: 38369512 PMCID: PMC10874978 DOI: 10.1038/s41368-024-00277-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 12/29/2023] [Accepted: 12/30/2023] [Indexed: 02/20/2024] Open
Abstract
Mammalian teeth, developing inseparable from epithelial-mesenchymal interaction, come in many shapes and the key factors governing tooth morphology deserve to be answered. By merging single-cell RNA sequencing analysis with lineage tracing models, we have unearthed a captivating correlation between the contrasting morphology of mouse molars and the specific presence of PRX1+ cells within M1. These PRX1+ cells assume a profound responsibility in shaping tooth morphology through a remarkable divergence in dental mesenchymal cell proliferation. Deeper into the mechanisms, we have discovered that Wnt5a, bestowed by mesenchymal PRX1+ cells, stimulates mesenchymal cell proliferation while orchestrating molar morphogenesis through WNT signaling pathway. The loss of Wnt5a exhibits a defect phenotype similar to that of siPrx1. Exogenous addition of WNT5A can successfully reverse the inhibited cell proliferation and consequent deviant appearance exhibited in Prx1-deficient tooth germs. These findings bestow compelling evidence of PRX1-positive mesenchymal cells to be potential target in regulating tooth morphology.
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Affiliation(s)
- Xiaoqiao Xu
- Department of Implantology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Xuyan Gong
- Department of Implantology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Lei Zhang
- Department of Implantology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Han Zhang
- Department of Implantology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Yao Sun
- Department of Implantology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China.
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18
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Hazrati P, Mirtaleb MH, Boroojeni HSH, Koma AAY, Nokhbatolfoghahaei H. Current Trends, Advances, and Challenges of Tissue Engineering-Based Approaches of Tooth Regeneration: A Review of the Literature. Curr Stem Cell Res Ther 2024; 19:473-496. [PMID: 35984017 DOI: 10.2174/1574888x17666220818103228] [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: 04/05/2022] [Revised: 05/17/2022] [Accepted: 06/01/2022] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Tooth loss is a significant health issue. Currently, this situation is often treated with the use of synthetic materials such as implants and prostheses. However, these treatment modalities do not fully meet patients' biological and mechanical needs and have limited longevity. Regenerative medicine focuses on the restoration of patients' natural tissues via tissue engineering techniques instead of rehabilitating with artificial appliances. Therefore, a tissue-engineered tooth regeneration strategy seems like a promising option to treat tooth loss. OBJECTIVE This review aims to demonstrate recent advances in tooth regeneration strategies and discoveries about underlying mechanisms and pathways of tooth formation. RESULTS AND DISCUSSION Whole tooth regeneration, tooth root formation, and dentin-pulp organoid generation have been achieved by using different seed cells and various materials for scaffold production. Bioactive agents are critical elements for the induction of cells into odontoblast or ameloblast lineage. Some substantial pathways enrolled in tooth development have been figured out, helping researchers design their experiments more effectively and aligned with the natural process of tooth formation. CONCLUSION According to current knowledge, tooth regeneration is possible in case of proper selection of stem cells, appropriate design and manufacturing of a biocompatible scaffold, and meticulous application of bioactive agents for odontogenic induction. Understanding innate odontogenesis pathways play a crucial role in accurately planning regenerative therapeutic interventions in order to reproduce teeth.
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Affiliation(s)
- Parham Hazrati
- School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Helia Sadat Haeri Boroojeni
- Oral and Maxillofacial Surgery Department, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Hanieh Nokhbatolfoghahaei
- Dental Research Center, Research Institute of Dental Sciences, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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19
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Wang H, Wang X, Huang L, Wang C, Yu F, Ye L. Overburdened ferroptotic stress impairs tooth morphogenesis. eLife 2023; 12:RP88745. [PMID: 37991825 PMCID: PMC10665014 DOI: 10.7554/elife.88745] [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] [Indexed: 11/23/2023] Open
Abstract
The role of regulated cell death in organ development, particularly the impact of non-apoptotic cell death, remains largely uncharted. Ferroptosis, a non-apoptotic cell death pathway known for its iron dependence and lethal lipid peroxidation, is currently being rigorously investigated for its pathological functions. The balance between ferroptotic stress (iron and iron-dependent lipid peroxidation) and ferroptosis supervising pathways (anti-lipid peroxidation systems) serves as the key mechanism regulating the activation of ferroptosis. Compared with other forms of regulated necrotic cell death, ferroptosis is critically related to the metabolism of lipid and iron which are also important in organ development. In our study, we examined the role of ferroptosis in organogenesis using an ex vivo tooth germ culture model, investigating the presence and impact of ferroptotic stress on tooth germ development. Our findings revealed that ferroptotic stress increased during tooth development, while the expression of glutathione peroxidase 4 (Gpx4), a crucial anti-lipid peroxidation enzyme, also escalated in dental epithelium/mesenchyme cells. The inhibition of ferroptosis was found to partially rescue erastin-impaired tooth morphogenesis. Our results suggest that while ferroptotic stress is present during tooth organogenesis, its effects are efficaciously controlled by the subsequent upregulation of Gpx4. Notably, an overabundance of ferroptotic stress, as induced by erastin, suppresses tooth morphogenesis.
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Affiliation(s)
- Haisheng Wang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan UniversityChengduChina
| | - Xiaofeng Wang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan UniversityChengduChina
- Department of Endodontics, West China School of Stomatology, Sichuan UniversityChengduChina
| | - Liuyan Huang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan UniversityChengduChina
- Department of Endodontics, West China School of Stomatology, Sichuan UniversityChengduChina
| | - Chenglin Wang
- Department of Endodontics, West China School of Stomatology, Sichuan UniversityChengduChina
| | - Fanyuan Yu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan UniversityChengduChina
- Department of Endodontics, West China School of Stomatology, Sichuan UniversityChengduChina
| | - Ling Ye
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan UniversityChengduChina
- Department of Endodontics, West China School of Stomatology, Sichuan UniversityChengduChina
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20
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Vaswani BK, Mundada BP, Bhola N, Paul P, Reche A, Ahuja KP. Stem-Cell Therapy: Filling Gaps in Oro-Maxillofacial Region. Cureus 2023; 15:e47171. [PMID: 38022051 PMCID: PMC10652057 DOI: 10.7759/cureus.47171] [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: 08/26/2023] [Accepted: 10/14/2023] [Indexed: 12/01/2023] Open
Abstract
How do stem cells function? Why should we, as dentists, care about stem cells? How might dental procedures be substituted by stem cells? Are stem cells capable of regenerating a tooth or temporomandibular joint (TMJ)? Although the ability to regenerate a destroyed tissue has been known for a while, research into regenerative medicine and dentistry has made significant strides in molecular biology. A paradigm shift in the therapeutic toolbox for dental and oral diseases is likely to result from a growing understanding of biological concepts in the regeneration of oral/dental tissues along with stem cell research, leading to an intense search for "biological solutions to biological problems." Among other tissues, orofacial tissues effectively separate stem cells from human tissues. Because they can self-renew and produce different cell types, stem cells offer novel techniques for regenerating damaged tissues and curing illnesses. A number of significant milestone successes have shown their practical applicability, traditional biomaterial-based treatments in regenerative dentistry as therapeutic alternatives that offer regeneration of damaged oral tissues rather than merely "filling the gaps." In order to use these innovative accomplishments for patient well-being, the ultimate goal of this ground-breaking technology, well-designed clinical studies must be implemented as a crucial next step. The review's objective is to briefly synthesize the literature on stem cells in terms of their traits, subtypes, and uses for dental stem cells. It has been highlighted that stem cell therapy has the ability to treat craniofacial abnormalities and regenerate teeth in the oral and maxillofacial regions.
