Immunomodulatory effects of stem cells

Adult‐derived mesenchymal stem cells have received considerable attention over the past two decades for their potential use in tissue engineering, principally because of their potential to differentiate into multiple stromal‐cell lineages. Recently, the immunomodulatory properties of mesenchymal stem cells have attracted interest as a unique property of these cells that may be harnessed for novel therapeutic approaches in immune‐mediated diseases. Mesenchymal stem cells have been shown to inhibit the proliferation of activated T‐cells both in vitro and in vivo but to stimulate T‐regulatory cell proliferation. Mesenchymal stem cells are also known to be weakly immunogenic and to exert immunosuppressive effects on B‐cells, natural killer cells, dendritic cells and neutrophils through various mechanisms. Furthermore, intravenous administration of allogeneic mesenchymal stem cells has shown a marked suppression of host immune reactions in preclinical animal models of large‐organ transplant rejection and in various autoimmune‐ and inflammatory‐based diseases. Some clinical trials utilizing human mesenchymal stem cells have also produced promising outcomes in patients with graft‐vs.‐host disease and autoimmune diseases. Mesenchymal stem cells identified from various dental tissues, including periodontal ligament stem cells, also possess multipotent and immunomodulatory properties. Hence, dental mesenchymal stem cells may represent an alternate cell source, not only for tissue regeneration but also as therapies for autoimmune‐ and inflammatory‐mediated diseases. These findings have elicited interest in dental tissue mesenchymal stem cells as alternative cell sources for modulating alloreactivity during tissue regeneration following transplantation into human leukocyte antigen‐mismatched donors. To examine this potential in periodontal regeneration, future work will need to assess the capacity of allogeneic periodontal ligament stem cells to regenerate periodontal ligament in animal models of periodontal disease. The present review describes the immunosuppressive effects of mesenchymal stem cells on various types of immune cells, the potential mechanisms through which they exert their mode of action and the preclinical animal studies and human clinical trials that have utilized mesenchymal stem cells, including those populations originating from dental structures.     

Dental follicle stem cells and tissue engineering

Adult stem cells are multipotent and can be induced experimentally to differentiate into various cell lineages. Such cells are therefore a key part of achieving the promise of tissue regeneration. The most studied stem cells are those of the hematopoietic and mesenchymal lineages. Recently, mesenchymal stem cells were demonstrated in dental tissues, including dental pulp, periodontal ligament, and dental follicle. The dental follicle is a loose connective tissue that surrounds the developing tooth. Dental follicle stem cells could therefore be a cell source for mesenchymal stem cells. Indeed, dental follicle is present in impacted teeth, which are commonly extracted and disposed of as medical waste in dental practice. Dental follicle stem cells can be isolated and grown under defined tissue culture conditions, and recent characterization of these stem cells has increased their potential for use in tissue engineering applications, including periodontal and bone regeneration. This review describes current knowledge and recent developments in dental follicle stem cells and their application.     

Stem cell‐based tooth and periodontal regeneration

Currently regeneration of tooth and periodontal damage still remains great challenge. Stem cell‐based tissue engineering raised novel therapeutic strategies for tooth and periodontal repair. Stem cells for tooth and periodontal regeneration include dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), stem cells from the dental apical papilla (SCAPs), and stem cells from human exfoliated deciduous teeth (SHEDs), dental follicle stem cells (DFSCs), dental epithelial stem cells (DESCs), bone marrow mesenchymal stem cells (BMMSCs), adipose‐derived stem cells (ADSCs), embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). To date, substantial advances have been made in stem cell‐based tooth and periodontal regeneration, including dentin–pulp, whole tooth, bioroot and periodontal regeneration. Translational investigations have been performed such as dental stem cell banking and clinical trials. In this review, we present strategies for stem cell‐based tissue engineering for tooth and periodontal repair, and the translational studies.     

