○会期：平成 29 年２月 12 日（日）10:00〜18:00○会場：福岡リーセントホテル

舞鶴の間

：下図参照

住所：福岡市東区箱崎 2-52-1
電話：092-641-7741○主催：九州大学大学院
日本学術振興会

歯学研究院
頭脳循環を加速する戦略的国際研究ネットワーク推進プログラム

口腔から健康長寿を支えるプロジェクト推進に向けた研究拠点構築プログラム

連絡先：

西村

英紀

九州大学大学院 歯学研究院・歯学府・歯学部 歯周病学分野〒812-8582

福岡市東区馬出 3-1-1

電話：092-642-6358
ファックス：092-642-6360
E-mail：fusanori@dent.kyushu-u.ac.jp

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PROGRAM頭脳循環第三回シンポジウム
3rd Symposium:
Program for Advancing Strategic International Networks to Accelerate theCirculation of Talented Researchers
2017年2月12日■

10：00〜10：10

Opening remarks■

10：10〜11：10 Session１

Masato Hirata

Chair :

Hidefumi Maeda

Dr. Yang Chai：
Molecular regulatory mechanism of mesenchymal stem cells
to transit-amplifying cells transition in tissue homeostasis
George and MaryLou Boone Chair in Craniofacial Molecular
Biology
Director, Center for Craniofacial Molecular Biology
Associate Dean of Research, Ostrow School of Dentistry
University of Southern California■■

11：10〜11：40

13：00〜14：00 Session２

Dr. Takayoshi Yamaza：
Orofacial stem cell-based medicine
Department of Molecular Cell Biology and Oral Anatomy,
Kyushu University Graduate School of Dental Science

Chair :

Fusanori Nishimura

Dr. Dana Graves：
Mechanisms of Diabetes Impaired Wound Healing
Vice Dean for Scholarship and Research & Interim Chair of
Periodontics Department, University of Pennsylvania Schoolof Dental Medicine■■

14：00〜14：30

14：50〜15：50 Session３

Dr. Fusanori Nishimura：
Adipose tissue inflammation may be a key player insystemic expansion of periodontal inflammation
Section of Periodontology, Department of Oral Rehabilitation,
Kyushu University Faculty of Dental Science

Chair :

Seiji Nakamura

Dr. Shiv Pillai：
Epigenetic Regulation of Lymphocytes in Health andDiseaseRagon Institute of MGH, MIT and Harvard
Harvard Medical School

■

■

■

15：50〜16：20

Dr. Masafumi Moriyama：
Possible involvement of toll-like receptors in IgG4-related
dacryoadenitis and sialoadenitis
Section of Oral and Maxillofacial Oncology, Division of
Maxillofacial Diagnostic and Surgical Sciences, Faculty of
Dental Science, Kyushu University
OBT Research Center, Faculty of Dental Science, Kyushu
University

16：20〜16：35

Dr. Takashi Maehara：
Human BATF + IL-4 + T follicular helper cells are linked toa polarized IgG4 switching event and accumulate primarily
outside germinal centers in IgG4-related disease lesions
Ragon Institute of MGH, MIT and Harvard, Massachusetts
General Hospital, Harvard Medical School

16：40〜17：25 Reports after circulation

Chair :

Noriatsu Shigemura

Dr. Urara Tanaka：Effects of Decitabine on Osteoclastogenesis
and Periodontal Bone loss in Mice
Dr. Akihito Furuhashi ：Generation of Salivary Gland-like Organoids
from Human Dental Follicle Epithelial
Stem Cells
Dr. Shingo Takai：T he function of insulin and insulinotropic
peptides in taste tissue

■

17：25

Closing remarks

■

17：30

Photo-taking

Kazuaki Nonaka

【MEMO】

Session1

Molecular regulatory mechanism of mesenchymal stem cells to transitamplifying cells transition in tissue homeostasis
Yang Chai, DDS, PhD
Professor
George and MaryLou Boone Chair in Craniofacial Molecular Biology
Director, Center for Craniofacial Molecular Biology
Associate Dean of Research, Ostrow School of Dentistry
University of Southern California