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Affiliation(s)
- Bhumika K Vaswani
- Public Health Dentistry, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Bhushan P Mundada
- Oral and Maxillofacial Surgery, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Nitin Bhola
- Oral and Maxillofacial Surgery, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Priyanka Paul
- Public Health Dentistry, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Amit Reche
- Public Health Dentistry, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Kajal P Ahuja
- Public Health Dentistry, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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21
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Takeo M, Toyoshima KE, Fujimoto R, Iga T, Takase M, Ogawa M, Tsuji T. Cyclical dermal micro-niche switching governs the morphological infradian rhythm of mouse zigzag hair. Nat Commun 2023; 14:4478. [PMID: 37542032 PMCID: PMC10403492 DOI: 10.1038/s41467-023-39605-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 06/21/2023] [Indexed: 08/06/2023] Open
Abstract
Biological rhythms are involved in almost all types of biological processes, not only physiological processes but also morphogenesis. Currently, how periodic morphological patterns of tissues/organs in multicellular organisms form is not fully understood. Here, using mouse zigzag hair, which has 3 bends, we found that a change in the combination of hair progenitors and their micro-niche and subsequent bend formation occur every three days. Chimeric loss-of-function and gain-of-function of Ptn and Aff3, which are upregulated immediately before bend formation, resulted in defects in the downward movement of the micro-niche and the rhythm of bend formation in an in vivo hair reconstitution assay. Our study demonstrates the periodic change in the combination between progenitors and micro-niche, which is vital for the unique infradian rhythm.
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Affiliation(s)
- Makoto Takeo
- Laboratory for Organ Regeneration, RIKEN Center for Developmental Biology (CDB) and RIKEN Center for Biosystems Dynamics Research (BDR), Hyogo, 650-0047, Japan
| | - Koh-Ei Toyoshima
- Laboratory for Organ Regeneration, RIKEN Center for Developmental Biology (CDB) and RIKEN Center for Biosystems Dynamics Research (BDR), Hyogo, 650-0047, Japan
- OrganTech Inc., Tokyo, 104-0028, Japan
| | - Riho Fujimoto
- Department of Bioscience, Graduate School of Science and Technology, Kwansei-Gakuin University, Hyogo, 669-1337, Japan
| | - Tomoyo Iga
- Laboratory for Organ Regeneration, RIKEN Center for Developmental Biology (CDB) and RIKEN Center for Biosystems Dynamics Research (BDR), Hyogo, 650-0047, Japan
| | - Miki Takase
- Laboratory for Organ Regeneration, RIKEN Center for Developmental Biology (CDB) and RIKEN Center for Biosystems Dynamics Research (BDR), Hyogo, 650-0047, Japan
| | | | - Takashi Tsuji
- Laboratory for Organ Regeneration, RIKEN Center for Developmental Biology (CDB) and RIKEN Center for Biosystems Dynamics Research (BDR), Hyogo, 650-0047, Japan.
- OrganTech Inc., Tokyo, 104-0028, Japan.
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22
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Sui BD, Zheng CX, Zhao WM, Xuan K, Li B, Jin Y. Mesenchymal condensation in tooth development and regeneration: a focus on translational aspects of organogenesis. Physiol Rev 2023; 103:1899-1964. [PMID: 36656056 DOI: 10.1152/physrev.00019.2022] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 12/26/2022] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
The teeth are vertebrate-specific, highly specialized organs performing fundamental functions of mastication and speech, the maintenance of which is crucial for orofacial homeostasis and is further linked to systemic health and human psychosocial well-being. However, with limited ability for self-repair, the teeth can often be impaired by traumatic, inflammatory, and progressive insults, leading to high prevalence of tooth loss and defects worldwide. Regenerative medicine holds the promise to achieve physiological restoration of lost or damaged organs, and in particular an evolving framework of developmental engineering has pioneered functional tooth regeneration by harnessing the odontogenic program. As a key event of tooth morphogenesis, mesenchymal condensation dictates dental tissue formation and patterning through cellular self-organization and signaling interaction with the epithelium, which provides a representative to decipher organogenetic mechanisms and can be leveraged for regenerative purposes. In this review, we summarize how mesenchymal condensation spatiotemporally assembles from dental stem cells (DSCs) and sequentially mediates tooth development. We highlight condensation-mimetic engineering efforts and mechanisms based on ex vivo aggregation of DSCs, which have achieved functionally robust and physiologically relevant tooth regeneration after implantation in animals and in humans. The discussion of this aspect will add to the knowledge of development-inspired tissue engineering strategies and will offer benefits to propel clinical organ regeneration.
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Affiliation(s)
- Bing-Dong Sui
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Chen-Xi Zheng
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Wan-Min Zhao
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Kun Xuan
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Bei Li
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yan Jin
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China
- Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, China
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23
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Abstract
Pathological hair loss (also known as alopecia) and shortage of hair follicle (HF) donors have posed an urgent requirement for HF regeneration. With the revelation of mechanisms in tissue engineering, the proliferation of HFs in vitro has achieved more promising trust for the treatments of alopecia and other skin impairments. Theoretically, HF organoids have great potential to develop into native HFs and attachments such as sweat glands after transplantation. However, since the rich extracellular matrix (ECM) deficiency, the induction characteristics of skin-derived cells gradually fade away along with their trichogenic capacity after continuous cell passaging in vitro. Therefore, ECM-mimicking support is an essential prelude before HF transplantation is implemented. This review summarizes the status of providing various epidermal and dermal cells with a three-dimensional (3D) scaffold to support the cell homeostasis and better mimic in vivo environments for the sake of HF regeneration. HF-relevant cells including dermal papilla cells (DPCs), hair follicle stem cells (HFSCs), and mesenchymal stem cells (MSCs) are able to be induced to form HF organoids in the vitro culture system. The niche microenvironment simulated by different forms of biomaterial scaffold can offer the cells a network of ordered growth environment to alleviate inductivity loss and promote the expression of functional proteins. The scaffolds often play the role of ECM substrates and bring about epithelial-mesenchymal interaction (EMI) through coculture to ensure the functional preservation of HF cells during in vitro passage. Functional HF organoids can be formed either before or after transplantation into the dermis layer. Here, we review and emphasize the importance of 3D culture in HF regeneration in vitro. Finally, the latest progress in treatment trials and critical analysis of the properties and benefits of different emerging biomaterials for HF regeneration along with the main challenges and prospects of HF regenerative approaches are discussed.
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Affiliation(s)
- Wei Zheng
- College of Food Science & Technology, Shanghai Ocean University, Shanghai 201306, P.R. China
| | - Chang-Hua Xu
- College of Food Science & Technology, Shanghai Ocean University, Shanghai 201306, P.R. China
- Shanghai Engineering Research Center of Aquatic-Product Processing & Preservation, Shanghai 201306, China
- Laboratory of Quality and Safety Risk Assessment for Aquatic Products on Storage and Preservation (Shanghai), Ministry of Agriculture, Shanghai 201306, China
- National R&D Branch Center for Freshwater Aquatic Products Processing Technology (Shanghai), Shanghai 201306, China
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24
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Hermans F, Hemeryck L, Bueds C, Torres Pereiro M, Hasevoets S, Kobayashi H, Lambrechts D, Lambrichts I, Bronckaers A, Vankelecom H. Organoids from mouse molar and incisor as new tools to study tooth-specific biology and development. Stem Cell Reports 2023; 18:1166-1181. [PMID: 37084723 DOI: 10.1016/j.stemcr.2023.03.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/22/2023] [Accepted: 03/23/2023] [Indexed: 04/23/2023] Open
Abstract
Organoid models provide powerful tools to study tissue biology and development in a dish. Presently, organoids have not yet been developed from mouse tooth. Here, we established tooth organoids (TOs) from early-postnatal mouse molar and incisor, which are long-term expandable, express dental epithelium stem cell (DESC) markers, and recapitulate key properties of the dental epithelium in a tooth-type-specific manner. TOs display in vitro differentiation capacity toward ameloblast-resembling cells, even more pronounced in assembloids in which dental mesenchymal (pulp) stem cells are combined with the organoid DESCs. Single-cell transcriptomics supports this developmental potential and reveals co-differentiation into junctional epithelium- and odontoblast-/cementoblast-like cells in the assembloids. Finally, TOs survive and show ameloblast-resembling differentiation also in vivo. The developed organoid models provide new tools to study mouse tooth-type-specific biology and development and gain deeper molecular and functional insights that may eventually help to achieve future human biological tooth repair and replacement.
