Papers by Koichiro Iohara
International Journal of Molecular Sciences, 2020
Aging, defined by a decrease in the physical and functional integrity of the tissues, leads to ag... more Aging, defined by a decrease in the physical and functional integrity of the tissues, leads to age-associated degenerative diseases. There is a relation between aged dental pulp and the senescence of dental pulp stem cells (DPSCs). Therefore, it is important to investigate the molecular processes underlying the senescence of DPSCs to elucidate the dental pulp aging mechanisms. p-Cresol (PC), a uremic toxin, is strongly related to cellular senescence. Here, age-related phenotypic changes including senescence, apoptosis, inflammation, and declining odontoblast differentiation in PC-treated canine DPSCs were investigated. Under the PC condition, cellular senescence was induced by decreased proliferation capacity and increased cell size, senescence-associated β-galactosidase (SA-β-gal) activity, and senescence markers p21, IL-1β, IL-8, and p53. Exposure to PC could stimulate inflammation by the increased expression of IL-6 and cause the distraction of the cell cycle by the increased lev...
The Japanese Journal of Conservative Dentistry, 2012
Additional file 1: Supplemental Fig. 1.
Figure S1. Histochemical analyses of normal pulp tissue. Immunostaining with (A) BS-1 lectin and ... more Figure S1. Histochemical analyses of normal pulp tissue. Immunostaining with (A) BS-1 lectin and (B) PGP 9.5. Neurite extension (arrow). (PDF 155Â kb)
The Japanese Journal of Conservative Dentistry, 2013
Journal of Endodontics, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Cell Transplantation, 2020
The coronavirus disease 2019 (COVID-19) pandemic, originating from Wuhan, China, is known to caus... more The coronavirus disease 2019 (COVID-19) pandemic, originating from Wuhan, China, is known to cause severe acute respiratory symptoms. The occurrence of a cytokine storm in the lungs is a critical step in the disease pathogenesis, as it causes pathological lesions, pulmonary edema, and acute respiratory distress syndrome, potentially resulting in death. Currently, there is no effective treatment that targets the cytokine storm and helps regenerate the damaged tissue. Mesenchymal stem cells (MSCs) are known to act as anti-inflammatory/immunomodulatory candidates and activate endogenous regeneration. As a result, MSC therapy is a potential treatment approach for COVID-19. Intravenous injection of clinical-grade MSCs into COVID-19 patients can induce an immunomodulatory response along with improved lung function. Dental pulp stem cells (DPSCs) are considered a potential source of MSCs for immunomodulation, tissue regeneration, and clinical application. Although some current clinical tri...
Journal of Endodontics, 2020
We showed the safety and efficacy of pulp regenerative therapy by the autologous transplantation ... more 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 demonstrating the potential utility of nanobubbles with antibacterial nanopolymers for the successful treatment of infected root canal and pulp regeneration. Therefore, enhanced pulp regeneration by trypsin pretreatment and complete disinfection by nanobubbles with antibacterial nanopolymers are discussed in this article. From the Departments of *Stem Cell Biology and Regenerative Medicine and
Tissue Engineering Part B: Reviews, 2019
Rapid progress has been made in the last decade related to stem cell-mediated pulp-dentin regener... more Rapid progress has been made in the last decade related to stem cell-mediated pulp-dentin regeneration, from characterization of dental pulp stem cells (DPSCs) to the first-ever reported clinical case in humans. However, many challenges still need to be addressed before such technology can become a common clinical practice; therefore, further rigorous research is needed. Animal study models are very important to test new ideas, concepts, and technologies. This review summarizes and discusses several key animal models that have been utilized to investigate pulp-dentin regeneration. From a tissue regeneration perspective, we categorize the animal model by the location where the regenerated pulp tissue is formed: ectopic, semiorthotopic, and orthotopic. Several animal species are discussed, including mouse, ferret, dog, and miniswine. Mouse is used for ectopic pulp-dentin regeneration in the dorsum subcutaneous space. A commonly tested approach is hydroxyapatite/tricalcium phosphate (HA-TCP) granules model used to observe ectopic pulp-dentin complex formation. The semiorthotopic model includes tooth slices or fragments with which de novo pulp regeneration in a root canal space can be tested in the mouse subcutaneous space. For orthotopic pulp regeneration, the canine teeth of ferrets are large enough for such purposes. As nonprimate large animal models, dog and miniswine teeth have many aspects quite similar to those of humans, allowing researchers to perform experiments that mimic clinical conditions in humans. The protocols established and the data obtained from large animal studies may directly relate to and apply to future human studies. Complete orthotopic pulp regeneration has been demonstrated in dogs and miniswine. The use of allogeneic and subpopulations of DPSCs for pulp regeneration, and testing of the periapical disease model and aging model have been performed in miniswine or dogs. In sum, all these animal models will help address challenges that still face pulp regeneration in humans. We need to thoroughly utilize these models to test new ideas, technologies, and strategies before reliable and predictable clinical protocols can be established for human clinical trials or treatment.