Stem cells are remarkable. They form tissues during development, maintain tissue homeostasis andperform injury repair in adults. The mouse incisor provides an excellent model for stem cell study
because it grows continuously throughout life. Stem cells residing in the proximal region of the incisor
in adult mice can replenish all incisor cells within one month. We have recently shown that themesenchymal stem cells (MSCs) in the adult mouse incisor are a Gli1+ cell population surrounding theneurovascular bundle (NVB) near the cervical loop region and that they govern tissue homeostasis
and repair. The NVB secretes Shh and provides a niche for MSCs in the incisor. However, thefunctional significance of Shh secreted from the sensory nerve within the NVB still needs to beinvestigated. During normal homeostasis, MSCs exit from their niche and become transit-amplifying(TA) cells, undergoing a series of divisions before terminal differentiation. The transition process from
MSC to TA cell is a common feature in diverse organs but little is known about the presumably
complex signaling network that governs this transition. Our studies show that (i) secretion of Shhby the sensory nerve supports MSCs in the adult mouse incisor and that (ii) molecular signaling
interactions control the MSC to TA cell transition and the fate of MSCs to maintain mesenchymal
cell homeostasis in the adult mouse incisor. Our study provides important knowledge of the signaling
network that regulates the transition from MSCs to TA cells in maintaining tissue homeostasis. The
understanding gained from this study will serve as the foundation for future studies in MSC biology
and stem cell-mediated tissue regeneration.
Supported by R37 DE012711 and R01 DE025221, NIDCR, NIH

1

CURRICULUM VITAE

Biography
Dr. Yang Chai is a Professor and the George and MaryLou Boone Chair in Craniofacial Biology at the
University of Southern California. He serves as the Director of the Center for Craniofacial Molecular
Biology (CCMB) and Associate Dean of Research at the Herman Ostrow School of Dentistry of the
University of Southern California. He is most noted for his research on the molecular regulation of
cranial neural crest cells during craniofacial development and malformations. Over the years, hislaboratory has developed multiple genetically engineered mouse models in order to investigate how
craniofacial organs such as the tooth, palate, mandible, maxilla, tongue and calvaria are formed,
and how tissue-tissue interactions control patterning and morphogenesis. Dr. Chai’s research work
has transformed our understanding of the regulatory mechanisms of craniofacial development. He
is currently also studying mesenchymal stem cells (MSCs), their niche environments, and how to
use innovative 3D-printed scaffolds with MSCs to support craniofacial tissue regeneration. Most
importantly, his research interest has always been focused on linking animal models with human birthdefects. His research has led to the successful rescue of craniofacial malformations by manipulating
signaling pathways during embryogenesis.
Dr. Chai has authored more than 140 scientific papers and numerous book chapters, and has recently
edited a book on craniofacial development. His work has earned him multiple awards including the2011 IADR (International Association of Dental Research) Distinguished Scientist Award. He is anelected member of the American Academy of Arts and Sciences (AAAS). He serves on the editorial
board of Developmental Biology. He has also served on the Board of Scientific Counselors at the
National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Health (NIH)
and is currently serving on the National Advisory Dental and Craniofacial Research Council for the
NIDCR, NIH. He also serves on NIH study sections and reviews grant applications for the Wellcome
Trust and other international research organizations. Dr. Chai earned a DMD degree from Peking
University School of Stomatology as well as DDS and PhD in Craniofacial Biology from the Universityof Southern California.

2Orofacial stem cell-based medicine

Takayoshi YAMAZA, DDS, PhD
Department of Molecular Cell Biology and Oral Anatomy, Kyushu University
Graduate School of Dental Science