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Affiliation(s)
- Florian Hermans
- Department of Morphology, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3590 Diepenbeek, Belgium; Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven (University of Leuven), 3000 Leuven, Belgium
| | - Lara Hemeryck
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven (University of Leuven), 3000 Leuven, Belgium
| | - Celine Bueds
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven (University of Leuven), 3000 Leuven, Belgium
| | - Marc Torres Pereiro
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven (University of Leuven), 3000 Leuven, Belgium
| | - Steffie Hasevoets
- Department of Morphology, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3590 Diepenbeek, Belgium
| | - Hiroto Kobayashi
- Department of Anatomy and Structural Science, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Diether Lambrechts
- Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium
| | - Ivo Lambrichts
- Department of Morphology, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3590 Diepenbeek, Belgium
| | - Annelies Bronckaers
- Department of Morphology, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3590 Diepenbeek, Belgium.
| | - Hugo Vankelecom
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven (University of Leuven), 3000 Leuven, Belgium.
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25
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Chen J, Sun T, You Y, Lin B, Wu B, Wu J. Genome-wide identification of potential odontogenic genes involved in the dental epithelium-mesenchymal interaction during early odontogenesis. BMC Genomics 2023; 24:163. [PMID: 37013486 PMCID: PMC10069120 DOI: 10.1186/s12864-023-09140-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 01/16/2023] [Indexed: 04/05/2023] Open
Abstract
BACKGROUND Epithelium-mesenchymal interactions are involved in odontogenic processes. Previous studies have focused on the intracellular signalling regulatory network in tooth development, but the functions of extracellular regulatory molecules have remained unclear. This study aims to explore the gene profile of extracellular proteoglycans and their glycosaminoglycan chains potentially involved in dental epithelium-mesenchymal interactions using high-throughput sequencing to provide new understanding of early odontogenesis. RESULTS Whole transcriptome profiles of the mouse dental epithelium and mesenchyme were investigated by RNA sequencing (RNA-seq). A total of 1,281 and 1,582 differentially expressed genes were identified between the dental epithelium and mesenchyme at E11.5 and E13.5, respectively. Enrichment analysis showed that extracellular regions and ECM-receptor interactions were significantly enriched at both E11.5 and E13.5. Polymerase chain reaction analysis confirmed that the extracellular proteoglycan family exhibited distinct changes during epithelium-mesenchymal interactions. Most proteoglycans showed higher transcript levels in the dental mesenchyme, whereas only a few were upregulated in the epithelium at both stages. In addition, 9 proteoglycans showed dynamic expression changes between these two tissue compartments. Gpc4, Sdc2, Spock2, Dcn and Lum were expressed at higher levels in the dental epithelium at E11.5, whereas their expression was significantly higher in the dental mesenchyme at E13.5, which coincides with the odontogenic potential shift. Moreover, the glycosaminoglycan biosynthetic enzymes Ext1, Hs3st1/5, Hs6st2/3, Ndst3 and Sulf1 also exhibited early upregulation in the epithelium but showed markedly higher expression in the mesenchyme after the odontogenic potential shift. CONCLUSION This study reveals the dynamic expression profile of extracellular proteoglycans and their biosynthetic enzymes during the dental epithelium-mesenchymal interaction. This study offers new insight into the roles of extracellular proteoglycans and their distinct sulfation underlying early odontogenesis.
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Affiliation(s)
- Jiawen Chen
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- School of Stomatology, Southern Medical University, Guangzhou, 510515, China
| | - Tianyu Sun
- Department of Periodontology, Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Yan You
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- School of Stomatology, Southern Medical University, Guangzhou, 510515, China
| | - Binbin Lin
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- School of Stomatology, Southern Medical University, Guangzhou, 510515, China
| | - Buling Wu
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
- School of Stomatology, Southern Medical University, Guangzhou, 510515, China.
- Southern Medical University- Shenzhen Stomatology Hospital (Pingshan), ShenZhen, 518118, China.
| | - Jingyi Wu
- Center of Oral Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China.
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26
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Zhang F, Yang S, Jiang L, Liu J, He Y, Sheng X, Chen H, Kang J, Jia S, Fan W, Huang F, He H. Melatonin-mediated malic enzyme 2 orchestrates mitochondrial fusion and respiratory functions to promote odontoblastic differentiation during tooth development. J Pineal Res 2023; 74:e12865. [PMID: 36864655 DOI: 10.1111/jpi.12865] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 12/15/2022] [Accepted: 01/12/2023] [Indexed: 03/04/2023]
Abstract
Tooth development is a complex process that is tightly controlled by circadian rhythm. Melatonin (MT) is a major hormonal regulator of the circadian rhythm, and influences dentin formation and odontoblastic differentiation during tooth development; however, the underlying mechanism remains elusive. This study investigated how MT regulates odontoblastic differentiation, with a special focus on its regulation of mitochondrial dynamics. In rat dental papilla cells (DPCs), we found that MT promotes odontoblastic differentiation concurrently with enhanced mitochondrial fusion, while disruption of mitochondrial fusion by depleting optic atrophy 1 (OPA1) impairs MT-mediated differentiation and mitochondrial respiratory functions. Through RNA sequencing, we discovered that MT significantly upregulated malic enzyme 2 (ME2), a mitochondrial NAD(P)+ -dependent enzyme, and identified ME2 as a critical MT downstream effector that orchestrates odontoblastic differentiation, mitochondrial fusion, and respiration functions. By detecting the spatiotemporal expression of ME2 in developing tooth germs, and using tooth germ reconstituted organoids, we also provided in vivo and ex vivo evidence that ME2 promotes dentin formation, indicating a possible involvement of ME2 in MT-modulated tooth development. Collectively, our findings offer novel understandings regarding the molecular mechanism by which MT affects cell differentiation and organogenesis, meanwhile, the critical role of ME2 in MT-regulated mitochondrial functions is also highlighted.
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Affiliation(s)
- Fuping Zhang
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Shengyan Yang
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Liulin Jiang
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Jiawei Liu
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Yifan He
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Xinyue Sheng
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Haoling Chen
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Jun Kang
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Shilin Jia
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Wenguo Fan
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Fang Huang
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Hongwen He
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
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27
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Ravi V, Murashima-Suginami A, Kiso H, Tokita Y, Huang C, Bessho K, Takagi J, Sugai M, Tabata Y, Takahashi K. Advances in tooth agenesis and tooth regeneration. Regen Ther 2023; 22:160-168. [PMID: 36819612 PMCID: PMC9931762 DOI: 10.1016/j.reth.2023.01.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 12/19/2022] [Accepted: 01/12/2023] [Indexed: 02/05/2023] Open
Abstract
The lack of treatment options for congenital (0.1%) and partial (10%) tooth anomalies highlights the need to develop innovative strategies. Over two decades of dedicated research have led to breakthroughs in the treatment of congenital and acquired tooth loss. We revealed that by inactivating USAG-1, congenital tooth agenesis can be successfully ameliorated during early tooth development and that the inactivation promotes late-stage tooth morphogenesis in double knockout mice. Furthermore, Anti- USAG-1 antibody treatment in mice is effective in tooth regeneration and can be a breakthrough in treating tooth anomalies in humans. With approximately 0.1% of the population suffering from congenital tooth agenesis and 10% of children worldwide suffering from partial tooth loss, early diagnosis will improve outcomes and the quality of life of patients. Understanding the role of pathogenic USAG-1 variants, their interacting gene partners, and their protein functions will help develop critical biomarkers. Advances in next-generation sequencing, mass spectrometry, and imaging technologies will assist in developing companion and predictive biomarkers to help identify patients who will benefit from tooth regeneration.
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Affiliation(s)
- V. Ravi
- Toregem BioPharma Inc., Kyoto, Japan
| | - A. Murashima-Suginami
- Toregem BioPharma Inc., Kyoto, Japan,Department of Oral and Maxillofacial Surgery, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan,Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - H. Kiso
- Toregem BioPharma Inc., Kyoto, Japan,Department of Oral and Maxillofacial Surgery, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan,Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Y. Tokita
- Department of Disease Model, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan
| | - C.L. Huang
- Department of ThoracicSurgery, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan
| | - K. Bessho
- Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - J. Takagi
- Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Osaka, Japan
| | - M. Sugai
- Department of Molecular Genetics, Division of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Y. Tabata
- Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - K. Takahashi
- Toregem BioPharma Inc., Kyoto, Japan,Department of Oral and Maxillofacial Surgery, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan,Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan,Corresponding author. Department of Oral and Maxillofacial Surgery, Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20, Ohgimachi, Kita-ku, Osaka, 530-8480, Japan. Fax: +81-6-6312-8867.