Oral Radiology, 2017
Objectives Magnetic resonance imaging (MRI) has recently been used for the evaluation of dental p... more Objectives Magnetic resonance imaging (MRI) has recently been used for the evaluation of dental pulp anatomy, vitality, and regeneration. This study reviewed the recent use of MRI in the endodontic field. Methods Literature published from January 2000 to March 2017 was searched in PubMed using the following Medical Subject Heading (MeSH) terms: (1) MRI and (dental pulp anatomy or endodontic pulp); (2) MRI and dental pulp regeneration. Studies were narrowed down based on specific inclusion criteria and categorized as in vitro, in vivo, or dental pulp regeneration studies. The MRI sequences and imaging findings were summarized. Results In the in vitro studies on dental pulp anatomy, T1weighted imaging with high resolution was frequently used to evaluate dental pulp morphology, demineralization depth, and tooth abnormalities. Other sequences such as apparent diffusion coefficient mapping and sweep imaging with Fourier transformation were used to evaluate pulpal fluid and decayed teeth, and short-T2 tissues (dentin and enamel), respectively. In the in vivo studies, pulp vitality and reperfusion were visible with fat-saturated T2-weighted imaging or contrast-enhanced T1-weighted imaging. In both the in vitro and in vivo studies, MRI could reveal pulp regeneration after stem cell therapy. Stem cells labeled with superparamagnetic iron oxide particles were also visible on MRI. Angiogenesis induced by stem cells could be confirmed on enhanced T1-weighted imaging. Conclusion MRI can be successfully used to visualize pulp morphology as well as pulp vitality and regeneration. The use of MRI in the endodontic field is likely to increase in the future.
Stem cell research & therapy, Mar 9, 2017
Experiments have previously demonstrated the therapeutic potential of mobilized dental pulp stem ... more Experiments have previously demonstrated the therapeutic potential of mobilized dental pulp stem cells (MDPSCs) for complete pulp regeneration. The aim of the present pilot clinical study is to assess the safety, potential efficacy, and feasibility of autologous transplantation of MDPSCs in pulpectomized teeth. Five patients with irreversible pulpitis were enrolled and monitored for up to 24 weeks following MDPSC transplantation. The MDPSCs were isolated from discarded teeth and expanded based on good manufacturing practice (GMP). The quality of the MDPSCs at passages 9 or 10 was ascertained by karyotype analyses. The MDPSCs were transplanted with granulocyte colony-stimulating factor (G-CSF) in atelocollagen into pulpectomized teeth. The clinical and laboratory evaluations demonstrated no adverse events or toxicity. The electric pulp test (EPT) of the pulp at 4 weeks demonstrated a robust positive response. The signal intensity of magnetic resonance imaging (MRI) of the regenerated...
