Allogeneic transplantation of mobilized dental pulp stem cells with the mismatched dog leukocyte antigen type is safe and efficacious for total pulp regeneration

Iohara, Koichiro; Utsunomiya, Shinji; Kohara, Saori; Nakashima, Mitsuyoshi

doi:10.1186/s13287-018-0855-8

Cited by 53 publications

(63 citation statements)

References 77 publications

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“…RNA was extracted using Trizol and the CM was collected and concentrated. The mRNA expression of immunosuppressive markers, IDO, TGF-β1, PTGE and IL-6 as our previous study [29] were examined by RT-PCR. The concentration of nitric oxide (NO) was examined by measuring its stable end product, nitrite, in the CM using a Griess reagent (Promega Corporation, Madison, WI, USA) according to manufacturer's protocol.…”

Section: Anti-apoptotic Activity Of the CMmentioning

confidence: 99%

Characterization of Stable Hypoxia-Preconditioned Dental Pulp Stem Cells: Implication for Pulp Regeneration

Zayed¹,

Iohara²,

Watanabe³

et al. 2020

Preprint

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Background: Dental pulp stem cells (DPSCs) have been developed as a potential source of mesenchymal stem cells (MSCs) for regeneration of dental pulp and other tissues. However, further strategies to isolate highly functional DPSCs beyond the colony-forming methods are required. Our clinical study has demonstrated safety and efficacy of DPSCs isolated by G-CSF-induced mobilization and cultured under normoxia (mobilized DPSCs, MDPSCs) for pulp regeneration. It is well known that the oxygen concentration is closely linked to the maintenance of stemness. Thus, in this investigation, hypoxia-preconditioned DPSCs (hpDPSCs) was characterized to develop and improve the clinical utility for regeneration of dental pulp in endodontics.Methods: Colony-forming DPSCs were isolated and preconditioned with hypoxia in a stable closed cultured system and compared with MDPSCs isolated from the individual dog teeth. We examined the proliferation rate, migration potential, anti-apoptotic activity and gene expression of the stem cell markers and angiogenic/neurotrophic factors. Trophic effects of the conditioned medium (CM) were also evaluated. In addition, the expression of immunomodulatory molecules upon stimulation with IFN-γ were investigated. The pulp regenerative potential and transplantation safety of hpDPSCs were further assessed in pulpectomized teeth in dogs by histological and immunohistochemical analyses and by chemistry of blood and urine. tests Results: hpDPSCs demonstrated higher proliferation rate and expression of a major regulator of oxygen homeostasis, HIF-1α, and a stem cell marker, CXCR-4. The direct migratory activity of hpDPSCs in response to G-CSF was significantly higher than MDPSCs. The CM of hpDPSCs stimulated neurite extension. However, there were no changes in angiogenic, migration and anti-apoptotic activities compared with the CM of MDPSCs. The expression of immunomodulatory gene, PTGE was significantly up-regulated by IFN gamma in hpDPSCs compared with MDPSCs. However, no difference in nitric oxide was observed. The regenerated pulp tissue was quantitatively and qualitatively similar in hpDPSC transplants compared with MDPSC transplants in dog teeth. There was no evidence of toxicity or adverse events of the hpDPSC transplantation Conclusions: These results demonstrated that hpDPSCs improved stem cell properties compared to MDPSCs, suggesting their potential clinical utility for pulp regeneration.

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Section: Anti-apoptotic Activity Of the CMmentioning

confidence: 99%

Characterization of Stable Hypoxia-Preconditioned Dental Pulp Stem Cells: Implication for Pulp Regeneration

Zayed¹,

Iohara²,

Watanabe³

et al. 2020

Preprint

Self Cite

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“…Studies focus on MSCs immunomodulatory effects to induce regeneration of dental and periodontal tissues, and differentiation potential of MSCs to improve implant strength and bone tissue repair in the alveolar defects. In addition to usual sources of stem cells such as bone marrow and adipose tissue, cells derived from local tissues such as dental pulp stem cells (DPSC) (200)(201)(202) or periodontal ligament stem cells (PDLSC) (203,204) are studied as a therapeutic option in orodental diseases. In experimental dog models, autologous BMMSCs or xenogeneic periodontal ligament MSCs have proven beneficial in periodontal ligament reconstruction, when combined with the growth factors (205), fibrin glue, PRP (206), ephrinB2-a membrane protein regulating bone homeostasis (204) or with a construct of porous biphasic calcium phosphate (203).…”