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28
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Abstract
Oral and maxillofacial organoids, as three-dimensional study models of organs, have attracted increasing attention in tissue regeneration and disease modeling. However, traditional strategies for organoid construction still fail to precisely recapitulate the key characteristics of real organs, due to the difficulty in controlling the self-organization of cells in vitro. This review aims to summarize the recent progress of novel approaches to engineering oral and maxillofacial organoids. First, we introduced the necessary components and their roles in forming oral and maxillofacial organoids. Besides, we discussed cutting-edge technology in advancing the architecture and function of organoids, especially focusing on oral and maxillofacial tissue regeneration via novel strategy with designed cell-signal scaffold compounds. Finally, current limitations and future prospects of oral and maxillofacial organoids were represented to provide guidance for further disciplinary progression and clinical application to achieve organ regeneration.
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Affiliation(s)
- Yu Wang
- Department of Implantology, School & Hospital of Stomatology, Tongji University Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai 200040, China
| | - Yao Sun
- Department of Implantology, School & Hospital of Stomatology, Tongji University Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai 200040, China
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29
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Zhang H, Gong X, Xu X, Wang X, Sun Y. Tooth number abnormality: from bench to bedside. Int J Oral Sci 2023; 15:5. [PMID: 36604408 PMCID: PMC9816303 DOI: 10.1038/s41368-022-00208-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 09/24/2022] [Accepted: 11/01/2022] [Indexed: 01/07/2023] Open
Abstract
Tooth number abnormality is one of the most common dental developmental diseases, which includes both tooth agenesis and supernumerary teeth. Tooth development is regulated by numerous developmental signals, such as the well-known Wnt, BMP, FGF, Shh and Eda pathways, which mediate the ongoing complex interactions between epithelium and mesenchyme. Abnormal expression of these crutial signalling during this process may eventually lead to the development of anomalies in tooth number; however, the underlying mechanisms remain elusive. In this review, we summarized the major process of tooth development, the latest progress of mechanism studies and newly reported clinical investigations of tooth number abnormality. In addition, potential treatment approaches for tooth number abnormality based on developmental biology are also discussed. This review not only provides a reference for the diagnosis and treatment of tooth number abnormality in clinical practice but also facilitates the translation of basic research to the clinical application.
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Affiliation(s)
- Han Zhang
- grid.24516.340000000123704535Department of Implantology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Xuyan Gong
- grid.24516.340000000123704535Department of Implantology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Xiaoqiao Xu
- grid.24516.340000000123704535Department of Implantology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Xiaogang Wang
- grid.64939.310000 0000 9999 1211Key Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, Beijing, China
| | - Yao Sun
- Department of Implantology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China.
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30
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Ostrovidov S, Ramalingam M, Bae H, Orive G, Fujie T, Shi X, Kaji H. Bioprinting and biomaterials for dental alveolar tissue regeneration. Front Bioeng Biotechnol 2023; 11:991821. [PMID: 37122863 PMCID: PMC10140526 DOI: 10.3389/fbioe.2023.991821] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 04/03/2023] [Indexed: 05/02/2023] Open
Abstract
Three dimensional (3D) bioprinting is a powerful tool, that was recently applied to tissue engineering. This technique allows the precise deposition of cells encapsulated in supportive bioinks to fabricate complex scaffolds, which are used to repair targeted tissues. Here, we review the recent developments in the application of 3D bioprinting to dental tissue engineering. These tissues, including teeth, periodontal ligament, alveolar bones, and dental pulp, present cell types and mechanical properties with great heterogeneity, which is challenging to reproduce in vitro. After highlighting the different bioprinting methods used in regenerative dentistry, we reviewed the great variety of bioink formulations and their effects on cells, which have been established to support the development of these tissues. We discussed the different advances achieved in the fabrication of each dental tissue to provide an overview of the current state of the methods. We conclude with the remaining challenges and future needs.
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Affiliation(s)
- Serge Ostrovidov
- Department of Biomechanics, Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Murugan Ramalingam
- Institute of Tissue Regeneration Engineering, Dankook University, Cheonan, Republic of Korea
- Department of Nanobiomedical Science, BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, Republic of Korea
- School of Basic Medical Science, Chengdu University, Chengdu, China
- Mechanobiology Dental Medicine Research Center, Dankook University, Cheonan, Republic of Korea
- UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan, Republic of Korea
- Department of Metallurgical and Materials Engineering, Faculty of Engineering, Atilim University, Ankara, Türkiye
| | - Hojae Bae
- Department of Stem Cell and Regenerative Biotechnology, KU Convergence Science and Technology Institute, Konkuk University, Hwayang-dong, Seoul, Republic of Korea
| | - Gorka Orive
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
- Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain
- Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - Toshinori Fujie
- School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
- Living System Materialogy (LiSM) Reseach Group, International Research Frontiers Initiative (IRFI), Tokyo Institute of Technology, Yokohama, Japan
| | - Xuetao Shi
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, Guangdong, China
| | - Hirokazu Kaji
- Department of Biomechanics, Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- *Correspondence: Hirokazu Kaji,
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31
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Hu H, Duan Y, Wang K, Fu H, Liao Y, Wang T, Zhang Z, Kang F, Zhang B, Zhang H, Huo F, Yin Y, Chen G, Hu H, Cai H, Tian W, Li Z. Dental niche cells directly contribute to tooth reconstitution and morphogenesis. Cell Rep 2022; 41:111737. [PMID: 36476878 DOI: 10.1016/j.celrep.2022.111737] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/10/2022] [Accepted: 11/07/2022] [Indexed: 12/12/2022] Open
Abstract
Mammalian teeth develop from the inductive epithelial-mesenchymal interaction, an important mechanism shared by many organs. The cellular basis for such interaction remains elusive. Here, we generate a dual-fluorescence model to track and analyze dental cells from embryonic to postnatal stages, in which Pitx2+ epithelium and Msx1+ mesenchyme are sufficient for tooth reconstitution. Single-cell RNA sequencing and spatial mapping further revealed critical cellular dynamics during molar development, where tooth germs are organized by Msx1+Sdc1+ dental papilla and surrounding dental niche. Surprisingly, niche cells are more efficient in tooth reconstitution and can directly regenerate papilla cells through interaction with dental epithelium. Finally, from the dental niche, we identify a group of previously unappreciated migratory Msx1+ Sox9+ cells as the potential cell origin for dental papilla. Our results indicate that the dental niche cells directly contribute to tooth organogenesis and provide critical insights into the essential cell composition for tooth engineering.
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Affiliation(s)
- Hong Hu
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu, China
| | - Yufeng Duan
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu, China; National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, China; National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Kun Wang
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu, China
| | - Huancheng Fu
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu, China
| | - Yuansong Liao
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu, China
| | - Tianshu Wang
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu, China
| | - Ziwei Zhang
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu, China
| | - Fanchen Kang
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu, China; National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Baiquan Zhang
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu, China
| | - Haiying Zhang
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu, China
| | - Fangjun Huo
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu, China; National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, China; National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yike Yin
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu, China
| | - Guoqing Chen
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Hongbo Hu
- Department of Rheumatology and Immunology, Department of Urology, Department of Pathology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Haoyang Cai
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu, China.
| | - Weidong Tian
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu, China; National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, China; National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
| | - Zhonghan Li
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu, China; National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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Ohlsson E, Galler KM, Widbiller M. A Compilation of Study Models for Dental Pulp Regeneration. Int J Mol Sci 2022; 23:ijms232214361. [PMID: 36430838 PMCID: PMC9695686 DOI: 10.3390/ijms232214361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/12/2022] [Accepted: 11/14/2022] [Indexed: 11/22/2022] Open
Abstract
Efforts to heal damaged pulp tissue through tissue engineering have produced positive results in pilot trials. However, the differentiation between real regeneration and mere repair is not possible through clinical measures. Therefore, preclinical study models are still of great importance, both to gain insights into treatment outcomes on tissue and cell levels and to develop further concepts for dental pulp regeneration. This review aims at compiling information about different in vitro and in vivo ectopic, semiorthotopic, and orthotopic models. In this context, the differences between monolayer and three-dimensional cell cultures are discussed, a semiorthotopic transplantation model is introduced as an in vivo model for dental pulp regeneration, and finally, different animal models used for in vivo orthotopic investigations are presented.