PLoS ONE, 2014
Insights into the understanding of the influence of the age of MSCs on their cellular responses a... more Insights into the understanding of the influence of the age of MSCs on their cellular responses and regenerative potential are critical for stem cell therapy in the clinic. We have isolated dental pulp stem cells (DPSCs) subsets based on their migratory response to granulocyte-colony stimulating factor (G-CSF) (MDPSCs) from young and aged donors. The aged MDPSCs were efficiently enriched in stem cells, expressing high levels of trophic factors with high proliferation, migration and anti-apoptotic effects compared to young MDPSCs. In contrast, significant differences in those properties were detected between aged and young colony-derived DPSCs. Unlike DPSCs, MDPSCs showed a small age-dependent increase in senescence-associated b-galactosidase (SA-b-gal) production and senescence markers including p16, p21, Interleukin (IL)-1b,-6,-8, and Groa in long-term culture. There was no difference between aged and young MDPSCs in telomerase activity. The regenerative potential of aged MDPSCs was similar to that of young MDPSCs in an ischemic hindlimb model and an ectopic tooth root model. These results demonstrated that the stem cell properties and the high regenerative potential of MDPSCs are independent of age, demonstrating an immense utility for clinical applications by autologous cell transplantation in dental pulp regeneration and ischemic diseases.
Journal of Dental Research, 2004
Regenerative medicine is based on stem cells, signals, and scaffolds. Dental pulp tissue has the ... more Regenerative medicine is based on stem cells, signals, and scaffolds. Dental pulp tissue has the potential to regenerate dentin in response to noxious stimuli, such as caries. The progenitor/stem cells are responsible for this regeneration. Thus, stem cell therapy has considerable promise in dentin regeneration. Culture of porcine pulp cells, as a three-dimensional pellet, promoted odontoblast differentiation compared with monolayers. The expression of dentin sialophosphoprotein (Dspp) and enamelysin/matrix metalloproteinase 20 (MMP20) mRNA confirmed the differentiation of pulp cells into odontoblasts and was stimulated by the morphogenetic signal, bone morphogenetic protein 2 (BMP2). Based on the in vitro experiments, an in vivo evaluation of pulp progenitor/stem cells in the dog was performed. The autogenous transplantation of the BMP2-treated pellet culture onto the amputated pulp stimulated reparative dentin formation. In conclusion, BMP2 can direct pulp progenitor/stem cell dif...
Biomaterials, 2013
Mesenchymal stem cells (MSCs) have been used for cell therapy in various experimental disease mod... more Mesenchymal stem cells (MSCs) have been used for cell therapy in various experimental disease models. However, the regenerative potential of MSCs from different tissue sources and the influence of the tissue niche have not been investigated. In this study, we compared the regenerative potential of dental pulp, bone marrow and adipose tissue-derived CD31(-) side population (SP) cells isolated from an individual porcine source. Pulp CD31(-) SP cells expressed the highest levels of angiogenic/neurotrophic factors and had the highest migration activity. Conditioned medium from pulp CD31(-) SP cells produced potent anti-apoptotic activity and neurite outgrowth, compared to those from bone marrow and adipose CD31(-) SP cells. Transplantation of pulp CD31(-) SP cells in a mouse hindlimb ischemia model produced higher blood flow and capillary density than transplantation of bone marrow and adipose CD31(-) SP cells. Motor function recovery and infarct size reduction were greater with pulp CD31(-) SP cells. Pulp CD31(-) SP cells induced maximal angiogenesis, neurogenesis and pulp regeneration in ectopic transplantation models compared to other tissue sources. These results demonstrate that pulp stem cells have higher angiogenic, neurogenic and regenerative potential and may therefore be superior to bone marrow and adipose stem cells for cell therapy.
Stem Cell Research & Therapy, 2021
Background Dental pulp stem cells (DPSCs) have been developed as a potential source of mesenchyma... more 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. We have demonstrated the safety and efficacy of DPSCs isolated by G-CSF-induced mobilization and cultured under normoxia (mobilized DPSCs, MDPSCs) for pulp regeneration. The device for isolation of MDPSCs, however, is not cost-effective and requires a prolonged cell culture period. It is well known that MSCs cultured under hypoxic-preconditions improved MSC proliferation activity and stemness. Therefore, in this investigation, we attempted to improve the clinical utility of DPSCs by hypoxia-preconditioned DPSCs (hpDPSCs) compared with MDPSCs to improve the potential clinical utility for pulp regeneration in endodontic dentistry. Methods Colony-forming DPSCs were isolated and preconditioned with hypoxia in a s...
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Papers by Koichiro Iohara