Kyudai Oral Bioscience&
OBT Research Center
5th Joint International Symposium 2021
PROGRAM & ABSTRACTS

November 27-28, 2021
Zoom meeting/Lecture Room AB,
Faculty of Dental Science,
Kyushu University

K OB

2021

■ Date:November 27-28, 2021
■ Hybrid: Zoom meeting/Lecture room AB■ Organization
Kyudai Oral Bioscience
Oral Health・Brain Health・Total Health Research Center■ Contact
Eijiro Jimi
Oral Health・Brain Health・Total Health Research Center
Laboratory of Molecular and Cellular Biochemistry,
Faculty of Dental Science, Kyushu University,
Fukuoka 812-8582, Japan
Tel & Fax: +81 92-642-6332
E-mail: ejimi@dent.kyushu-u.ac.jp

5th KOB & OBT Joint International Symposium 2021

PROGRAMDAY 1Time

November 27 (Saturday)

Title

Presenter

13:00-13:10 Opening Remark
Session 1

Prof. Seiji Nakamura
Chair: Soi Kimura

Graduate Student's Session (1)13:10-13:25 ﻿The effects of Toll-like receptor 7 on sialadenitis

Kotono Kibe

13:25-13:40 ﻿Inhibition of c-Jun N-terminal kinase affects regeneration of periodontal tissues

Hiroshi Kaneko

13:40-13:55 ﻿Effect of carbonate content in carbonate apatite on bone remodeling

Kaai Deguchi

13:55-14:10

﻿Relationship between anterior tongue movement and masticatory performanceand pre-frailty in community-dwelling older individuals

Asuka Tani

14:10-14:20 Break
14:20-14:35 Award Presentation (IF and FWCI Award)
Session 2

Award Lectures (IF Award winners)

Chair:
Prof. Hidefumi Maeda

14:35-15:00

Exosomes from TNF- α-treated human gingiva-derived MSCs enhance M2 macrophage polarizationand inhibit periodontal bone loss

Dr. Yuki Nakao

15:00-15:25 YAP signaling induces PIEZO1 to promote oral squamous cell carcinoma cell proliferation

Dr. Kana Hasegawa

Human autoimmune diseases, systemic sclerosis and IgG4-related disease:
15:25-15:50
latest immunological approaches into the pathogenesis

Dr. Takashi Maehara

15:50-16:10 BreakSession 3

Chair:
Prof. Eijiro Jimi

KOB Special Lecture (1)16:10-16:50 APPLICATION OF TECHNOLOGIES IN DENTISTRY AND DENTAL RESEARCH

Dr. Kuson Tuntiwong
Dr. Tharathip Kulchotirat
King Mongkut's Institute ofTechnology, Thailand

16:50-17:00 BreakSession 4

Chair:
Dr. Masafumi Moriyama

OBT Special Lecture (1)17:00-18:00 Specific immune response in COVID-19

Dr. Kaneko
Kyushu University

DAY 1

November 28 (Sunday)

Time

Title

Presenter

Session 5

KOB Special Lecture (2) -Sharing JICA Memories and Our Success Stories-

Chair:
Dr. Tomoyo Yasukochi

9:00-10:00

My experience as a Kyushu University Fellow Student. A lifelong inspiration

Dr. Francisco Munoz Thomson
Universidad de los Andes Dental
SchoolSantiago, Chile

10:00-10:10 BreakSession 6

Chair:
Dr. Zhou Wu

Undergraduate Student's Session

10:10-10:20 Relation between oral hypofunction and nutrient intake condition in the elderly

Kaoruko Hirata

10:20-10:30 Bring out immune ability from mouth

Kouki Inoue, Saki Imamura,
Ryo Hirabar～Proposing from dental students～

Session 7

Graduate Student's Session (2)Chair:
Asuka Tani

10:35-10:50

Exosomal miR-1260b derived from TNF-α-treated hGMSCs
inhibits periodontal bone loss by targeting ATF6β-mediated regulation of ER stress

Chikako Hayashi

10:50-11:05 The role of basement membrane protein Nephronectin in tooth development

Kanji Mizuta

11:05-11:20 Soluble RANKL exacerbates menopause-associated obesity via non-canonical NF-κB signaling pathway

Kayo Mori

11:20-11:35 Physiological and Pathological Roles of Inhibitor of Differentiation 4 in the Salivary GlandSoi Kimura

11:35-11:50 BreakSession 8

OBT Special Lecture (2)Chair:
Prof. Eijiro Jimi

11:50-12:50 Exercising for future generations

Dr. Joji Kusuyama
Tohoku University

12:50-13:00 Closing Remarks

Prof. Eijiro Jimi

5th KOB & OBT Joint International Symposium 2021

Graduate Student’s Session (1)Chaired by Soi Kimura

The effects of Toll-like receptor 7 on sialadenitis
Kotono Kibe1,2, Takuma Shibata2, Masafumi Moriyama1,3,
Kensuke Miyake2, and Seiji Nakamura1
1