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Affiliation(s)
- Ella Ohlsson
- Department of Operative Dentistry and Periodontology, Friedrich-Alexander-University Erlangen-Nuernberg, D-91054 Erlangen, Germany
| | - Kerstin M. Galler
- Department of Operative Dentistry and Periodontology, Friedrich-Alexander-University Erlangen-Nuernberg, D-91054 Erlangen, Germany
| | - Matthias Widbiller
- Department of Conservative Dentistry and Periodontology, University Hospital Regensburg, D-93053 Regensburg, Germany
- Correspondence:
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Neural Regulations in Tooth Development and Tooth-Periodontium Complex Homeostasis: A Literature Review. Int J Mol Sci 2022; 23:ijms232214150. [PMID: 36430624 PMCID: PMC9698398 DOI: 10.3390/ijms232214150] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 11/10/2022] [Accepted: 11/14/2022] [Indexed: 11/19/2022] Open
Abstract
The tooth-periodontium complex and its nerves have active reciprocal regulation during development and homeostasis. These effects are predominantly mediated by a range of molecules secreted from either the nervous system or the tooth-periodontium complex. Different strategies mimicking tooth development or physiological reparation have been applied to tooth regeneration studies, where the application of these nerve- or tooth-derived molecules has been proven effective. However, to date, basic studies in this field leave many vacancies to be filled. This literature review summarizes the recent advances in the basic studies on neural responses and regulation during tooth-periodontium development and homeostasis and points out some research gaps to instruct future studies. Deepening our understanding of the underlying mechanisms of tooth development and diseases will provide more clues for tooth regeneration.
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Dalir Abdolahinia E, Safari Z, Sadat Kachouei SS, Zabeti Jahromi R, Atashkar N, Karbalaeihasanesfahani A, Alipour M, Hashemzadeh N, Sharifi S, Maleki Dizaj S. Cell homing strategy as a promising approach to the vitality of pulp-dentin complexes in endodontic therapy: focus on potential biomaterials. Expert Opin Biol Ther 2022; 22:1405-1416. [PMID: 36345819 DOI: 10.1080/14712598.2022.2142466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Elaheh Dalir Abdolahinia
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Safari
- Faculty of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | | | | | - Nastaran Atashkar
- Department of Orthodontics, Faculty of Dentistry, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | | | - Mahdieh Alipour
- Center for Craniofacial Regeneration, Department of Oral and Craniofacial Sciences, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA, United States
- Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nastaran Hashemzadeh
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Simin Sharifi
- Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Solmaz Maleki Dizaj
- Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Dental Biomaterials, Tabriz University of Medical Sciences, Tabriz, Iran
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Chibly AM, Aure MH, Patel VN, Hoffman MP. Salivary gland function, development, and regeneration. Physiol Rev 2022; 102:1495-1552. [PMID: 35343828 PMCID: PMC9126227 DOI: 10.1152/physrev.00015.2021] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 11/27/2021] [Accepted: 03/17/2022] [Indexed: 02/08/2023] Open
Abstract
Salivary glands produce and secrete saliva, which is essential for maintaining oral health and overall health. Understanding both the unique structure and physiological function of salivary glands, as well as how they are affected by disease and injury, will direct the development of therapy to repair and regenerate them. Significant recent advances, particularly in the OMICS field, increase our understanding of how salivary glands develop at the cellular, molecular, and genetic levels: the signaling pathways involved, the dynamics of progenitor cell lineages in development, homeostasis, and regeneration, and the role of the extracellular matrix microenvironment. These provide a template for cell and gene therapies as well as bioengineering approaches to repair or regenerate salivary function.
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Affiliation(s)
- Alejandro M Chibly
- Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
| | - Marit H Aure
- Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
| | - Vaishali N Patel
- Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
| | - Matthew P Hoffman
- Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
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Zhang L, Zhang Y, Yu T, Peng L, Sun Q, Han B. Engineered Fabrication of Enamel-Mimetic Materials. ENGINEERING 2022; 14:113-123. [DOI: 10.1016/j.eng.2021.02.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/05/2024]
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37
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Veernala I, Jaffet J, Fried J, Mertsch S, Schrader S, Basu S, Vemuganti G, Singh V. Lacrimal gland regeneration: The unmet challenges and promise for dry eye therapy. Ocul Surf 2022; 25:129-141. [PMID: 35753665 DOI: 10.1016/j.jtos.2022.06.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 06/20/2022] [Accepted: 06/20/2022] [Indexed: 11/29/2022]
Abstract
DED (Dry eye disease) is a common multifactorial disease of the ocular surface and the tear film. DED has gained attention globally, with millions of people affected.. Although treatment strategies for DED have shifted towards Tear Film Oriented Therapy (TFOT), all the existing strategies fall under standard palliative care when addressed as a long-term goal. Therefore, different approaches have been explored by various groups to uncover alternative treatment strategies that can contribute to a full regeneration of the damaged lacrimal gland. For this, multiple groups have investigated the role of lacrimal gland (LG) cells in DED based on their regenerating, homing, and differentiating capabilities. In this review, we discuss in detail therapeutic mechanisms and regenerative strategies that can potentially be applied for lacrimal gland regeneration as well as their therapeutic applications. This review mainly focuses on Aqueous Deficiency Dry Eye Disease (ADDE) caused by lacrimal gland dysfunction and possible future treatment strategies. The current key findings from cell and tissue-based regenerative therapy modalities that could be utilised to achieve lacrimal gland tissue regeneration are summarized. In addition, this review summarises the available literature from in vitro to in vivo animal studies, their limitations in relation to lacrimal gland regeneration and the possible clinical applications. Finally, current issues and unmet needs of cell-based therapies in providing complete lacrimal gland tissue regeneration are discussed.
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Affiliation(s)
- Induvahi Veernala
- School of Medical Sciences, University of Hyderabad, Prof C R Rao Road, Gachibowli, Hyderabad, 500046, India
| | - Jilu Jaffet
- Centre for Ocular Regeneration, Brien Holden Eye Research Centre, Champalimaud Translational Centre for Eye Research, LV Prasad Eye Institute, Kallam Anji Reddy Campus, L V Prasad Marg, Hyderabad, 500 034, India; Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India
| | - Jasmin Fried
- Laboratory of Experimental Ophthalmology, Department of Ophthalmology, Pius-Hospital, Carl von Ossietzky University Oldenburg, Germany
| | - Sonja Mertsch
- Laboratory of Experimental Ophthalmology, Department of Ophthalmology, Pius-Hospital, Carl von Ossietzky University Oldenburg, Germany
| | - Stefan Schrader
- Laboratory of Experimental Ophthalmology, Department of Ophthalmology, Pius-Hospital, Carl von Ossietzky University Oldenburg, Germany
| | - Sayan Basu
- Centre for Ocular Regeneration, Brien Holden Eye Research Centre, Champalimaud Translational Centre for Eye Research, LV Prasad Eye Institute, Kallam Anji Reddy Campus, L V Prasad Marg, Hyderabad, 500 034, India
| | - Geeta Vemuganti
- School of Medical Sciences, University of Hyderabad, Prof C R Rao Road, Gachibowli, Hyderabad, 500046, India.
| | - Vivek Singh
- Centre for Ocular Regeneration, Brien Holden Eye Research Centre, Champalimaud Translational Centre for Eye Research, LV Prasad Eye Institute, Kallam Anji Reddy Campus, L V Prasad Marg, Hyderabad, 500 034, India.