Mesenchymal stem cells in the dental tissues: perspectives for tissue regeneration

In recent years, stem cell research has grown exponentially owing to the recognition that stem cell-based therapies have the potential to improve the life of patients with conditions that range from Alzheimer's disease to cardiac ischemia and regenerative medicine, like bone or tooth loss. Based on their ability to rescue and/or repair injured tissue and partially restore organ function, multiple types of stem/progenitor cells have been speculated. Growing evidence demonstrates that stem cells are primarily found in niches and that certain tissues contain more stem cells than others. Among these tissues, the dental tissues are considered a rich source of mesenchymal stem cells that are suitable for tissue engineering applications. It is known that these stem cells have the potential to differentiate into several cell types, including odontoblasts, neural progenitors, osteoblasts, chondrocytes, and adipocytes. In dentistry, stem cell biology and tissue engineering are of great interest since may provide an innovative for generation of clinical material and/or tissue regeneration. Mesenchymal stem cells were demonstrated in dental tissues, including dental pulp, periodontal ligament, dental papilla, and dental follicle. These stem cells can be isolated and grown under defined tissue culture conditions, and are potential cells for use in tissue engineering, including, dental tissue, nerves and bone regeneration. More recently, another source of stem cell has been successfully generated from human somatic cells into a pluripotent stage, the induced pluripotent stem cells (iPS cells), allowing creation of patient- and disease-specific stem cells. Collectively, the multipotency, high proliferation rates, and accessibility make the dental stem cell an attractive source of mesenchymal stem cells for tissue regeneration. This review describes new findings in the field of dental stem cell research and on their potential use in the tissue regeneration.     

Dental stem cells and their promising role in neural regeneration: an update

Introduction

Stem cell-based therapies are considered to be a promising treatment method for several clinical conditions such as Alzheimer's disease, Parkinson's disease, spinal cord injury, and many others. However, the ideal stem cell type for stem cell-based therapy remains to be elucidated.

Discussion

Stem cells are present in a variety of tissues in the embryonic and adult human body. Both embryonic and adult stem cells have their advantages and disadvantages concerning the isolation method, ethical issues, or differentiation potential. The most described adult stem cell population is the mesenchymal stem cells due to their multi-lineage (trans)differentiation potential, high proliferative capacity, and promising therapeutic values. Recently, five different cell populations with mesenchymal stem cell characteristics were identified in dental tissues: dental pulp stem cells, stem cells from human exfoliated deciduous teeth, periodontal ligament stem cells, dental follicle precursor cells, and stem cells from apical papilla.

Conclusion

Each dental stem cell population possesses specific characteristics and advantages which will be summarized in this review. Furthermore, the neural characteristics of dental pulp stem cells and their potential role in (peripheral) neural regeneration will be discussed.     

Adipose-derived stem cells in dentistry

In the last decade, applications of tissue engineering technology in dental regenerative medicine have expanded enormously. In particular, the use of mesenchymal stem cells, which are highly proliferative and have the capacity to differentiate into osteogenic, chondrogenic, and adipogenic cells, promises to have a positive impact on the future of dentistry. The therapeutic potential of human multipotent mesenchymal stem cells, which are harvested from bone marrow and adipose tissue, has generated a markedly increased interest within a wide range of biomedical disciplines. Adipose-derived stem cells are especially interesting because of their strong potential for cell differentiation and growth factor secretion. Furthermore, these cells have some advantages over stem cells from other sources, including the fact that a large number of stem cells can be easily and quickly isolated from subcutaneous adipose tissue.In clinical dental therapy, several non-stem-cell-based methods have been developed for periodontal and bone tissue engineering. These methods include the stimulation of regeneration using enamel matrix proteins, guided tissue regeneration, various bone grafting techniques, and the application of growth factors and have been applied either alone or in combination. However, there are various limitations and shortcomings in the currently available methods. Therefore, it will be a significant step forward to establish dental tissue engineering techniques using mesenchymal stem cells. In this review, the fundamentals of periodontal tissue regeneration and bone tissue engineering are discussed. In particular, the use of adipose-derived stem cells in periodontal tissue regeneration, bone tissue engineering, and the engineering of other complex tissues are discussed.     

Identification of multipotent stem cells from adult dog periodontal ligament

Periodontal diseases, which are characterized by destruction of the connective tissues responsible for restraining the teeth within the jaw, are the main cause of tooth loss. Periodontal regeneration mediated by human periodontal ligament stem cells (hPDLSCs) may offer an alternative strategy for the treatment of periodontal disease. Dogs are a widely used large-animal model for the study of periodontal-disease progression, tissue regeneration, and dental implants, but little attention has been paid to the identification of the cells involved in this species. This study aimed to characterize stem cells isolated from canine periodontal ligament (cPDLSCs). The cPDLSCs, like hPDLSCs, showed clonogenic capability and expressed the mesenchymal stem cell markers STRO-1, CD146, and CD105, but not CD34. After induction of osteogenesis, cPDLSCs showed calcium accumulation in vitro. Moreover, cPDLSCs also showed both adipogenic and chondrogenic potential. Compared with cell-free controls, more cementum/periodontal ligament-like structures were observed in CB-17/SCID mice into which cPDLSCs had been transplanted. These results suggest that cPDLSCs are clonogenic, highly proliferative, and have multidifferentiation potential, and that they could be used as a new cellular therapeutic approach to facilitate successful and more predictable regeneration of periodontal tissue using a canine model of periodontal disease.     