Division of Maxillofacial Diagnostic and Surgical Sciences, Section of Oral andMaxillofacial Oncology, Faculty of Dental Science, Kyushu University
2
Division of Innate Immunity, Department of Microbiology and Immunology, The
Institute of Medical Science, The University of Tokyo
3
OBT Research Center, Faculty of Dental Science, Kyushu University【Objective】
Recent studies indicate that Toll-like receptors (TLRs) play an important role in chronic sialadenitis
such as Sjogren's syndrome (SS) and IgG4-related disease (IgG4-RD). Our recent study demonstrated
that human TLR7 transgenic / mouse TLR7 knock-out mice showed infiltration of inflammatory cells andfibrosis by stimulation with TLR7 agonists. SLC29A3 is considered as a nucleoside transporter thatsuppresses the TLR7 response. We currently established SLC29A3 knock-out (SLC29A3 KO) mice,
which constantly activated TLR7 signaling. In this study, we thus examined the sialadenitis dependent on
TLR7 in SLC29A3 KO mice.
【Methods】
We performed (1) measurement of submandibular glands (SMGs) shape and weight, (2) measurement ofsaliva secretion induced by pilocarpin, (3) histopathological analysis of SMGs, (4) identification of SMGs
infiltrating cells by flow cytometry analysis, (5) quantitative analysis of cytokines and chemokines of SMGs
tissue lysate by proteome profiler, (6) analysis of mRNA expression of SMGs tissue by real-time PCR and(7) comparison with human samples by using wild type and SLC29A3 KO mice.
【Results】
SLC29A3 KO mice showed the significant hyposalivation and atrophy of SMGs with strong infiltrationof inflammatory cells compared with wild type mice. Immunohistochemical analysis confirmed that themain components of the infiltrating cells were CD4-, CD8-, and CD19-positive cells, and CD11b- andF480-positive cells were diffusely detected throughout the SMG tissues. Flow cytometric analysis showed
an increase in patrolling monocytes and classical monocytes in SLC29A3 KO mice. These phenotypes
completely disappeared in SLC29A3 KO/ TLR7 KO mice. Proteome profiler was performed using SMGs
tissue lysate, the expression of CXCL9, CCL5, IL16 and CXCL13 was specifically increased. Moreover,the mRNA expression levels of these chemokines were enhanced by real-time PCR using SMG tissues.
Both of SS and IgG4-RD patient showed the increase in number of CD11b- positive cells in SMG tissues.
Especially, SS patients showed the increased in mRNA expression levels of cDNA of CXCL9 and CCL5
by using DNA microarray.
【Conclusion】
These results suggest that TLR7 might promote monocytes/macrophages to induce infiltration of
inflammatory cells via the production of CXCL9, CCL5, IL16, and CXCL13.

Inhibition of c-Jun N-terminal kinase affects regeneration of
periodontal tissues
Hiroshi Kaneko1, Daigaku Hasegawa2, Tomohiro Itoyama2, Shinichiro Yoshida2,
Atsushi Tomokyo2, Sayuri Hamano1,3, Hideki Sugii1, Hidefumi Maeda1,2
1

Department of Endodontology and Operative Dentistry, Faculty of Dental Science,
Kyushu University, 2Department of Endodontology, Kyushu University Hospital, 3OBT
Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan

Few clinical treatments to regenerate periodontal tissue lost due to severe endodontic andperiodontal disease have yet been developed. Therefore, the development of newtreatment methods for the regeneration of periodontal tissue is expected. The purpose ofthis study was to investigate the effects of a c-Jun N-terminal kinase (JNK) inhibitor,
SP600125, on the osteoblastic differentiation of human periodontal ligament stem cells(HPDLSCs) in vitro, and the function of SP600125 on the regeneration of alveolar bonein periodontal defects in vivo.
First, we investigated the effect of JNK inhibition on osteoblastic differentiation of
HPDLSCs. SP600125 promoted Alizarin red S-positive mineralized nodule formationand the expression of osteoblast-related genes such as osterix, bone sialoprotein, andosteopontin in HPDLSCs under osteogenic conditions. Next, we clarify the intracellularsignaling molecules. This inhibitor upregulated BMP2 expression and phosphorylationof Smad1/5/8 in HPDLSCs under the same conditions while it did not affectphosphorylation of Erk1/2. Furthermore, we assessed the effects of JNK inhibition on theregeneration of bone tissue by using a rat periodontal defect model. SP600125 promoted
the regeneration of alveolar bone compared with that in the control at 2 weeks after its
application into periodontal defects, which involved the regeneration of periodontal
tissues.
This study suggests that inhibition of JNK signaling promotes osteoblastic
differentiation of HPDLSCs, probably through increased expressions of BMP2 and thephosphorylation of Smad1/5/8, leading to the regeneration of periodontal tissues. Ourfindings may lead to the development of a novel periodontal regeneration therapy.

Effect of carbonate content in carbonate apatite on bone remodeling
Kaai Deguchi1,2, Shunsuke Nomura1, Akira Tsuchiya2, Kunio Ishikawa2
and Ichiro Takahashi1.
1

Section of Orthodontics, Division of Oral Health, Growth and Development, Faculty of
Dental Science, Kyushu University
2
Department of Biomaterials, Faculty of Dental Science, Kyushu University