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Wang Y, Zhao Y, Chen S, Chen X, Zhang Y, Chen H, Liao Y, Zhang J, Wu D, Chu H, Huang H, Wu C, Huang S, Xu H, Jia B, Liu J, Feng B, Li Z, Qin D, Pei D, Cai J. Single cell atlas of developing mouse dental germs reveals populations of CD24 + and Plac8 + odontogenic cells. Sci Bull (Beijing) 2022; 67:1154-1169. [PMID: 36545982 DOI: 10.1016/j.scib.2022.03.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 02/01/2022] [Accepted: 02/23/2022] [Indexed: 01/07/2023]
Abstract
The spatiotemporal relationships in high-resolution during odontogenesis remain poorly understood. We report a cell lineage and atlas of developing mouse teeth. We performed a large-scale (92,688 cells) single cell RNA sequencing, tracing the cell trajectories during odontogenesis from embryonic days 10.5 to 16.5. Combined with an assay for transposase-accessible chromatin with high-throughput sequencing, our results suggest that mesenchymal cells show the specific transcriptome profiles to distinguish the tooth types. Subsequently, we identified key gene regulatory networks in teeth and bone formation and uncovered spatiotemporal patterns of odontogenic mesenchymal cells. CD24+ and Plac8+ cells from the mesenchyme at the bell stage were distributed in the upper half and preodontoblast layer of the dental papilla, respectively, which could individually induce nonodontogenic epithelia to form tooth-like structures. Specifically, the Plac8+ tissue we discovered is the smallest piece with the most homogenous cells that could induce tooth regeneration to date. Our work reveals previously unknown heterogeneity and spatiotemporal patterns of tooth germs that may lead to tooth regeneration for regenerative dentistry.
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Affiliation(s)
- Yaofeng Wang
- Innovation Centre for Advanced Interdisciplinary Medicine, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510799, China; CAS Key Laboratory of Regenerative Biology, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, China
| | - Yifan Zhao
- CAS Key Laboratory of Regenerative Biology, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China
| | - Shubin Chen
- CAS Key Laboratory of Regenerative Biology, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China
| | - Xiaoming Chen
- CAS Key Laboratory of Regenerative Biology, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial People's Hospital Ganzhou Hospital, Ganzhou Municipal Hospital, Ganzhou 341099, China
| | - Yanmei Zhang
- CAS Key Laboratory of Regenerative Biology, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China
| | - Hong Chen
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Yuansong Liao
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Jiashu Zhang
- CAS Key Laboratory of Regenerative Biology, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Department of Regeneration Medicine, School of Pharmaceutical Science, Jilin University, Changchun 130012, China
| | - Di Wu
- CAS Key Laboratory of Regenerative Biology, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China; Department of Regeneration Medicine, School of Pharmaceutical Science, Jilin University, Changchun 130012, China
| | - Hongxing Chu
- Department of Periodontics and Implantology, Stomatological Hospital, Southern Medical University (Guangdong Provincial Stomatological Hospital), Guangzhou 510515, China
| | - Hongying Huang
- Animal Center, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Caixia Wu
- Animal Center, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Shijuan Huang
- CAS Key Laboratory of Regenerative Biology, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Huichao Xu
- Animal Center, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Bei Jia
- The Center for Prenatal and Hereditary Disease Diagnosis, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jie Liu
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Bo Feng
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Zhonghan Li
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Dajiang Qin
- Innovation Centre for Advanced Interdisciplinary Medicine, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510799, China; Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China
| | - Duanqing Pei
- CAS Key Laboratory of Regenerative Biology, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, China; Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China; Laboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou 310024, China.
| | - Jinglei Cai
- Innovation Centre for Advanced Interdisciplinary Medicine, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510799, China; CAS Key Laboratory of Regenerative Biology, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, China.
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Advances of Engineered Hydrogel Organoids within the Stem Cell Field: A Systematic Review. Gels 2022; 8:gels8060379. [PMID: 35735722 PMCID: PMC9222364 DOI: 10.3390/gels8060379] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/10/2022] [Accepted: 06/13/2022] [Indexed: 02/06/2023] Open
Abstract
Organoids are novel in vitro cell culture models that enable stem cells (including pluripotent stem cells and adult stem cells) to grow and undergo self-organization within a three-dimensional microenvironment during the process of differentiation into target tissues. Such miniature structures not only recapitulate the histological and genetic characteristics of organs in vivo, but also form tissues with the capacity for self-renewal and further differentiation. Recent advances in biomaterial technology, particularly hydrogels, have provided opportunities to improve organoid cultures; by closely integrating the mechanical and chemical properties of the extracellular matrix microenvironment, with novel synthetic materials and stem cell biology. This systematic review critically examines recent advances in various strategies and techniques utilized for stem-cell-derived organoid culture, with particular emphasis on the application potential of hydrogel technology in organoid culture. We hope this will give a better understanding of organoid cultures for modelling diseases and tissue engineering applications.
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Kilic Bektas C, Zhang W, Mao Y, Wu X, Kohn J, Yelick PC. Self-Assembled Hydrogel Microparticle-Based Tooth-Germ Organoids. Bioengineering (Basel) 2022; 9:bioengineering9050215. [PMID: 35621493 PMCID: PMC9137977 DOI: 10.3390/bioengineering9050215] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/09/2022] [Accepted: 05/11/2022] [Indexed: 11/16/2022] Open
Abstract
Here, we describe the characterization of tooth-germ organoids, three-dimensional (3D) constructs cultured in vitro with the potential to develop into living teeth. To date, the methods used to successfully create tooth organoids capable of forming functional teeth have been quite limited. Recently, hydrogel microparticles (HMP) have demonstrated utility in tissue repair and regeneration based on their useful characteristics, including their scaffolding ability, effective cell and drug delivery, their ability to mimic the natural tissue extracellular matrix, and their injectability. These outstanding properties led us to investigate the utility of using HMPs (average diameter: 158 ± 32 µm) derived from methacrylated gelatin (GelMA) (degree of substitution: 100%) to create tooth organoids. The tooth organoids were created by seeding human dental pulp stem cells (hDPSCs) and porcine dental epithelial cells (pDE) onto the HMPs, which provided an extensive surface area for the cells to effectively attach and proliferate. Interestingly, the cell-seeded HMPs cultured on low-attachment tissue culture plates with gentle rocking self-assembled into organoids, within which the cells maintained their viability and morphology throughout the incubation period. The self-assembled organoids reached a volume of ~50 mm3 within two weeks of the in vitro tissue culture. The co-cultured hDPSC-HMP and pDE-HMP structures effectively attached to each other without any externally applied forces. The presence of polarized, differentiated dental cells in these composite tooth-bud organoids demonstrated the potential of self-assembled dental cell HMPs to form tooth-bud organoid-like structures for potential applications in tooth regeneration strategies.
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Affiliation(s)
- Cemile Kilic Bektas
- Department of Chemistry and Chemical Biology, Rutgers University, 123 Bevier Rd, Piscataway, NJ 08854, USA; (C.K.B.); (Y.M.); (X.W.); (J.K.)
| | - Weibo Zhang
- Division of Craniofacial and Molecular Genetics, Department of Orthodontics, Tufts University School of Dental Medicine, 1 Kneeland Avenue, Boston, MA 02111, USA;
| | - Yong Mao
- Department of Chemistry and Chemical Biology, Rutgers University, 123 Bevier Rd, Piscataway, NJ 08854, USA; (C.K.B.); (Y.M.); (X.W.); (J.K.)
| | - Xiaohuan Wu
- Department of Chemistry and Chemical Biology, Rutgers University, 123 Bevier Rd, Piscataway, NJ 08854, USA; (C.K.B.); (Y.M.); (X.W.); (J.K.)
| | - Joachim Kohn
- Department of Chemistry and Chemical Biology, Rutgers University, 123 Bevier Rd, Piscataway, NJ 08854, USA; (C.K.B.); (Y.M.); (X.W.); (J.K.)
| | - Pamela C. Yelick
- Division of Craniofacial and Molecular Genetics, Department of Orthodontics, Tufts University School of Dental Medicine, 1 Kneeland Avenue, Boston, MA 02111, USA;
- Correspondence:
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Mohabatpour F, Chen X, Papagerakis S, Papagerakis P. Novel trends, challenges and new perspectives for enamel repair and regeneration to treat dental defects. Biomater Sci 2022; 10:3062-3087. [PMID: 35543379 DOI: 10.1039/d2bm00072e] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Dental enamel is the hardest tissue in the human body, providing external protection for the tooth against masticatory forces, temperature changes and chemical stimuli. Once enamel is damaged/altered by genetic defects, dental caries, trauma, and/or dental wear, it cannot repair itself due to the loss of enamel producing cells following the tooth eruption. The current restorative dental materials are unable to replicate physico-mechanical, esthetic features and crystal structures of the native enamel. Thus, development of alternative approaches to repair and regenerate enamel defects is much needed but remains challenging due to the structural and functional complexities involved. This review paper summarizes the clinical aspects to be taken into consideration for the development of optimal therapeutic approaches to tackle dental enamel defects. It also provides a comprehensive overview of the emerging acellular and cellular approaches proposed for enamel remineralization and regeneration. Acellular approaches aim to artificially synthesize or re-mineralize enamel, whereas cell-based strategies aim to mimic the natural process of enamel development given that epithelial cells can be stimulated to produce enamel postnatally during the adult life. The key issues and current challenges are also discussed here, along with new perspectives for future research to advance the field of regenerative dentistry.