Role of the epithelial cell rests of Malassez in the development,maintenance and regeneration of periodontal ligament tissues

Periodontitis is a highly prevalent inflammatory disease that results in damage to the tooth‐supporting tissues, potentially leading to tooth loss. Periodontal tissue regeneration is a complex process that involves the collaboration of two hard tissues (cementum and alveolar bone) and two soft tissues (gingiva and periodontal ligament). To date, no periodontal‐regenerative procedures provide predictable clinical outcomes. To understand the rational basis of regenerative procedures, a better understanding of the events associated with the formation of periodontal components will help to establish reliable strategies for clinical practice. An important aspect of this is the role of the Hertwig's epithelial root sheath in periodontal development and that of its descendants, the epithelial cell rests of Malassez, in the maintenance of the periodontium. An important structure during tooth root development, the Hertwig's epithelial root sheath is not only a barrier between the dental follicle and dental papilla cells but is also involved in determining the shape, size and number of roots and in the development of dentin and cementum, and may act as a source of mesenchymal progenitor cells for cementoblasts. In adulthood, the epithelial cell rests of Malassez are the only odontogenic epithelial population in the periodontal ligament. Although there is no general agreement on the functions of the epithelial cell rests of Malassez, accumulating evidence suggests that the putative roles of the epithelial cell rests of Malassez in adult periodontal ligament include maintaining periodontal ligament homeostasis to prevent ankylosis and maintain periodontal ligament space, to prevent root resorption, to serve as a target during periodontal ligament innervation and to contribute to cementum repair. Recently, ovine epithelial cell rests of Malassez cells have been shown to harbor clonogenic epithelial stem‐cell populations that demonstrate similar properties to mesenchymal stromal/stem cells, both functionally and phenotypically. Therefore, the epithelial cell rests of Malassez, rather than being ‘cell rests’, as indicated by their name, are an important source of stem cells that might play a pivotal role in periodontal regeneration.     

The efficacy of mesenchymal stem cells to regenerate and repair dental structures

OBJECTIVES: Identification, characterization, and potential application of mesenchymal stem cells (MSC) derived from human dental tissues. METHODS: Dental pulp and periodontal ligament were obtained from normal human impacted third molars. The tissues were digested in collagenase/dispase to generate single cell suspensions. Cells were cultured in alpha-MEM supplemented with 20% fetal bovine serum, 2 mM l-glutamine, 100 microM l-ascorbate-2-phosphate. Magnetic and fluorescence activated cell sorting were employed to characterize the phenotype of freshly isolated and ex vivo expanded cell populations. The developmental potential of cultured cells was assessed following co-transplantation with hydroxyapetite/tricalcium phosphate (HA/TCP) particles into immunocompromised mice for 8 weeks. RESULTS: MSC were identified in adult human dental pulp (dental pulp stem cells, DPSC), human primary teeth (stem cells from human exfoliated deciduous teeth, SHED), and periodontal ligament (periodontal ligament stem cells, PDLSC) by their capacity to generate clongenic cell clusters in culture. Ex vivo expanded DPSC, SHED, and PDLSC populations expressed a heterogeneous assortment of makers associated with MSC, dentin, bone, smooth muscle, neural tissue, and endothelium. PDLSC were also found to express the tendon specific marker, Scleraxis. Xenogeneic transplants containing HA/TCP with either DPSC or SHED generated donor-derived dentin-pulp-like tissues with distinct odontoblast layers lining the mineralized dentin-matrix. In parallel studies, PDLSC generated cementum-like structures associated with PDL-like connective tissue when transplanted with HA/TCP into immunocompromised mice. CONCLUSION: Collectively, these data revealed the presence of distinct MSC populations associated with dental structures with the potential of stem cells to regenerate living human dental tissues in vivo.     