Carbonate apatite [CO3Ap: Ca10-a(PO4)6-b(CO3)c] is an inorganic component ofbone, and CO3Ap artificial bone was approved for its clinical use in dentistry. CO3Ap
artificial bone demonstrate much higher osteoconductivity than hydroxyapatite [HAp:
Ca10(PO4)6(OH)2]. A key difference between HAp and CO3Ap is the absence andpresence of CO3 in apatitic structure. If so, content of CO3 seems to affect bone
remodeling behavior of CO3Ap artificial bone. Therefore, in this study, feasibility tofabricate CO3Ap with different CO3 content was investigated along with the effects of
CO3 content on bone remodeling process. CO3Ap granules with different CO3 contents
were prepared by a dissolution–precipitation reaction using gypsum granules as aprecursor by immersing in a Na–PO4–CO3 mixed solution containing different
concentration of CO3. The composition of the prepared samples was analyzed using
powder X-ray diffractometer and a CHN coder. The dissolution rates of the samples inacetate buffer solution of pH 5.5, which mimics the Howship’s lacuna formed byosteoclasts, was quantified using an inductively coupled plasma-optical emission
spectrometer. For histological study, bone defects formed in the distal femur of 18-weekold Japanese rabbits were reconstructed with CO3Ap granules with different CO3 contents,
and their behavior was investigated by histological analysis at 4 and 8 weeks postimplantation. CO3Ap containing larger amount of CO3 could be fabricated by increasing
the CO3 concentration in Na–PO4–CO3 mixed solution. Dissolution rate of the CO3Ap
artificial bone at pH 5.5 mimicking Howship’s lacuna increased with increasing the CO3
contents in the CO3Ap granules. Histological analysis revealed that replacement of
CO3Ap to a new bone was quicker for CO3Ap granules with larger CO3 content in theapatitic structure. Due to replacement of CO3Ap to a new bone, structure of the bone
defect reconstructed by CO3Ap granules was close to the that of the bone. From theseresults, it was found that CO3Ap containing different amount of CO3 in apatitic structure
was possible. CO3Ap with higher CO3Ap content dissolves quickly at weak acidic
solution mimicking Howship’s lacuna formed by osteoclasts, and quickly replaced to a
new bone based on bone remodeling process.

Relationship between anterior tongue movement and masticatory
performance and pre-frailty in community-dwelling older individuals
Asuka Tani1, Shinsuke Mizutani1,2, Saori Oku1, Kiyomi Iyota1, Xin Liu3,
Hiro Kishimoto3,4, Haruhiko Kashiwazaki1
1

Section of Geriatric Dentistry and Perioperative Medicine in Dentistry, Division of
Maxillofacial Diagnostic and Surgical Science, Faculty of Dental Science Kyushu
University, Japan
2
OBT Research Center, Faculty of Dental Science Kyushu University, Japan3
Department of Behavior and Health Sciences, Graduate School of HumanEnvironment Studies, Kyushu University, Japan
4
Faculty of Arts and Science, Kyushu University, Japan

Background: Pre-frailty stage interventions can effectively prevent the need for long-termcare. However, only a few studies have investigated the relationship between oral
function and pre-frailty; therefore, this study aimed to examine the association between
oral function and physical pre-frailty.
Methods: A total of 381 individuals (mean ± S.D., 72.6 ± 3.9 years), included in the
Itoshima Frail Study, were analyzed. Physical pre-frailty was assessed by two physicalindicators (fatigue and unintentional weight loss), two functional components (decreased
walking speed and grip strength), and physical activity (social activity and exercise
habits). The number of the remaining teeth and oral functions, tongue and lip motor
function, masticatory performance, and tongue pressure were also assessed. The
participants were divided into robust group (n = 255) and physical pre-frailty group (n =126). Odds ratio (ORs) and 95% confidence interval (CIs) for physical pre-frailty were
calculated using binomial logistic regression analysis.
Results: Significant differences between robust and physical pre-frailty groups wereobserved in the maximum handgrip strength, 5-m maximum gait speed, body fat ratio of
the body trunk, skeletal muscle mass, masticatory performance, oral diadochokinesis /ta/,(anterior tongue movement), and social activity. Logistic regression analysis revealed thatanterior tongue movement, masticatory performance, and social activity were associatedwith physical pre-frailty (OR: 1.846, 95%CI: 1.060–3.215, p = 0.030; OR: 0.806, 95%CI:
0.672–0.967, p = 0.020; and OR: 2.234, 95%CI: 1.288–3.876, p = 0.004, respectively)
after adjusting for confounding factors.
Conclusion: Decreased anterior tongue movement, low masticatory performance, andlow social activity were associated with physical pre-frailty.

5th KOB & OBT Joint International Symposium 2021

Award Lectures

Chaired by Prof. Hidefumi Maeda

2021 年度

九⼤⻭学優秀研究者賞

受賞者

IF 部⾨

基礎系

教員

⻑⾕川 佳那 助教

臨床系

教員

前原 隆 助教

臨床系

教員以外

中尾 雄紀 助教

FWCI 部⾨

清島 保 教授

FWCI

1.72

⽵下 徹 准教授

FWCI

1.45

論⽂発表時：⼤学院⽣

Exosomes from TNF- α-treated human gingiva-derived MSCs enhance
M2 macrophage polarization and inhibit periodontal bone loss
Yuki Nakao1, Yukari Watanabe1, Chikako Hayashi1, Hiroaki Yamato1, Karen
Yotsumoto1, Terukazu Sanui1, Takanori Shinjo1, Takao Fukuda1, Fusanori Nishimura1
1

Department of Periodontology, Division of Oral Rehabilitation, Faculty of Dental
Science, Kyushu University, Fukuoka, Japan