Over fifteen years have been passed after the first discovery of human orofacial stem cells in theworld. Origin of orofacial stem cells is considered to be cranial neural crest cells (CNCCs). In embryo,neural crest cells (NCCs) separate from neural crest, which is temporally formed between ectoderm
and neural plate during neural tube formation, and migrate into various places to participate invariety of organ and tissue development. During the migration, NCCs translate into mesenchymal
cells (epithelial-mesenchymal transition). Particularly, CNCCs concentrate in facial and pharyngeal
arches, and form not only sensory VII, IX, X cranial nerves, thymus, thyroid follicular cells,
parathyroid, and cornea, but also most of orofacial mesenchymal organs including facial skeleton suchas maxilla and mandible, dentin/pulp complex, cementum, periodontal ligament, and alveolar bone.
Today, several types of stem cells are isolated and characterized from human orofacial tissues such as
dental pulp stem cells (DPSCs), stem cells form human exfoliated deciduous teeth (SHED), stem cells
from apical papilla (SCAP), periodontal ligament stem cells (PDLSCs), and gingival mesenchymal stem
cells (GMSCs). Among the orofacial stem cells, SHED are considerably focused on the outstanding
properties of multidifferentiation, tissue regeneration, and immunomodulation. Therefore, many basic
and clinical researchers have expected the clinical success of SHED-based regenerative therapy,
especially to interactive diseases. Here, among recent works on translational research, regulatory
science, and reverse translational research using SHED, we will provide our current research anddevelopment for diseases of digestive system, and will discuss regarding to the future direction.

3

Takayoshi YAMAZA, DDS, PhD.
Affiliation
Associate Professor
Department of Molecular Cell Biology and Oral Anatomy
Kyushu University Graduate School of Dental Science
3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Tel: +81-92-642-6305; Fax: +81-92-642-6304; E-mail: yamazata@dent.kyushu-u.ac.jp
Education
1994-1998

Ph.D.
Kyushu University Graduate School of Dentistry, Fukuoka, Japan

1988-1994

DDS
Faculty of Dentistry, Kyushu University, Fukuoka, Japan

Brief Chronology of Employment
2015-present

Associated Professor
Department of Molecular Cell Biology and Oral Anatomy
Kyushu University Graduate School of Dental Science

2012-2015

LectureDepartment of Molecular Cell Biology and Oral Anatomy
Kyushu University Graduate School of Dental Science

2006-2009

Postdoctoral Research Fellow
Center for Craniofacial Molecular Biology
University of Southern California School of Dentistry
Los Angels, CA, USA
PI: Dr. Songtao SHI, DDS, PhD

2005-2006

Postdoctoral Research Fellow
National Institute of Dental and Craniofacial Research,
National Institutes of Health, Bethesda, MD, USA
PI: Dr. Songtao SHI, DDS, PhD

2001-2012

Assistant Professor
Department of Oral Anatomy and Cell Biology
Kyushu University Graduate School of Dental Science

1998-2001

Assistant Professor
Department of Endodontlogy and Operative Dentistry
Kyushu University Graduate School of Dental Science4

【MEMO】

Session2

Mechanisms of Diabetes Impaired Wound Healing

Dana T. Graves, DDS, DMSc
Vice Dean for Scholarship and Research & Interim Chair of Periodontics
Department, University of Pennsylvania School of Dental Medicine

Abstract:
Diabetes mellitus has a significant and negative impact on wound healing. It is a major contributor
non-healing wounds that lead to limb amputation. Diabetic humans and animal models have impaired
wound healing that is characterized by high levels of inflammation. Many of the wound healing
deficits can be reversed by inhibiting inflammation. Diabetes-enhanced inflammation leads toactivation of the transcription factor FOXO1 during wound healing. To investigate how FOXO1 may
mediate the effect of diabetes on wound repair we examined mice with lineage specific deletionof FOXO1 in oral and dermal wounds. Deletion of Foxo1 in keratinocytes in normoglycemic wounds
impaired healing but had the opposite effect in diabetic wounds. In normoglycemic conditions FOXO1
up-regulated TGF β 1 but failed to bind to the TGF β 1 promoter or stimulate TGF β 1 expression
in high glucose. Instead, in high glucose FOXO1 enhanced expression of inflammatory mediators,
chemokine (C-C motif) ligand 20 (CCL20) and IL-36 γ . The enhanced inflammation associated withdiabetic wounds in vivo could be reversed by inhibiting FOXO1. Moreover, high levels of CCL20
and IL-36γ were detrimental to healing by interfering with cell migration in vivo and in vitro. Thus,
FOXO1 can positively modulate wound healing in normal conditions by inducing TGF β 1, but
in a high glucose environment fails to induce TGF β 1 and instead stimulates expression of proinflammatory mediators that interfere with the healing process.