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Affiliation(s)
- Fatemeh Mohabatpour
- Division of Biomedical Engineering, University of Saskatchewan, 57 Campus Dr., S7N 5A9, SK, Canada. .,College of Dentistry, University of Saskatchewan, 105 Wiggins Rd, Saskatoon, S7N 5E4, SK, Canada
| | - Xiongbiao Chen
- Division of Biomedical Engineering, University of Saskatchewan, 57 Campus Dr., S7N 5A9, SK, Canada. .,Department of Mechanical Engineering, University of Saskatchewan, 57 Campus Dr., Saskatoon, S7N 5A9, SK, Canada
| | - Silvana Papagerakis
- Division of Biomedical Engineering, University of Saskatchewan, 57 Campus Dr., S7N 5A9, SK, Canada. .,Department of Surgery, College of Medicine, University of Saskatchewan, 107 Wiggins Rd B419, S7N 0 W8, SK, Canada
| | - Petros Papagerakis
- Division of Biomedical Engineering, University of Saskatchewan, 57 Campus Dr., S7N 5A9, SK, Canada. .,College of Dentistry, University of Saskatchewan, 105 Wiggins Rd, Saskatoon, S7N 5E4, SK, Canada
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Furquim CP, Kumagai RY, Bustillos-Torrez W, Meza-Mauricio J, Tanaka CJ, Santana V, Retamal-Valdes B, Shibli JA. Whole Tooth Regeneration: Can Animal Studies be Translated into Clinical Application? Tissue Eng Part C Methods 2022; 28:104-112. [PMID: 35172636 DOI: 10.1089/ten.tec.2022.0022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
Tooth loss leads to several oral problems and although a large number of treatments have been proposed to rehabilitate partially or totally edentulous patients, none of them is based on replacement of a missing tooth by a new natural whole tooth. In the field of tissue engineering, some animal models have been developed to regenerate a natural tooth in the oral cavity. This review shows the state of the art in whole tooth regeneration based on data from in vivo studies. A systematic scoping review was conducted to evaluate studies that described whole-tooth regeneration and eruption in the oral cavity. The data demonstrated that over 100 animals were used in experimental studies and all of them received implants of tooth germs constructed by bioengineering processes. Mini pigs and pigs were used in four studies followed by mice (n = 1) and dog (n = 1). Over 58 (44%) animals showed whole tooth eruption around 3.5 months after tooth germ implantation (1 to 13.5 months). Most of specimens revealed the presence of odontoblasts, dentin, dentinal tubules, dental pulp, root analogue, cementum, blood vessels, and alveolar bone. It could be concluded that in vivo whole tooth regeneration was proved to be possible, but the challenge to overcome translational barriers and test these approaches in humans still remains. Impact Statement Advances in tissue engineering have led to the development of new methods to regenerate and replace tissues and organs, including teeth. Tooth regeneration is the main goal for the replacement of tooth loss and therefore current evidence showed that tissue engineering might provide this treatment in future.
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Affiliation(s)
- Camila Pinheiro Furquim
- Dental Research Division, Department of Periodontology, Guarulhos University, Guarulhos, Brazil
| | - Rose Yakushijin Kumagai
- Dental Research Division, Department of Periodontology, Guarulhos University, Guarulhos, Brazil
| | - Willy Bustillos-Torrez
- Dental Research Division, Department of Periodontology, Guarulhos University, Guarulhos, Brazil
| | - Jonathan Meza-Mauricio
- Dental Research Division, Department of Periodontology, Guarulhos University, Guarulhos, Brazil
| | - Caio Junji Tanaka
- Dental Research Division, Department of Periodontology, Guarulhos University, Guarulhos, Brazil
| | - Veronica Santana
- Dental Research Division, Department of Periodontology, Guarulhos University, Guarulhos, Brazil
| | - Belen Retamal-Valdes
- Dental Research Division, Department of Periodontology, Guarulhos University, Guarulhos, Brazil
| | - Jamil Awad Shibli
- Dental Research Division, Department of Periodontology, Guarulhos University, Guarulhos, Brazil
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Rosa V, Sriram G, McDonald N, Cavalcanti BN. A critical analysis of research methods and biological experimental models to study pulp regeneration. Int Endod J 2022; 55 Suppl 2:446-455. [PMID: 35218576 PMCID: PMC9311820 DOI: 10.1111/iej.13712] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 02/23/2022] [Accepted: 02/24/2022] [Indexed: 12/01/2022]
Abstract
With advances in knowledge and treatment options, pulp regeneration is now a clear objective in clinical dental practice. For this purpose, many methodologies have been developed in attempts to address the putative questions raised both in research and in clinical practice. In the first part of this review, laboratory‐based methods will be presented, analysing the advantages, disadvantages, and benefits of cell culture methodologies and ectopic/semiorthotopic animal studies. This will also demonstrate the need for alignment between two‐dimensional and three‐dimensional laboratory techniques to accomplish the range of objectives in terms of cell responses and tissue differentiation. The second part will cover observations relating to orthotopic animal studies, describing the current models used for this purpose and how they contribute to the translation of regenerative techniques to the clinic.
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Affiliation(s)
- Vinicius Rosa
- Faculty of Dentistry, National University of Singapore, Singapore
| | - Gopu Sriram
- Faculty of Dentistry, National University of Singapore, Singapore
| | - Neville McDonald
- Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Bruno Neves Cavalcanti
- Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA
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Organoids from human tooth showing epithelial stemness phenotype and differentiation potential. Cell Mol Life Sci 2022; 79:153. [PMID: 35217915 PMCID: PMC8881251 DOI: 10.1007/s00018-022-04183-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 01/27/2022] [Accepted: 02/01/2022] [Indexed: 01/09/2023]
Abstract
Insight into human tooth epithelial stem cells and their biology is sparse. Tissue-derived organoid models typically replicate the tissue’s epithelial stem cell compartment. Here, we developed a first-in-time epithelial organoid model starting from human tooth. Dental follicle (DF) tissue, isolated from unerupted wisdom teeth, efficiently generated epithelial organoids that were long-term expandable. The organoids displayed a tooth epithelial stemness phenotype similar to the DF’s epithelial cell rests of Malassez (ERM), a compartment containing dental epithelial stem cells. Single-cell transcriptomics reinforced this organoid-ERM congruence, and uncovered novel, mouse-mirroring stem cell features. Exposure of the organoids to epidermal growth factor induced transient proliferation and eventual epithelial-mesenchymal transition, highly mimicking events taking place in the ERM in vivo. Moreover, the ERM stemness organoids were able to unfold an ameloblast differentiation process, further enhanced by transforming growth factor-β (TGFβ) and abrogated by TGFβ receptor inhibition, thereby reproducing TGFβ's known key position in amelogenesis. Interestingly, by creating a mesenchymal-epithelial composite organoid (assembloid) model, we demonstrated that the presence of dental mesenchymal cells (i.e. pulp stem cells) triggered ameloblast differentiation in the epithelial stem cells, thus replicating the known importance of mesenchyme-epithelium interaction in tooth development and amelogenesis. Also here, differentiation was abrogated by TGFβ receptor inhibition. Together, we developed novel organoid models empowering the exploration of human tooth epithelial stem cell biology and function as well as their interplay with dental mesenchyme, all at present only poorly defined in humans. Moreover, the new models may pave the way to future tooth-regenerative perspectives.