Periodontitis is one of the most common osteolytic inflammatory diseases in human thatadversely affects systemic disorders, such as diabetes. Accumulation of periodontal
bacteria-associated biofilm is thought to trigger periodontitis, but is not believed to be
sufficient to sustain the disease as the host immune response is critical for inflammatory
tissue breakdown and disease progression. Macrophages play an important role in the
immune response both during the initiation and resolution of inflammation. Macrophages
are broadly classified into two phenotypes, pro-inflammatory M1 and wound-healing M2
cells. Macrophages are involved in bone homeostasis and the increased M1/M2 ratio
leads to enhanced osteoclastogenesis. As M2 macrophages contribute to the tissueremodeling process, effective M2 macrophage induction would provide favorable
environment for lower inflammation and better regeneration.
We identified that gingiva-derived MSCs (GMSCs) have unique immunoregulatory
capacity and secret large amounts of exosomes. Considering the facts that therapeutic
effect of MSC largely depends on the paracrine efficiency of MSC and the advantages of
the use of GMSCs include easier isolation from small pieces of gingival tissue (∼2×2mm2) and rapid cell proliferation, we hypothesized that GMSC-derived exosome-based
therapy could be suitable for clinical use. Moreover, recent studies indicated thatappropriate preconditioning of MSC with disease-related stimuli can optimize contentsof exosomes to efficiently support the repair of the tissues in particular diseases. In thiscontext, proteins or miRNA profiles in exosomes may be influenced by the pre-treatment
regimens. Therefore, optical molecular-based protocol for MSC-preconditioning needs to
be investigated and established.
In this presentation, we report the therapeutic effects of TNF-a preconditioned-GMSCderived exosomes on periodontal disease and demonstrate underlying molecularmechanisms. Our study revealed that TNF-a-enhanced exosomal CD73 expression
leading to anti-inflammatory M2 macrophage polarization and exosomal miR-1260b was
important negative regulator of osteoclastogenesis. Accordingly, our findings may
provide a novel therapeutic strategy for patients with periodontitis and otherinflammatory osteoimmune disorders.

YAP signaling induces PIEZO1 to promoteoral squamous cell carcinoma cell proliferation
Kana Hasegawa, Shinsuke Fujii, Tamotsu Kiyoshima
Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical
Sciences, Faculty of Dental Science, Kyushu University
It has been reported that there are few target molecules for anti-tumor therapy, such as
gene mutations, in the head and neck squamous cell carcinoma. Therefore, in oral
squamous cell carcinoma (OSCC), we hypothesized that abnormally activated signaltransduction could be involved in tumorigenesis. Stiffness is one of the important clinicalfeatures of OSCC. In addition, recent studies showed that increased extracellular matrix
stiffness promotes tumorigenesis. The Hippo pathway responds to the extracellularenvironment and regulates cell proliferation through the nuclear localization of major
downstream effector, yes-associated protein (YAP), resulting in the induction of target
gene transcription. Its pathway also has been linked to tumorigenesis. However,downstream target genes of YAP signaling in OSCC tumorigenesis remain unclear.
Piezo-type mechanosensitive ion channel component 1 (PIEZO1), a mechanosensitiveion channel, is reported to be associated with organ morphogenesis, but its expression andfunction in OSCC tumorigenesis are unknown. Herein, we investigated the effect of YAP
on the cell proliferation through PIEZO1 in OSCC cells. In OSCC cells, proliferation
capabilities in suspension culture were lower than those in 2D or 3D culture. Microarray
analysis and GO analysis demonstrated that several genes related to cell growth were
down-regulated in suspension culture compared with those in 2D culture. The
experiments using suspension culture and chromatin immunoprecipitation (ChIP)
demonstrated that YAP signaling regulates PIEZO1 expression. Elevated PIEZO1
expression was required for PIEZO1 agonist-dependent Ca2+ influx and cell proliferationin OSCC cells. Furthermore, YAP signaling regulated OSCC cell growth throughPIEZO1 expression in 3D culture. In addition, YAP was frequently expressed in the
nucleus in tumor lesion where PIEZO1 and Ki-67 expression were detected. These results
suggest that hyperactivated YAP signaling promotes OSCC cell proliferation throughPIEZO1 expression.

Human autoimmune diseases, systemic sclerosis and IgG4-relateddisease: latest immunological approaches into the pathogenesis
Takashi Maehara1, Naoki Kaneko1, Ryusuke Munemura1, Yuka Murakami1,
Shiv Pillai2, Seiji Nakamura1
1

Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic andSurgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
2
Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital,
Harvard Medical School, Boston, MA, USA

We examine the contributions of B cells to the development and function of CD4+T cells
in human inflammatory disease. We study these cells and their subsets in the context of
autoimmune fibrotic diseases like systemic sclerosis (SSc) and IgG4-related disease(IgG4-RD). Activated B cells and CD4+T cell which likely cause organ damage and tissue
fibrosis, constitute the major inflammatory cell population in these patients. We thus
focused on CD4+T cell subsets and the T-cell clones that are involved in the pathogenesisof these disease, by using single-cell RNA sequencing, T cell receptor repertoire analysis,
and multicolor immunofluorescence staining. These latest approaches revealed prominentclonal expansions of CD4+ cytotoxic T cells (CD4+CTLs) in these diseases. SSc and
IgG4-RD are autoimmune fibrotic disease whose pathogenesis is poorly understood andlacks effective therapies. The definitive identification of self-antigens that are recognizedby expanded T cell clones that infiltrate tissues in patients with these inflammatory
fibrotic diseases would strengthen the view that self-reactive T cells drive this disease
process. We undertook quantitative analyses of T cell infiltrates in the skin of 35 untreatedpatients with early diffuse SSc and here show that CD4+CTLs and CD8+T cells contributeprominently to these infiltrates. We also observed an accumulation of apoptotic cells in
SSc tissues, suggesting that recurring cell death may contribute to tissue damage andremodeling in this fibrotic disease. HLA-DR expressing endothelial cells were frequent
targets of apoptosis in SSc. Consistent with the prominent vasculopathy seen in patientswith SSc. A circulating effector population of CD4+CTLs was clonally expanded in SSc
patients. These data suggest that CD4+CTLs may induce the apoptotic death ofendothelial and other cells in SSc. Therapies should be focused on targeting these cells
and studies on pathogenesis should examine the antigenic sources and mechanisms of
their generation. In this session, we thus focus on the latest immunological approaches to
elucidate the pathogenesis of SSc and IgG4-RD.