5

CURRICULUM VITAE

Biography
Dana Graves completed his DDS training at Columbia University in 1980, and a certificate in
Periodontology and DMSc in Oral Biology from Harvard University in 1984. Prior to his arrival atPenn Dental Medicine he was Assistant Professor at the University of Texas Health Science Centerfrom 1985-87, and at Boston University Goldman School of Dental Medicine from 1987-90. He waspromoted to Associate Professor from 1990-93 and then to Professor in 1993. From 2008-2010, Dr.
Graves was Chair and Professor of Periodontics at University of Medicine and Dentistry of New
Jersey. He arrived at Penn Dental Medicine in 2010 and is currently the Interim Chair and Professorof Periodontics and serves as Vice Dean for Scholarship and Research. He is the Associate Editor for
the Journal of Dental Research and sees patients at the Penn Dental Faculty Practice. Dr. Graves’
research focuses on inflammation and diabetes.

6Adipose tissue inflammation may be a key player in systemic
expansion of periodontal inflammation
Fusanori Nishimura
Section of Periodontology, Department of Oral Rehabilitation, Kyushu University
Faculty of Dental Science

Periodontal treatment has been suggested to exhibit beneficial effects not only for local oral healthbut also for our overall general health, especially for the subjects with diabetes. In this context, wepreviously reported that periodontal treatment for the subjects with type 2 diabetes accompanied bysevere periodontal disease who exhibited elevated level of high sensitivity c-reactive protein (hs-CRP)
resulted in significant improvement in glycated hemoglobin level (Munenaga Y et al., Diab Res Clin
Pract, 2013). On the other hand, this beneficial effect was not observed in subjects whose initial hsCRP was not elevated even though the severity of periodontal disease was not different from high hsCRP subjects at clinical level. Therefore, we are interested to see the differences between high andlow hs-CRP groups and compared the differences of several parameters between them, and foundthat, although the difference itself was small, high hs-CRP group showed significantly higher bodymass index than the subjects with low hs-CRP group (Nishimura F, Current Oral Health reports, inpress, 2017). Since these subjects are all suffering from type 2 diabetes, it is very unlikely that highhs-CRP subjects are characterized by more advanced muscularity, suggesting that hs-CRP subjects
had slightly matured adipose tissue. These findings also suggest that adipose tissue inflammation play
crucial role in expanding periodontal inflammation to the systemic level. This would also suggest thatlife style intervention such as exercise and diet intervention is very important to lower the unwantedside effects of periodontal disease. It is well known that the effect of life style intervention is superior
to medication in preventing type 2 diabetes for the subjects with impaired glucose tolerance,
although, at the same time, complete achievement of life style intervention is quite difficult. Therefore,
to overcome this problem, use of many supplemental materials are suggested. We are interested insome flavonol intake as adjunct strategy to life style intervention. Here we report recent findings
indicating the beneficial effect of epicatechin, major component of cocoa flavonol, on the developmentof obesity and subsequent metabolic parameters (Sano T et al., Nutr Metab Cardiovasc Dis, in press,
2017). Based on our recent studies, we also suggest that appropriate life style intervention is anadditional requirement in addition to reducing other obvious risk factors such as smoking, in theoverall management of periodontal disease in subjects with diabetes.

7

CURRICULUM VITAE

Brief biography
Dr. Fusanori Nishimura graduated from Kyushu University Faculty of Dentistry and received DDS
degree in 1985. He moved to Okayama University Dental School where he primarily studied theinteraction between periodontal bacterial components and host immune responses. From 1991 to
1995, he studied at Columbia University School of Dental and Oral Surgery as post-doctoral research
fellow from 1991 to 1993, and as associate research scientist from 1994 to 1995. In the United States,
he studied biology and regeneration of periodontal ligament and discovered cell type specificchemoattractant against periodontal ligament cells.
Upon completion of his research in US, he moved again to Okayama University where he started
the study associated with periodontal medicine. During this period, from 2002 to 2004, he served
as an Editorial Board Member of the Journal of Dental research. He received Young InvestigatorAward from the Japan Society for Conservative Dentistry in 1999, and also received Lion Award
from the Japanese Society of Periodontology in 2005. His research was further expanded in Hiroshima
University where he served as Professor of the Department of Dental Science for Health Promotion
at Institute of Biomedical and Health Sciences from 2006 to 2012.
In 2013, he had back to his home University, Kyushu University as Professor of Department of
Periodontology, and currently still continues his research on periodontal medicine especially fromthe standpoint of understanding the cellular and molecular basis of periodontal micro-inflammation.
Currently, he is a vice dean for international affairs and acting as a group leader of the JSPS program
called “Program for advancing strategic international networks to accelerate the circulation oftalented researchers”.