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45
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Y Baena AR, Casasco A, Monti M. Hypes and Hopes of Stem Cell Therapies in Dentistry: a Review. Stem Cell Rev Rep 2022; 18:1294-1308. [PMID: 35015212 PMCID: PMC8748526 DOI: 10.1007/s12015-021-10326-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/29/2021] [Indexed: 12/20/2022]
Abstract
One of the most exciting advances in life science research is the development of 3D cell culture systems to obtain complex structures called organoids and spheroids. These 3D cultures closely mimic in vivo conditions, where cells can grow and interact with their surroundings. This allows us to better study the spatio-temporal dynamics of organogenesis and organ function. Furthermore, physiologically relevant organoids cultures can be used for basic research, medical research, and drug discovery. Although most of the research thus far focuses on the development of heart, liver, kidney, and brain organoids, to name a few, most recently, these structures were obtained using dental stem cells to study in vitro tooth regeneration. This review aims to present the most up-to-date research showing how dental stem cells can be grown on specific biomaterials to induce their differentiation in 3D. The possibility of combining engineering and biology principles to replicate and/or increase tissue function has been an emerging and exciting field in medicine. The use of this methodology in dentistry has already yielded many interesting results paving the way for the improvement of dental care and successful therapies.
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Affiliation(s)
- Alessandra Rodriguez Y Baena
- Program in Biomedical Sciences and Engineering, Department of Molecular, Cell, and Developmental Biology, University of California-Santa Cruz, Santa Cruz, CA, 95064, USA
| | - Andrea Casasco
- Department of Public Health, Experimental and Forensic Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy.,Dental & Face Center, CDI, Milan, Italy
| | - Manuela Monti
- Department of Public Health, Experimental and Forensic Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy. .,Research Center for Regenerative Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
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Tauqir S, Ali S, Marya A. The Use of Bio-Inks and the Era of Bioengineering and Tooth Regeneration. PESQUISA BRASILEIRA EM ODONTOPEDIATRIA E CLÍNICA INTEGRADA 2022. [DOI: 10.1590/pboci.2022.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
| | - Saqib Ali
- Imam Abdulrahman Bin Faisal University, Saudi Arabia
| | - Anand Marya
- University of Puthisastra, Cambodia; Saveetha University, India
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In Vivo Evaluation of Decellularized Human Tooth Scaffold for Dental Tissue Regeneration. APPLIED SCIENCES (BASEL, SWITZERLAND) 2021; 11. [PMID: 36003951 PMCID: PMC9397400 DOI: 10.3390/app11188472] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Conventional root canal treatment may result in loss of tooth vitality, which can lead to unfavorable treatment outcomes. Notably, a ceased tooth development of immature permanent teeth with open apices, regeneration of periodontal ligaments (PDL), and pulp is highly expected healing process. For regeneration, the scaffold is one of the critical components that carry biological benefits. Therefore, this study evaluated a decellularized human tooth as a scaffold for the PDL and pulp tissue regeneration. A tooth scaffold was fabricated using an effective decellularization method as reported in previous studies. PDL stem cells (PDLSCs) and dental pulp stem cells (DPSCs) obtained from human permanent teeth were inoculated onto decellularized scaffolds, then cultured to transplant into immunosuppressed mouse. After 9 weeks, PDLSCs and DPSCs that were inoculated onto decellularized tooth scaffolds and cultured in an in vivo demonstrated successful differentiation. In PDLSCs, a regeneration of the cementum/PDL complex could be expected. In DPSCs, the expression of genes related to revascularization and the hard tissue regeneration showed the possibility of pulp regeneration. This study suggested that the potential possible application of decellularized human tooth could be a scaffold in regeneration PDL and pulp tissue along with PDLSCs and DPSCs, respectively, as a novel treatment method.
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Capparè P, Tetè G, Sberna MT, Panina-Bordignon P. The Emerging Role of Stem Cells in Regenerative Dentistry. Curr Gene Ther 2021; 20:259-268. [PMID: 32811413 DOI: 10.2174/1566523220999200818115803] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/25/2020] [Accepted: 07/29/2020] [Indexed: 02/06/2023]
Abstract
Progress of modern dentistry is accelerating at a spectacular speed in the scientific, technological and clinical areas. Practical examples are the advancement in the digital field, which has guaranteed an average level of prosthetic practices for all patients, as well as other scientific developments, including research on stem cell biology. Given their plasticity, defined as the ability to differentiate into specific cell lineages with a capacity of almost unlimited self-renewal and release of trophic/immunomodulatory factors, stem cells have gained significant scientific and commercial interest in the last 15 years. Stem cells that can be isolated from various tissues of the oral cavity have emerged as attractive sources for bone and dental regeneration, mainly due to their ease of accessibility. This review will present the current understanding of emerging conceptual and technological issues of the use of stem cells to treat bone and dental loss defects. In particular, we will focus on the clinical application of stem cells, either directly isolated from oral sources or in vitro reprogrammed from somatic cells (induced pluripotent stem cells). Research aimed at further unraveling stem cell plasticity will allow to identify optimal stem cell sources and characteristics, to develop novel regenerative tools in dentistry.
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Affiliation(s)
- Paolo Capparè
- Department of Dentistry, IRCCS San Raffaele Hospital, Milan, Italy,Dental School, Vita-Salute San Raffaele University, School of Medicine, Milan, Italy
| | - Giulia Tetè
- Department of Dentistry, IRCCS San Raffaele Hospital, Milan, Italy
| | | | - Paola Panina-Bordignon
- Neuroimmunology Unit, Institute of Experimental Neurology, IRCCS San Raffaele Hospital, Milan, Italy,Dental School, Vita-Salute San Raffaele University, School of Medicine, Milan, Italy
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Shoushrah SH, Transfeld JL, Tonk CH, Büchner D, Witzleben S, Sieber MA, Schulze M, Tobiasch E. Sinking Our Teeth in Getting Dental Stem Cells to Clinics for Bone Regeneration. Int J Mol Sci 2021; 22:6387. [PMID: 34203719 PMCID: PMC8232184 DOI: 10.3390/ijms22126387] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/27/2021] [Accepted: 06/02/2021] [Indexed: 12/12/2022] Open
Abstract
Dental stem cells have been isolated from the medical waste of various dental tissues. They have been characterized by numerous markers, which are evaluated herein and differentiated into multiple cell types. They can also be used to generate cell lines and iPSCs for long-term in vitro research. Methods for utilizing these stem cells including cellular systems such as organoids or cell sheets, cell-free systems such as exosomes, and scaffold-based approaches with and without drug release concepts are reported in this review and presented with new pictures for clarification. These in vitro applications can be deployed in disease modeling and subsequent pharmaceutical research and also pave the way for tissue regeneration. The main focus herein is on the potential of dental stem cells for hard tissue regeneration, especially bone, by evaluating their potential for osteogenesis and angiogenesis, and the regulation of these two processes by growth factors and environmental stimulators. Current in vitro and in vivo publications show numerous benefits of using dental stem cells for research purposes and hard tissue regeneration. However, only a few clinical trials currently exist. The goal of this review is to pinpoint this imbalance and encourage scientists to pick up this research and proceed one step further to translation.
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Affiliation(s)
| | | | | | | | | | | | | | - Edda Tobiasch
- Department of Natural Sciences, Bonn-Rhein-Sieg University of Applied Sciences, von-Liebig- Strasse. 20, 53359 Rheinbach, Germany; (S.H.S.); (J.L.T.); (C.H.T.); (D.B.); (S.W.); (M.A.S.); (M.S.)
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Morrison DG, Tomlinson RE. Leveraging Advancements in Tissue Engineering for Bioprinting Dental Tissues. ACTA ACUST UNITED AC 2021; 23. [PMID: 34268456 DOI: 10.1016/j.bprint.2021.e00153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
3D bioprinting allows biocompatible materials and cells to be deposited in precise locations in three-dimensional space, enabling researchers to surpass the limitations of traditional 2D cell culture and to create innovative therapies. 3D bioprinting is one of the newest tools developed in the field of tissue engineering, which has traditionally utilized a paradigm revolving around scaffolds, cells, and signals. In this review, we discuss how new developments in each of these three research areas relates to bioprinting dental tissues - specifically teeth, periodontal ligament, and alveolar bone. Important considerations include how scaffold materials and geometry affect regeneration of dental tissues, the importance of using dental cells in these applications, and the role of signaling molecules for creating a clinically relevant bioengineered dental implant. We conclude with potential new directions for research that would allow the burgeoning field of regenerative dentistry to achieve its lofty goals.
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Affiliation(s)
- Devin Grace Morrison
- Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Ryan E Tomlinson
- Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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