Section: Orodental Diseasesmentioning

confidence: 99%

Stem Cells in Veterinary Medicine—Current State and Treatment Options

et al. 2020

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Regenerative medicine is a branch of medicine that develops methods to grow, repair, or replace damaged or diseased cells, organs or tissues. It has gained significant momentum in recent years. Stem cells are undifferentiated cells with the capability to self-renew and differentiate into tissue cells with specialized functions. Stem cell therapies are therefore used to overcome the body's inability to regenerate damaged tissues and metabolic processes after acute or chronic insult. The concept of stem cell therapy was first introduced in 1991 by Caplan, who proposed that massive differentiation of cells into the desired tissue could be achieved by isolation, cultivation, and expansion of stem cells in in vitro conditions. Among different stem cell types, mesenchymal stem cells (MSC) currently seem to be the most suitable for therapeutic purposes, based on their simple isolation and culturing techniques, and lack of ethical issues regarding their usage. Because of their remarkable immunomodulatory abilities, MSCs are increasingly gaining recognition in veterinary medicine. Developments are primarily driven by the limitations of current treatment options for various medical problems in different animal species. MSCs represent a possible therapeutic option for many animal diseases, such as orthopedic, orodental and digestive tract diseases, liver, renal, cardiac, respiratory, neuromuscular, dermal, olfactory, and reproductive system diseases. Although we are progressively gaining an understanding of MSC behavior and their mechanisms of action, some of the issues considering their use for therapy are yet to be resolved. The aim of this review is first to summarize the current knowledge and stress out major issues in stem cell based therapies in veterinary medicine and, secondly, to present results of clinical usage of stem cells in veterinary patients.

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“…Well-vascularized and reinnervated regenerated pulp tissues were quantitatively and qualitatively similar in the mismatched DLA transplants and the matched DLA transplants, even with dual transplantation. Thus, the allogeneic transplantation of mismatched HLA MDPSCs with G-CSF might be safe and effective for total pulp regeneration 39 . Furthermore, banked allogeneic MDPSCs would be highly advantageous to save time and cost and to confirm high quality, especially in aged patients.…”

Section: Future Perspectivesmentioning

confidence: 99%

Pulp Regeneration: Current Approaches, Challenges, and Novel Rejuvenating Strategies for an Aging Population

Nakashima

Iohara

Zayed

2020

Journal of Endodontics

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We showed the safety and efficacy of pulp regenerative therapy by the autologous transplantation of mobilized dental pulp stem cells with granulocyte colony-stimulating factor in a pilot clinical study of young and middle-aged pulpectomized teeth. An experimental study in dogs further demonstrated an age-dependent decline in the amount of regenerated pulp tissue. In our society, in which people will soon live beyond 100 years, this therapy should be efficacious for contributing to the functional survival and endurance of the tooth not only for pulpectomized young teeth but also for aged teeth with periapical disease. However, there are 2 challenges: 1 is enhancing pulp regeneration in aged teeth, and another is complete disinfection before cell transplantation. Thus, this review presents trypsin pretreatment for the former and a novel irrigant, nanobubbles with antibacterial nanopolymers, for the latter, thus demonstrating potential utility for pulp regenerative therapy in aged teeth with periapical disease. (J Endod 2020;46:S135-S142.) KEY WORDS Aged teeth; dental pulp stem cells; nanobubbles; pulpectomy; pulp regeneration; trypsin We previously showed the safety and efficacy of pulp regenerative therapy by the autologous transplantation of mobilized dental pulp stem cells (MDPSCs) with granulocyte colony-stimulating factor (G-CSF) in preclinical and clinical studies of young and middle-aged teeth 1. The MDPSCs isolated from aged donors were similar to those from young donors with regard to stem cell properties, including trophic effects, migration activity in vitro, and regenerative potential in vivo 2. However, there was an agedependent decline in pulp regeneration using MDPSCs. It was suggested that this observation was partly because of the reduction of the migration, proliferation, and cell survival of resident stem cells 3. The aging of teeth is characterized by the decline of the fibroblast density of the periodontal ligament tissue, widening of cementum, and constriction of the apical region 4,5. The decline might also be attributed to the extrinsic alteration of the microenvironment or "niche," including systemic proteins and localized structural and soluble factors that affect transcriptional regulation, the cell cycle, and biomechanical properties. Thus, to enhance pulp regeneration in aged teeth, a therapeutic strategy using trypsin, a proteolytic enzyme that targets the resident stem cells, and the microenvironment/niche was developed. On the other hand, in the age of the 100-year life, pulp regenerative cell therapy should be efficacious not only for noninfected pulpectomized cases but also for infected root canals in order to provide the functional survival and longevity of the tooth. However, complete disinfection before cell transplantation by irrigants and intracanal medication is a challenge. We recently developed negatively charged nanobubbles containing pressured air, which have the ability to remove the smear layer and enhance the delivery of medications to dentinal tubules, thus demonstrat...

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Allogeneic transplantation of mobilized dental pulp stem cells with the mismatched dog leukocyte antigen type is safe and efficacious for total pulp regeneration

Cited by 53 publications

References 77 publications

Characterization of Stable Hypoxia-Preconditioned Dental Pulp Stem Cells: Implication for Pulp Regeneration

Characterization of Stable Hypoxia-Preconditioned Dental Pulp Stem Cells: Implication for Pulp Regeneration

Stem Cells in Veterinary Medicine—Current State and Treatment Options

Pulp Regeneration: Current Approaches, Challenges, and Novel Rejuvenating Strategies for an Aging Population

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