8

【MEMO】

Session3

Epigenetic Regulation of Lymphocytes in Health andDiseaseShiv Pillai
Ragon Institute of MGH, MIT and Harvard
Harvard Medical School

In this talk I will discuss the potential role of the epigenetic regulation of lymphoid cells in thegeneration of specific lymphocyte populations and in the pathogenesis of chronic inflammation andspecific human malignancies. In particular the role of DNA methylation in B cell self-renewal andtransformation will be discussed in the context of B-1 B cell self renewal and the pathogenesis ofchronic lymphocytic leukemia. The use of chromatin accessibility assays on a genome wide basis toassess the "regulome" in conjunction with the transcriptome, to identify drivers of specific lymphocyte
populations that can contribute to disease will be described and discussed.

9

CURRICULUM VITAE

Biography
Shiv Pillai MD, PhD is a Professor of Medicine and Health Sciences and Technology at Harvard
Medical School. He is the Program Director of an NIH Funded Autoimmune Center of Excellence at
Massachusetts General Hospital, Director of the Harvard Immunology PhD program, Director of the
Masters in Medical Sciences in Immunology Program at Harvard Medical School, and Director of MD
Student Research at Harvard Medical School for the Harvard-MIT Division of Health Sciences andTechnology. He is a Member of the Ragon Institute of MGH, MIT and Harvard and a Member of the
MGH Cancer Center.
Dr. Pillai coined the term “surrogate light chains” for proteins that he identified (with David
Baltimore) as part of a novel receptor, now known as the pre-B receptor, which drives early B cell
development. His laboratory provided evidence for the first ligand-independent signaling model
during lymphocyte development, now a widely accepted mechanism for both pre-B receptor andpre-T receptor signaling. His laboratory also showed that Btk, the product of the gene mutated in
X-linked agammaglobulinemia, is functionally linked to the pre-B receptor and the B cell receptor.
This work contributed to the eventual development of Btk inhibitors now used widely in patientswith chronic lymphocytic leukemia and autoimmunity. His group developed the concept of a follicularversus marginal zone B lymphoid cell-fate decision and has made many contributions to the study of
B cell biology. More recently his laboratory has established that IgG4 related disease is causally linked
to the clonal expansion and tissue infiltration of CD4+cytotoxic T lymphocytes.
The laboratory currently pursues three main directions:
The immunological, genetic and epigenetic mechanisms underlying chronic inflammatory diseases inhumansThe group examines pathogenic mechanisms that are of importance in lupus, rheumatoid arthritis,
scleroderma, sarcoidosis, and IgG4-related disease. This work has led to the detailed study of thedevelopment of human CD4+ cytotoxic T lymphocytes and their function in the context of chronic
inflammation and the containment of viral infections. The role of 9-O-acetylation of sialic acid on B
cells and the relevance of this modification to autoimmune susceptibility is also being investigated.
The role of DNA methylation in the B lineage
An important current direction is the role of DNA methylation in the self-renewal of B-1 B cells, andthe relevance of DNA methylation to immunological memory, autoimmunity and chronic lymphocytic
leukemia.
The biology of B cell memory and T follicular helper cells and its relevance to future vaccination
approaches
B cell memory, T follicular helper cells and the germinal center response are being examined usinglarge scale CRISPR screens and on the basis of whole genome chromatin accessibility screens.
Applying this basic knowledge to vaccination is one of the goals of the laboratory.
Dr. Pillai received his medical degree from Christian Medical College in Vellore and trained with Dr.
Bimal Bachhawat for his PhD. He performed postdoctoral research with Dr. David Baltimore at theWhitehead Institute at MIT. He is the co-author of two widely used textbooks of immunology, and is
the course director of immunology courses at Harvard Medical School, Harvard College and for theFederation of Clinical Immunology Societies.
10Possible involvement of toll-like receptors in IgG4-related
dacryoadenitis and sialoadenitis
Masafumi Moriyama1, 2, Noriko Ishiguro1, Akihiko Tanaka1, Takashi
Maehara1, 3, Sachiko Furukawa1, Miho Ohta1, Masaki Yamauchi1,
Mizuki Sakamoto1, Jun-Nosuke Hayashida1, and Seiji Nakamura1.
1

Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic andSurgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan

2

OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan

3

Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

ABSTRACT
Objectives: IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) is a unique inflammatory disordercharacterized by the elevation of serum IgG4 and infiltration of IgG4-positive plasma cells in lacrimaland salivary glands (SGs). Since it is well known that IgG4 is induced by T helper type 2 (Th2)cytokines such as IL-4 and IL-13, IgG4-DS is speculated to be a Th2-dominant disease. In addition,
recent studies suggested that the activation of innate immunity also plays a key role in the IgG4
production upon stimulation with toll-like receptor (TLR) ligands. In this study, we thus examined theexpression of TLRs in SGs from patients with IgG4-DS.
Methods: Gene expression was analyzed by DNA microarray in submandibular glands (SMGs) frompatients with IgG4-DS (n=6), chronic sialoadenitis (CS) (n=3), and controls (n=3). TLR family (TLR110) was validated by real-time PCR and immunohistochemical staining in SGs from patient with
IgG4-DS (n=15), Sjögren’s syndrome (SS) (n=15), CS (n=9), and controls (n=9). Finally, we assessed
the phenotype (lymphocytic infiltration, fibrosis, and weight of the affected organs) of human TLR7
(huTLR7)-transgenic C57BL/6 mice, compared with that of wild-type mice.
Results: In IgG4-DS, 5 genes of TLR family (TLR4, TLR7-10) were overexpressed by DNA microarray
analysis. PCR validated significantly higher expression of TLR7 in IgG4-DS compared with that in
the other groups. Immunohistochemical analysis confirmed that the expression pattern of TLR7 wassimilar to that of the M2 macrophage marker CD163. Recent studies demonstrated that TLR7 agonist
stimulates macropages to produce IL-33, which is identified as a cytokine that activates Th2 immune
responses. Therefore, we focused on the relationship between TLR7 an IL-33 in IgG4-DS. The results
showed that the mRNA expression of TLR7 was positively correlated with that of IL-33 in only IgG4DS. In huTLR7-transgenic mice, the number of infiltrating lymphocytes and fibrosis score in the
SMGs and pancreas were significantly higher than those in wild-type mice.
Conclusions: Our current data suggest that TLR7-expressing M2 macrophages might promote thelocal inflammation in IgG4-DS.

11

CURRICULUM VITAE

Masafumi Moriyama, D.D.S. Ph.D.
Section of Oral and Maxillofacial Oncology
Division of Maxillofacial Diagnostic and Surgical Sciences
Faculty of Dental Science, Kyushu University
EDUCATION
1996-2003

D.D.S. Faculty of Dentistry, Kyushu University, Fukuoka, Japan

2003-2007

Ph.D.

Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic
and Surgical Sciences, Faculty of Dental Science, Kyushu University

PROFESSIONAL APPOINTMENTS
2007-2011

Clinical Fellow

Oral and Maxillofacial Surgery, Kyushu University Hospital

2012-2013

Assistant Professor

Oral and Maxillofacial Surgery, Kyushu University Hospital

2013-present Assistant Professor

Section of Oral and Maxillofacial Oncology, Division of
Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental
Science, Kyushu University

2015-present Principal Investigator OBT Research Center, Faculty of Dental Science, Kyushu
University
AWARDSMEDARTIS® Award in Japan Society of Oral and Maxillofacial Surgeons
nd