5th KOB & OBT Joint International Symposium 2021

KOB Special Lecture (1)Chaired by Prof. Eijiro JimiAPPLICATION OF TECHNOLOGIES IN DENTISTRY AND
DENTAL RESEARCH
Kuson Tuntiwong1, Tharathip Kulchotirat 1
1

School of Dentistry, King Mongkut’s Institute of Technology Ladkrabang, Bangkok,
ThailandNowadays, technologies are continuously developing. Various types of technologicalapplications were Internet of Things, Virtual and Augmented reality, Artificial
Intelligence, etc. These were named as The Gaming Changing Technologies. The
applications were typically based on mathematical problems, like, optimization, patternrecognition, classifications, clustering, or continuous estimation. Likewise, in dental
field, these technologies had become a part of dentistry, shifted to the new perspectivesof dental treatment planning and dental research. The increasing use of the Finite Element
Analysis in dental research was published to solve simulation and optimization problems
in CAD environment. It provided stress analysis in specific scenario and simulated stress
distribution beyond the visibility of human eyes [1]. Deep learning was also used toinitially detect the radiographic findings in dental images [2]. In 3D tasks, digital
geometry processing was also used to analyze the error 3D scanning [3]. These are justsome examples of technologies that applied to the dental field. There are a lot more
problems in dentistry that waits for us to use these as analytic tools.

References
1. Tuntiwong K., Hsu J.-T., Yang S.-G., Yu J.-H.& Huang H.-L.(2021).BiomechanicalEffect of Orthodontic Treatment of Canine Retraction by Using Metallic Orthodontic
Mini-Implant (OMI) Covered with Various Angles of Revolving Cap. Applied Bionics
and Biomechanics;2021:9952392.
2. Yasa Y., Çelik Ö., Bayrakdar I. S., et al.(2021).An artificial intelligence proposal toautomatic teeth detection and numbering in dental bite-wing radiographs. Acta Odontol
Scand;79(4):275-81.
3. Thanasrisuebwong P., Kulchotirat T.& Anunmana C.(2021).Effects of inter-implantdistance on the accuracy of intraoral scanner: An in vitro study. The journal of advanced
prosthodontics;13(2):107-16.

5th KOB & OBT Joint International Symposium 2021

OBT Special Lecture (1)Chaired by Dr. Masafumi Moriyama

Specific immune response in COVID-19
Naoki Kaneko1,2, Shiv Pillai2
1

Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic andSurgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan,
2
Ragon Institute of MGH, MIT and Harvard

Despite the rapid spread of vaccines, COVID-19 is still rampant around the world. Oneof the reasons is SARS-CoV2 infection does not elicit an appropriate humoral immune
response and often lacks durability in humans. It is well known that proper immune
memory is not induced, especially in natural infections. We demonstrate an unexpectedpaucity of germinal center and germinal center-related T cells and B cells in thelymphoid organs in acute COVID-19. Considering that germinal center is involved in
the production of high-quality antibodies, these phenomena may explain the mechanismof limited durability against COVID-19. Furthermore, apart from broadly compromising
the generation of germinal centers in lymph nodes, acute COVID-19 is also linked toattenuated CD8+ T cell activation and infiltration of the lungs, and the delayed
pulmonary accumulation of CD4+T cells with a cytotoxic phenotype. Theseobservations might help explain why SARS-CoV-2 is slowly eliminated from the lungs
and why "COVID-19 long-hauler" exists who may have conditions ripe for the selectionof viral variants with a transmission advantage. Many new variants of SARS-CoV2
have been reported since the first report of that, and it may be another reason why thecovid pandemic has not come to an end.

5th KOB & OBT Joint International Symposium 2021

KOB Special Lecture (2)Chaired by Dr. Tomoyo Yasukochi

Sharing JICA Memories and Our Success Stories
The medical, research and educational fields today are facing big challenges due to the
Covid 19. In the midst of these uncertainties, as part of our globalization effort ourfaculty set up the International office in April this year. We plan to increase our partner
universities, and to recruit more international students by hosting online recruitment
events.
One of the most important mission of the International office is to maintain the strong
bonds and build new ones with the International students and researchers who areaffiliated to us.
Our faculty welcomed and hosted 248 students from all over the world under the JICA
(Japan International Cooperation Agency) Oral Health Science Education Program overa span of 23 years, from 1988 to 2010. Our International office initiated a JICA network
and we also started a Facebook page and quarterly newsletter to keep the participants
updated of the events at our faculty.
Starting from this year, we plan to invite JICA participants to give a presentation at our
KOB/OBT symposium every year. The theme of this session would be “Sharing JICA
memories and our success stories” and we would get presenters to share theirmemories with us under the JICA program, as well as how this program has created apositive impact on their lives.

You can see our Facebook page from this QR code.