外周神经胶质细胞：牙髓干细胞的新来源

来源于早期外胚间充质组织头部的神经嵴细胞迁移衍生出牙髓间充质干细胞,随后这些细胞产生牙髓细胞和成牙本质细胞。神经胶质细胞是另外一个神经嵴细胞衍生迁移而形成的细胞系。神经胶质细胞有广泛的分化发育潜能,研究发现神经胶质细胞可以分化为神经细胞和牙髓间充质干细胞,并且神经胶质细胞的不同分化发育阶段间可以互相转变。通常认为,大多数组织中的间充质干细胞来源于血管周细胞,但有研究发现相当一部分牙髓间充质干细胞来源于外周神经相关的神经胶质。本文通过对神经嵴细胞、牙髓间充质干细胞和神经胶质细胞的分化发育以及神经胶质细胞的衍生细胞的概述,介绍牙髓再生领域一种新的更有前景的牙髓间充质干细胞来源。     

Dental stem cells and their sources

The search for more accessible mesenchymal stem cells than those found in bone marrow has propelled interest in dental tissues. Human dental stem/progenitor cells (collectively termed dental stem cells [DSCs]) that have been isolated and characterized include dental pulp stem cells, stem cells from exfoliated deciduous teeth, stem cells from apical papilla, periodontal ligament stem cells, and dental follicle progenitor cells. Common characteristics of these cell populations are the capacity for self-renewal and the ability to differentiate into multiple lineages. In?vitro and animal studies have shown that DSCs can differentiate into osseous, odontogenic, adipose, endothelial, and neural-like tissues.     

Dental stem cells for craniofacial tissue engineering

This article focuses on the biological characterization and discussion of the potential application of oral-derived adult stem cells for craniofacial tissue engineering applications. The authors reviewed experimental (in vitro and in vivo) and clinical reports regarding the isolation, characterization, modulation, and translational clinical application of human precursor cell populations derived from postnatal dental tissues. Five different human dental stem/progenitor cell populations have been isolated and characterized. These postnatal populations present mesenchymal stem cell-like characteristics and enjoy forceful capabilities regarding the differentiation into odontogenic/osteogenic lineages, supporting evidence-in preclinical and clinical trials-for the regeneration of oral/dental tissues.     

Recovery of stem cells from cryopreserved periodontal ligament

Human post-natal stem cells possess a great potential to be utilized in stem-cell-mediated clinical therapies and tissue engineering. It is not known whether cryopreserved human tissues contain functional post-natal stem cells. In this study, we utilized human periodontal ligament to test the hypothesis that cryopreserved human periodontal ligament contains retrievable post-natal stem cells. These cryopreserved periodontal ligament stem cells maintained normal periodontal ligament stem cell characteristics, including expression of the mesenchymal stem cell surface molecule STRO-1, single-colony-strain generation, multipotential differentiation, cementum/periodontal-ligament-like tissue regeneration, and a normal diploid karyotype. Collectively, this study provides valuable evidence demonstrating a practical approach to the preservation of solid-frozen human tissues for subsequent post-natal stem cell isolation and tissue regeneration. The present study demonstrates that human post-natal stem cells can be recovered from cryopreserved human periodontal ligament, thereby providing a practical clinical approach for the utilization of frozen tissues for stem cell isolation.     

Dental pulp stem cells: what,where, how?

Introduction.  It is now accepted that progenitor/stem cells reside within the post-natal dental pulp. Studies have identified several niches of multipotent mesenchymal progenitor cells, known as dental pulp stem cells, which have a high proliferative potential for self-renewal. These progenitor stem cells are now recognized as being vital to the dentine regeneration process following injury. Understanding the nature of these progenitor/stem cell populations in the pulp is important in determining their potentialities and development of isolation or recruitment strategies for use in regeneration and tissue engineering. Characterization of these cells, and determination of their potentialities in terms of specificity of regenerative response, may help direct new clinical treatment modalities. Such novel treatments may involve controlled direct recruitment of the cells in situ and possible seeding of stem cells at sites of injury for regeneration or use of the stem cells with appropriate scaffolds for tissue engineering solutions. Such approaches may provide an innovative and novel biologically based new generation of clinical materials and/or treatments for dental disease.
Aim.  This study aimed to review the body of knowledge relating to stem cells and to consider the possibility of these cell populations, and related technology, in future clinical applications.     