2006

2 prize (Oral presentation category) in European Association of Oral Medicine

2006

Academic Research Award in Kyushu University Student Support Association

2008

Young Researcher's Award in Japan Society of Oral and Maxillofacial Surgeons

2013

Young Researcher's Award in Japan Society for Sjögren’s syndrome

2013

Encouraging Prize in Fukuoka foundation for Sound Health

2013

12

Human BATF+ IL-4+ T follicular helper cells are linked to a polarized IgG4
switching event and accumulate primarily outside germinal
centers in IgG4-related disease lesions
Takashi Maehara and Shiv Pillai
Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital,
Harvard Medical School

Background/Statement of Purpose
Although the germinal center is considered to be a major site of isotype switching, it is unclear
whether class switching occurs primarily at the T-B interface outside germinal centers or within thelight zone of the germinal center. We show here that IL-4 expressing T follicular helper (TFH) cells
are sparse in human secondary lymphoid organs and are primarily located outside germinal centers.
In IgG4-related disease (IgG4-RD), a disorder characterized by polarized Ig class switching andprominent tertiary lymphoid organs, most TFH cells in disease lesions make IL-4.
Methods & materials
We used quantitative multicolor immuno-fluorescence to identify IL-4 secreting TFH cells in secondary
lymphoid organs from healthy individuals and affected tissues from IgG4-RD and Sjögren's syndrome(SS) with active disease.
Results
The relative proportion of IL-4 expressing TFH cells is 10-20 fold higher in disease lesions compared
to control secondary lymphoid organs. These IL-4 expressing TFH cells are found in tertiary lymphoidorgans but are primarily located outside germinal centers and large numbers of IgG4 expressing B
cells are also seen in their vicinity. Human IL-4+ TFH cells do not express GATA-3 but express BATF.
In contrast to the situation in IgG4-RD, IL-4+ TFH cells are rarely found in or around germinal centersin SS, a disorder in which IgG4 is not elevated. The proportion of CD4+IL-4+BATF+ T cells as well
as of CD4+IL-4+CXCR5+ T cells in IgG4-RD tissues correlates tightly with tissue IgG4 plasma cellnumbers and plasma IgG4 levels in patients but not with the total plasma levels of other isotypes.
Conclusions
These data describe a TFH sub-population in human tertiary lymphoid organs with IgG4-RD thatis linked to a very specific Ig isotype switching event in vivo and support the view that isotype
switching occurs primarily outside germinal centers.

13

CURRICULUM VITAE

Biography
Dr. Maehara is an oral surgeon and researchers primarily focusing on understanding the pathophysiology of oral immune disorder-related diseases and development of new therapeutic strategy
against IgG4-related diseases. Currently, he is continuing his research as postdoctoral fellow for
research abroad at Ragon Institute of MGH, MIT, and Harvard sponsored by JSPS, after his
successful achievement at the same institute as a delegate sponsored by the “Program for advancing
strategic international networks to accelerate the circulation of talented researchers” for one year alsosponsored by JSPS.

14【MEMO】

15

Reports after circulationEffects of Decitabine on Osteoclastogenesis and Periodontal Bone loss in MiceUrara Tanaka1, Manju Benakanakere2, Denis Kinane2 and Fusanori Nishimura1

1

Department of Periodontics, Kyushu University Hospital, Japan2

Department of Periodontics and Pathology, School of Dental Medicine, University of Pennsylvania,
Philadelphia PA 19004