My experience as a Kyushu University Fellow Student.
A lifelong inspiration
Dr. Francisco Muñoz Thomson
Chair Oral and Maxillofacial Department
Universidad de los Andes Dental School
Santiago - Chile

In 2004 I was one of the 12 dentists participating in the JICA Dental Education Course.
The months I got to spend as a Kyushu University fellow student introduced me to awhole new world within dentistry; I got the chance to have a broad insight of the different
specialties which I had lost track of because of my total dedication to Oral andMaxillofacial Surgery.
We were exposed to state of the art technology and were inspired by top researchers andProfessors who generously shared their experience. From the very first moment I had the
feeling of being immerse in the centenary prestige of Kyushu University and felt
privileged to be, if at least for a couple of months, part of this thriving and challenging
community.
Even though it was designed to be an academic experience, it was so much more than
that! Having the chance of living in a multicultural environment such us the Kyushu
International Centre and spend time with fellow dental students at the Campus, I soon
realized that this would be a social and personal experience that would positively impact
my life.
During those months, I reassured my passion for Oral and Maxillofacial Surgery underthe example of Professor Yuji Shiratsuchi and made strong friendships in the Kyushu
University Karate Team. I confirmed my lifetime admiration for Japanese culture andhumbly learnt the basics of the language expanding my chances to relate with more people
and make new friends.
It is fair to say that this experience somehow modeled the rest of my career.
This professional and cultural experience set a new standard which I have tried to reachever since. I came back to Chile with a clear vision of excellence and used it as aninspiration in my upcoming professional challenges with my students, then my colleagues
and later on the staff members in the OMS Department which I now lead.
I traveled to Japan expecting to become a better professional and I flew back to Chile
being a better person that is committed to work day after day for a better Society.

5th KOB & OBT Joint International Symposium 2021

Undergraduate Student’s Session

Chaired by Dr. Zhou Wu

Relation between oral hypofunction and nutrient intake condition in
the elderly
Kaoruko Hirata1, Tomomi Ohmaru2, Naohisa Wada2
1

2

Kyushu University School of Dentistry,
Division of General Dentistry, Kyushu University Hospital, Japan;

Japan has become a super-aging society. Roles of dentists change variety from thetreatments to the improvement of oral function and prevention of frail, dementia oreldercare. However, there is a serious concern that oral hypofunction or alteration ofnutrient intake is often overlooked, because of the large elderly populations.
【 Hypothesis 】 We hypothesized that avoidance of oral hypofunction would help toimprove general health, and analyzed whether trouble of oral condition would influenceoral function and nutrient intake in the elderly.
【 Method 】 Subjects are 27 people with more than 65 years-old, and they were thepatients who visited to receive dental treatments in university hospital and agreed to be
included in this study.
Measurement items were Examination of oral function (seven items), questionnaire(Mini Nutritional Assessment: MNA®), and record of food intake (Balance guide madeby Ministry of Agriculture).
【Results and Discussion】Seventeen subjects (63%) resulted to be oral hypofunction.
Hypofunctions with tongue and lip motor function, tongue pressure, and occlusal force
were more than 50%.
Over 90% subjects kept full support in Eichner classification when including denture
support. This might influence the low percentage of masticatory hypofunction. Thus, it
was important to recover masticatory area by introducing denture.
On investigation with five subjects, the amount of foods other than main dishes wererelatively small, compared with standard value of similar age. Also, three of them werediagnosed as a “risk of malnutrition” or “malnutrition” in MNA examination, but there
was one subject who was diagnosed as “oral hypofunction”.
There was a positive correlation between occlusal force and MNA score, but a negative
correlation between occlusal force and oral hygiene. Therefore, maintenance of occlusal
support can improve nutritional status. Then, it was considered that recovery of occlusal
force following improvements of occlusal support or masticatory area by dental
treatments could improve nutritional status.
【Conclusion】Dentists could notice a sign of flail by evaluation of oral function andnutrient intake. Furthermore, it was suggested that dental treatment affect prevention oforal hypofunction and malnutrition.

Bring out immune ability from mouth～Proposing from dental students～

Kouki Inoue, Saki Imamura, Ryo Hirabara
5th grade, Undergraduate, School of Dentistry, Kyushu University, Japan

Novel Coronavirus (COVID-19) is seriously damaging people's lives andeconomy worldwide, and immunity of people is considered as a key forpreventing the virus infection and aggravation of the infection. As dental
students, the future health-care professionals, we eager to seek the ways toovercome the virus infection from the perspective of oral medicine. During
our research lecture, we set up a project and have made a proposal as"maintain and improve immunity from the mouth." based on the literaturesearch. In the present presentation, we firstly review the impacts of oral
conditions (periodontal disease, etc.) on systemic immunity. In ourconstructed proposals, we will introduce how to enhance immunity by
nutrition intake from the mouth and how to enhance immunity by
improving quantity and quality of saliva in the mouth. We hope our
proposal will contribute to the prevention of infection and the spread of
infection.

5th KOB & OBT Joint International Symposium 2021

Graduate Student’s Session

Chaired by Asuka TaniExosomal miR-1260b derived from TNF-α-treated hGMSCs
inhibits periodontal bone loss by targeting ATF6β-mediated regulationof ER stress◯Chikako Hayashi, Takao Fukuda, Yukari Watanabe, Kentaro Kawakami,
Masaaki Toyoda, Yuki Nakao, Karen Yotsumoto, Hiroaki Yamato,
Takanori Shinjo, Terukazu Sanui, Fusanori Nishimura
Department of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science,
Kyushu University