Mesenchymal stem cells from the oral cavity and their potential value in tissue engineering

Periodontal disease is one of the most common conditions affecting humans, and current treatment strategies, which focus on the removal and long‐term control of dental plaque, are generally successful in eliminating active disease and promoting tissue repair. However, regeneration of the supporting structures of the tooth remains an elusive goal and a challenge. The formation of new bone and cementum with supportive periodontal ligament is the ultimate objective, but current regeneration therapies are incapable of achieving this in a predictable way. The regeneration of periodontal tissue requires a combination of fundamental events, such as appropriate level and sequencing of regulatory signals, the presence of progenitor cells, an extracellular matrix or carrier and an adequate blood supply. Based on tissue‐engineering concepts, the regeneration process may be modulated by manipulating the signaling pathways of regulatory molecules, the extracellular matrix or scaffold, or the cellular components. The identification of mesenchymal stem cells from bone marrow started a new era in regenerative medicine. Tissue engineering using mesenchymal stem cells became a therapeutic option with several advantages, including high‐quality regeneration of damaged tissues without the formation of fibrous tissue, minimal donor‐site morbidity compared with autografts and a low risk of autoimmune rejection and disease transmission. The aim of this review was to describe the main sources of mesenchymal stem cells from tissues in the oral cavity and the potential of these cells in regenerative therapy. Special attention is paid to gingival tissue‐derived mesenchymal stem cells because they represent the most accessible source of stem cells in the human mouth.     

人乳牙牙髓干细胞在干细胞治疗中的应用

乳牙牙髓干细胞（SHED）是牙源性干细胞的一种,属外胚间充质干细胞。作为一种理想的干细胞来源,SHED在干细胞治疗中有良好的应用前景。本文阐述了SHED的生物学特征及其在干细胞治疗中的优势,探讨了SHED在组织再生和修复中发挥的多向分化潜能、细胞分泌功能和免疫调节功能等方面的功能作用。此外,本文还介绍了SHED在各系统、器官疾病治疗中的临床应用,重点阐述了用SHED进行干细胞移植在牙髓—牙本质再生、颌骨再生、神经系统疾病治疗和免疫系统疾病治疗方面的研究进展。     

Stem cells and the dental pulp: potential roles in dentine regeneration and repair

The dentine-pulp complex displays exquisite regenerative potential in response to injury. The postnatal dental pulp contains a variety of potential progenitor/stem cells, which may participate in dental regeneration. A population of multipotent mesenchymal progenitor cells known as dental pulp stem cells with high proliferative potential for self-renewal has been described and may be important to the regenerative capacity of the tissue. The nature of the progenitor/stem cell populations in the pulp is of importance in understanding their potentialities and development of isolation or recruitment strategies, and allowing exploitation of their use in regeneration and tissue engineering. Various strategies will be required to ensure not only effective isolation of these cells, but also controlled signalling of their differentiation and regulation of secretory behaviour. Characterization of these cells and determination of their potentialities in terms of specificity of regenerative response will form the foundation for development of new clinical treatment modalities, whether involving directed recruitment of the cells and seeding of stem cells at sites of injury for regeneration or use of the stem cells with appropriate scaffolds for tissue engineering solutions. Such approaches will provide an innovative and novel biologically based new generation of clinical treatments for dental disease.     

Dental pulp stem cells in regenerative dentistry

Stem cells constitute the source of differentiated cells for the generation of tissues during development, and for regeneration of tissues that are diseased or injured postnatally. In recent years, stem cell research has grown exponentially owing to the recognition that stem cell-based therapies have the potential to improve the life of patients with conditions that span from Alzheimer’s disease to cardiac ischemia to bone or tooth loss. Growing evidence demonstrates that stem cells are primarily found in niches and that certain tissues contain more stem cells than others. Among these tissues, the dental pulp is considered a rich source of mesenchymal stem cells that are suitable for tissue engineering applications. It is known that dental pulp stem cells have the potential to differentiate into several cell types, including odontoblasts, neural progenitors, osteoblasts, chondrocytes, and adipocytes. The dental pulp stem cells are highly proliferative. This characteristic facilitates ex vivo expansion and enhances the translational potential of these cells. Notably, the dental pulp is arguably the most accessible source of postnatal stem cells. Collectively, the multipotency, high proliferation rates, and accessibility make the dental pulp an attractive source of mesenchymal stem cells for tissue regeneration. This review discusses fundamental concepts of stem cell biology and tissue engineering within the context of regenerative dentistry.