Objectives: Periodontitis is a common chronic inflammatory disease which is initiated by a complex
microbial biofilm. We have previously shown that DNA methylation is involved in periodontal
inflammation that may contribute to periodontal disease susceptibility. We sought to determine
whether DNA methyl transferase inhibitor namely, Decitabine (5-aza-2’-deoxycytidine) can protect
experimentally induced bone loss in mice.
Methods: We used a ligature induced periodontitis mouse model to determine the effects of Decitabine
in C57BL/6J mice. Decitabine (1 mg/kg) or vehicle was applied for 5 days. Mice were sacrificed andthe gingiva was excised for real-time PCR. Bone loss measurement was done by defleshing, bleaching
the maxilla and subjecting it to manual measurement as well as microtomography. Images were
captured and the distance between the cementoenamel junction (CEJ) - alveolar bone crest (ABC) was
measured using a Nikon Digital Sight DS-U3 system. Paraffin sections of maxilla were used for TRAP
staining and immunofluorescence. CD14+ monocytes were used to examine the effects of Decitabinefor osteoclastogenesis in vitro. Luciferase reporter assays were performed to unravel transcriptional
activation.
Results: We observed severe bone loss in the ligature induced periodontitis model and Decitabinesignificantly inhibited the bone loss. We found that the treatment with Decitabine significantly
reduced osteoclasts both in vivo and in vitro and up-regulated the anti-inflammatory cytokines (IL10 and TGF- β ) in vitro. Furthermore Single-cell analysis of CD14+ monocytes showed that there
is a possibility that Decitabine regulates some genes involved in inflammation. Bioinformatic analysis
revealed that Krüppel-like Factor 2 (KLF2) is highly guanine-cytocine rich, and possess a long
CpG island spanning the entire gene. As expected, Decitabine increased KLF2 mRNA expression.
Luciferase reporter assay showed KLF2 up-regulated the transcriptional activity of CCAAT/enhancer
binding protein beta (CEBPB) and the anti-inflammatory cytokines IL-10 and TBF- β .
Conclusions: Decitabine inhibits alveolar bone loss by limiting osteoclastogenesis in mice and shows
KLF2 can regulate that. Taken together, Decitabine may have utility in treating chronic inflammatory
periodontal disease in humans.
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Generation of Salivary Gland-like Organoids from Human Dental Follicle
Epithelial Stem Cells
Akihiro Furuhashi, DDS, PhD

Section of Implant and Rehabilitative Dentistry, Division of Oral Rehabilitation, Faculty of Dental
Science, Kyushu University, Fukuoka, JapanThe dental follicle (DF) is a dental tissue composed of a condensation of ectomesenchymal cells thatsurrounds the tooth germ in early stages of tooth formation. In the present study, we aim to isolate
epithelial stem cells from human DF tissues and explore their potential application in stem cell-based
therapy for hyposalivation syndrome (xerostomia). We demonstrated the expression of stem cellrelated proteins in the epithelial components of human DF tissues and epithelial cells can be steadilyisolated and ex vivo expanded from human DF tissues. These DF-derived epithelial cells possessclonogenic and sphere-forming capabilities and express epithelial stem cell-related markers, thus
conferring stem cell properties (hDF-EpiSCs). When culturing under special 3D induction conditions,these hDF-EpiSCs can differentiate into salivary gland (SG) acinar and duct cells and generate SG-like3D organoids. Transplantation of hDF-EpiSCs-loaded native decellularized rat parotid gland scaffolds
into renal capsule of nude mice led to the creation of SG-like tissues in vivo. These findings suggestthat hDF-EpiSCs might be a potential source of epithelial stem cells for the development of stem cellbased therapy or bioengineering SG tissues to repair/regenerate SG dysfunction.

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The function of insulin and insulinotropic peptides in taste tissue
Shingo Takaia, Yuzo Ninomiyab, c, Noriatsu Shigemuraa, b, Robert F. MargolskeecaSection of Oral Neuroscience, Graduate School of Dental Sciences, Kyushu UniversitybDivision of Sensory Physiology, Research and Development Center for Taste and Odor Sensing,
Kyushu UniversitycMonell Chemical Senses Center

Recent studies revealed that the hormones and their receptors originally identified in the gut are
shown to be expressed in peripheral taste tissue, but their functions are still largely unclear. Our
previous study reported that an inslinotropic hormone called glucagon like peptide-1 (GLP-1) may
function as a sweet-specific taste transmitter in mouse peripheral taste system. We next looked atother insulinotropic peptide called glucose-dependent insulinotropic polypeptide (GIP) and its receptor(GIPR), insulin and insulin receptor (IR) in mouse taste tissue and newly developed 3-dimentional
cell culture ‘taste organoid’. In immunohistochemical experiments, GIPR was mainly coexpressedwith T1R3 (a component of sweet taste receptor), not with GAD67 (a sour taste cell marker), in bothanterior and posterior part of tongue and the taste organoids. IR was also expressed in a subset of
taste cells. Furthermore, when insulin was added to the culture medium, the taste organoids grewfaster and larger, and they contained more taste cells compared to them in the medium without
insulin. These results suggest that these two hormones may be involved in taste sensation and/or
taste cell proliferation.

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