Objectives: Human MSCs from gingiva (hGMSCs) are easier to isolate, and appear tosecret higher amounts of exosome than other MSCs. We recently demonstrated that
exosome from TNF-a treated GMSCs increased the level of miR-1260b and inhibited
periodontal bone loss（Nakao Y, et al., Acta Biomater, 2021）. We further screened novel
miR-1260b targeting genes by database analysis and found that it could be associatedwith ER stress by targeting ATF6b. It has reported that ER stress-related genes were upregulated in periodontal tissue（Yamada H, et al. J Periodontal Res., 2002）. In this study,
we investigated the therapeutic effect of miR-1260b in periodontal disease by targeting
ATF6b-mediated regulation of ER stress.
Materials and Methods: Human periodontal ligament cells (hPDLCs) were transfectedwith miR-1260b mimic to validate miR-1260b-mediated inhibition of ATF6b. The
effect of miR-1260b on inflammatory bone loss were examined using mouse ligatureinduced periodontitis model under an institutionally approved animal research protocol(Kyushu University, #A21-131-0). The expression levels of ATF6b in mice werecompared by qRT-PCR and immunohistochemistry, and alveolar bone loss wasanalyzed by Micro CT. To validate the effect of miR-1260b on osteoclastogenesis, miR1260b mimic transfected THP-1 cells and PBMC were stimulated with M-CSF andRANKL for osteoclast differentiation and the number of TRAP-positive cells werecounted.
Results: Transfection of miR-1260b mimic inhibited ATF6b expression and knock
down of ATF6b decreased expression of RANKL mRNA in hPDLCs. Increased
expression of ATF6b was observed in the ligated periodontal tissue and local injection
miR-1260b mimic decreased periodontal bone resorption in mice. The number of TRAP
positive cells were decreased in miR-1260b mimic transfected THP-1 and PBMC differentiated osteoclasts.
Conclusion: miR-1260b inhibited osteoclastogenesis and periodontal bone loss bytargeting ATF6b-mediated regulation of ER stress. miR-1260b may be a target formiRNA mimic-based treatment against inflammation-induced bone loss diseases such as
osteoporosis and rheumatoid arthritis.

The role of basement membrane protein Nephronectin in toothdevelopment
Kanji Mizuta1, Keigo Yoshizaki1, Kanako Miyazaki1, Keita Funada1, Tomomi
Yuta1, Tian Tian1, Yao Fu1, Jumpei Kawahara1, Ichiro Takahashi1
1

Section of Orthodontics, Faculty of Dental Science, Kyushu University, Fukuoka, Japan

Tooth development is initiated by epithelial-mesenchymal interactions. The basement
membrane between the epithelium and mesenchyme is an essential scaffold that regulates
various signals. We focused on Nephronectin (NPNT), which is specifically localized in
the basement membrane during epithelial-mesenchymal interaction. NPNT has an EGFlike repeats domain on the N-terminus and an RGD domain, known as an integrin binding
domain, on the C-terminus. Previously we reported that NPNT plays critical roles indental epithelial stem cell differentiation through regulation of SOX2 expression via the
EGF signaling pathway through its EGF-like repeats domain.
In this study, we analyzed the function of RGD domain of NPNT using Npnt-ΔEGF and
Npnt-ΔRGD expression vectors, lacking the EGF-like repeats and the RGD domain of
NPNT. Npnt-FL and Npnt-ΔEGF overexpression in dental epithelial cells (M3H1)
resulted in increased expression of ameloblastin (Ambn), which is a differentiation
marker for ameloblasts. However, overexpression of Npnt-ΔRGD did not alter the
expression level of Ambn in M3H1 cells. These data suggest that the RGD domain of
NPNT may play an important role for ameloblast differentiation.
In addition, we revealed that BMP2 decreased the mRNA level of Egfr, so that thesignaling of EGF-like repeats domain is downregulated. We also confirmed that thefunctional domain of NPNT was switched to the RGD domain in M3H1 cells with
reduced EGFR expression.
In conclusion, NPNT regulates dental epithelial cell proliferation by using the EGF-like
repeats domain during morphogenesis stage, followed by switching to the function of
RGD domain in differentiation stage. NPNT plays critical role for tooth development byusing the two functional domains as the extracellular scaffold.

Soluble RANKL exacerbates menopause-associated obesity
via non-canonical NF-κB signaling pathway
Kayo Mori1,2, Akiko Mizokami3, Tomomi Sano4, Yasunori Ayukawa2, Takashi
Kanematsu4, Eijiro Jimi1,3
1

Laboratory of Molecular and Cellular Biochemistry, 2Section of Implant andRehabilitative Dentistry, Division of Oral Rehabilitation, 3OBT Research Center,4
Department of Cell Biology, Aging Science & Pharmacology, Faculty of Dental
Science, Kyushu University[Objectives] It is well known that obesity is commonly associated with chronic lowgrade systemic inflammation. Immune cells infiltrated in obese adipose tissues produce
proinflammatory cytokines that can exacerbate insulin resistance, leading to metabolic
disorders such as type 2 diabetes and dyslipidemia. Rapid decrease of estrogen due tomenopause makes women more susceptible to visceral obesity. However, the precise
mechanism of menopause-induced obesity is still unclear. It has been reported thatcirculating levels of receptor activator of NF-κB ligand (RANKL) is increased in both
postmenopausal women and mice models of menopause. RANKL activates bothcanonical and non-canonical pathways of NF-κB. In this study, we investigated thepotential role of RANKL-induced NF-κB activation, specifically focusing on noncanonical pathway, in inducing systemic chronic inflammation and menopause-related
lipid accumulation.
[Material and methods] We used ovariectomized mice as a surgical model ofmenopause (OVX) using WT and Alymphoplasia (aly/aly) mice, and fed a high-fat,high-sucrose diet to induce obesity. aly/aly is a naturally occurring strain with amutation in nuclear factor-kappa B inducing kinase (NIK), and therefore cannot activate
the non-canonical NF-kB pathway. Model of postmenopausal obesity was generated by
ovariectomy and subsequent high-fat and high-sucrose diet feeding.
[Results] We confirmed that RANKL stimulation induced Tnfa expression via
non-canonical NF-κB pathway in bone marrow cells. In aly/aly mouse model ofmenopause-induced obesity, all the deleterious effects of ovariectomy in wild-typemice such as adipocyte hypertrophy with increased macrophage infiltration in the
adipose tissue accompanied by increased mRNA expression of inflammatory
cytokines, hepatic lipid accumulation, and glucose intolerance caused by systemic
insulin resistance.
[Conclusion] Our results suggest that the elevation of serum RANKL levels
contributes to the development of glucose intolerance, insulin resistance, andobesity in menopausal women through the activation of NF-κB non-canonicalpathway.

Physiological and Pathological Rolesof Inhibitor of Differentiation 4 in the Salivary GlandSoi Kimura1,2, Tomoyo Kawakubo-Yasukochi1, Yoshikazu Hayashi1,3, Ena Yano1,
Masafumi Moriyama2, Seiji Nakamura2, Eijiro Jimi1
1

OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic andSurgical Sciences, Faculty of Dental Sciences, Kyushu University, Fukuoka, Japan
3
Section of Functional Structure, Fukuoka dental college, Fukuoka, Japan

2

Inhibitor of differentiation 4 (Id4) is a dominant negative transcriptional regulator ofbasic helix-loop-helix (bHLH) transcription factors that lack the basic DNA binding
domain, but have an intact HLH domain. It regulates the function of various ubiquitously
expressed or tissue-specific bHLH transcription factors as well as many non-bHLH
proteins with different affinities. The molecular mechanism responsible for the uniquerole of Id4 as compared to other Id proteins still remains largely unexplored.
Recently, we identified Id4 as a molecule involved in the pathogenesis of IgG4-relateddiseases (IgG4RD) from the results of a comprehensive miRNA-mRNA pairing analysis
focusing on patient serum miRNA and intracellular mRNA in normal salivary epithelial
cells. IgG4-related disease is a disease in which infiltration of IgG4-positive plasma cells
into various organs including salivary glands and hyper-IgG4emia are observed; however,its pathogenic mechanism is still unknown. In fact, Id4 expression at the protein level inthe salivary glands of IgG4RD was significantly decreased compared with that in normal
tissue. This indicated that Id4 may be involved in the pathophysiology of salivary glanddiseases.
Thus, we further investigated the physiological roles of Id4 in the salivary gland byusing Id4-deficient mice and RSMG-1 rat salivary gland epithelial cell line. In the cell
culture experiment, the expression level of Id4 was decreased in RSMG-1 treated with
Activin A, but its expression level returned to normal level after 72 h. From histologicalanalysis, PAS-positive granules were more abundant in the acinar lumen of Id4-deficient
submandibular gland than in that of wild-type littermates, and abnormal expression ofvarious differentiation markers was observed in Id4-deficient salivary glands.
From these results, it was suggested that Id4 plays an important role in the development
and cell differentiation of the salivary gland, and decrease in its expression affects thepathophysiology of various salivary gland diseases including IgG4-related diseases.

5th KOB & OBT Joint International Symposium 2021

OBT Special Lecture (2)Chaired by Prof. Eijiro Jimi

Exercising for future generations
Joji Kusuyama
Frontier Research Institute for Interdisciplinary Sciences (FRIS)
Tohoku University, JapanThe global prevalence of type 2 diabetes is expected to rise to 630 million by 2045,
resulting in a worldwide health care crisis, which will require drastic intervention.
Recently, we and other groups studies have reported that maternal obesity and type 2
diabetes increase the risk of diabetes in offspring, despite healthy offspring lifestyle.
Therefore, determining an effective means to reduce the transmission of metabolic
disease from mother to offspring, as well as understanding the mechanisms for theseeffects, will have invaluable impact on health care policy. We establish that maternal
exercise improves the metabolic health of offspring through enhanced liver function,
leading to improved glucose tolerance. We are the first to discover that placenta-derived
superoxide dismutase 3 (SOD3) mediates the transmission of the favorable effects ofmaternal exercise to offspring. The mechanism for this effect involves SOD3 functioning
as a signaling protein, activating DNA demethylation at the promoter of key glucose
metabolic genes in the liver, which increases expression of these genes and improves liverfunction. Finally, these discoveries bear the clinical relevance; our animal work is
recapitulated by our human data, showing that SOD3 is upregulated in the serum andplacenta from highly physically active pregnant women. We demonstrated that maternal
exercise is a promising method as a “preemptive medical treatment” to prevent thetransmission obesity and diabetes from the current generation to the next generation. We
also identified that placenta-derived proteins are important factors that transmit thebeneficial effects of exercise to offspring. The placental–fetal system is another hotspot
for offspring developmental programming, because it has a major role during the critical
windows of prenatal offspring development. This talk summarizes our latest finding about
the exercise-nutrition crosstalk pathway and our hypothesis that the placenta is atransducer that conveys maternal information to their children. Identifying the mediating
factors and signaling pathways that connect exercise stimuli to these phenotypic anddevelopmental outcomes is essential for human translation, and given the ever-expanding
issues of global obesity, these issues will only become more relevant in the future.