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Regeneration of dentin-pulp complex from iPS cells using new odontoblasts differentiation mechanism and polarity regulation

Research Project

Project/Area Number 18H02984
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 57040:Regenerative dentistry and dental engineering-related
Research InstitutionIwate Medical University

Principal Investigator

Harada Hidemitsu  岩手医科大学, 歯学部, 教授 (70271210)

Co-Investigator(Kenkyū-buntansha) 大津 圭史  岩手医科大学, 歯学部, 准教授 (60509066)
横山 拓矢  岩手医科大学, 医学部, 講師 (70772094)
Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000)
Fiscal Year 2021: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2018: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000)
KeywordsiPS細胞 / 再生 / 象牙芽細胞 / 象牙質歯髄複合体 / iPS / 歯髄再生 / Semaphorin4D / Copine-7 / 象牙質再生 / ヒトiPS細胞 / 極性制御 / CPNE7 / iPSC / Semaphorin / 象牙芽細胞分化 / 歯の再生 / 3Dオルガノイド / 神経堤細胞 / 象牙質歯髄複合体再生 / 細胞極性制御
Outline of Final Research Achievements

The aim of this study was to develop a technology to induce dentin-pulp complex formation from human iPS cells (hiPS) by using human Copine-7 (hCPNE7) and Semaphorin4D, which regulates cell polarity. MSCs) induced from hiPS and miPS cells were differentiated into odontoblasts when exposed to hCPNE7 or hCPNE7-expressing HAT7 (rat enamel blast cell line) culture supernatant. Furthermore, the basement membrane component secreted by the newly established Hertwig epithelial sheath cell line (HERS02T) also showed high induction of odontblast differentiation and polarity toward mouse incisor papillary mesenchymal stem cells, and similar results were obtained for NCLCs. The combined 3D culture of epithelial cell organoids and NCLC organoids showed enhanced differentiation induction and calcification formation.

Academic Significance and Societal Importance of the Research Achievements

歯髄は疎性結合組織でできており,歯の感覚や防御機構を担っている。この歯髄に感染が及んだ場合は抜髄(歯髄除去)が必要となるが,除去された歯髄腔内は人工的材料で充填するのみである。そのため象牙質の知覚や修復能は失われ,歯自体も脆弱になる。歯髄の再生に関する研究は,不用となった歯の間葉系幹細胞を用いた再生が臨床トライアルまで来たが,具体的な実績にはなっていない。本研究の成果によってiPS細胞を利用することで生体から細胞を採取するリスクもなくなり,より現実味が帯びてきたと言える。iPS細胞を使った再生医療は他の器官を含めて本質的課題が多く残るが,将来的な医療としての基礎データを提示できた。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (40 results)

All 2021 2020 2019 2018 Other

All Int'l Joint Research (4 results) Journal Article (13 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 12 results,  Open Access: 5 results) Presentation (19 results) (of which Int'l Joint Research: 7 results,  Invited: 8 results) Book (1 results) Remarks (2 results) Funded Workshop (1 results)

  • [Int'l Joint Research] Seoul National Univ(韓国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Yonsei University/Seoul National University(韓国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] Yonsei Univ./Seoul National Univ.(韓国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Yonsei Univ./Seoul National University(韓国)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Local application of Usag-1 siRNA can promote tooth regeneration in Runx2-deficient mice2021

    • Author(s)
      Mishima Sayaka、Takahashi Katsu、Kiso Honoka、Murashima-Suginami Akiko、Tokita Yoshihito、Jo Jun-Ichiro、Uozumi Ryuji、Nambu Yukiko、Huang Boyen、Harada Hidemitsu、Komori Toshihisa、Sugai Manabu、Tabata Yasuhiko、Bessho Kazuhisa
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 13674-13674

    • DOI

      10.1038/s41598-021-93256-y

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Oxygen regulates epithelial stem cell proliferation via RhoA-actomyosin-YAP/TAZ signal in mouse incisor2021

    • Author(s)
      Otsu Keishi、Ida-Yonemochi Hiroko、Ikezaki Shojiro、Ema Masatsugu、Hitomi Jiro、Ohshima Hayato、Harada Hidemitsu
    • Journal Title

      Development

      Volume: 148 Issue: 4

    • DOI

      10.1242/dev.194787

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cell dynamics in Hertwig's epithelial root sheath are regulated by β‐catenin activity during tooth root development2021

    • Author(s)
      Yang Siqin、Choi Hwajung、Kim Tak‐Heun、Jeong Ju‐Kyung、Liu Yudong、Harada Hidemitsu、Cho Eui‐Sic
    • Journal Title

      Journal of Cellular Physiology

      Volume: 236 Issue: 7 Pages: 5387-5398

    • DOI

      10.1002/jcp.30243

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Activation of Wnt signalling reduces the population of cancer stem cells in ameloblastoma2021

    • Author(s)
      Kim Hyun‐Yi、Li Shujin、Lee Dong‐Joon、Park Jin Hoo、Muramatsu Takashi、Harada Hidemitsu、Jung Young‐Soo、Jung Han‐Sung
    • Journal Title

      Cell Proliferation

      Volume: 54 Issue: 7

    • DOI

      10.1111/cpr.13073

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A novel cyclic peptide (Naturido) modulates glia?neuron interactions in vitro and reverses ageing-related deficits in senescence-accelerated mice2021

    • Author(s)
      Ishiguro Shinichi、Shinada Tetsuro、Wu Zhou、Karimazawa Mayumi、Uchidate Michimasa、Nishimura Eiji、Yasuno Yoko、Ebata Makiko、Sillapakong Piyamas、Ishiguro Hiromi、Ebata Nobuyoshi、Ni Junjun、Jiang Muzhou、Goryo Masanobu、Otsu Keishi、Harada Hidemitsu、Suzuki Koichi
    • Journal Title

      PLOS ONE

      Volume: 16 Issue: 1 Pages: 0245235-0245235

    • DOI

      10.1371/journal.pone.0245235

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mast4 knockout shows the regulation of spermatogonial stem cell self-renewal via the FGF2/ERM pathway2020

    • Author(s)
      Lee Seung-Jun、Park Jinah、Lee Dong-Joon、Otsu Keishi、Kim Pyunggang、Mizuno Seiya、Lee Min-Jung、Kim Hyun-Yi、Harada Hidemitsu、Takahashi Satoru、Kim Seong-Jin、Jung Han-Sung
    • Journal Title

      Cell Death & Differentiation

      Volume: 20 Issue: 5 Pages: 1441-1454

    • DOI

      10.1038/s41418-020-00670-2

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Functional Expression of Sodium-Dependent Glucose Transporter in Amelogenesis.2020

    • Author(s)
      Ida-Yonemochi H, Otsu K, Harada H, Ohshima H.
    • Journal Title

      Journal of Dental Research

      Volume: - Issue: 8 Pages: 1-10

    • DOI

      10.1177/0022034520916130

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Vesicular nucleotide transporter‐immunoreactive type I cells associated with P2X3‐immunoreactive nerve endings in the rat carotid body2019

    • Author(s)
      Yokoyama Takuya、Yamamoto Yoshio、Hirakawa Masato、Kato Kouki、Saino Tomoyuki
    • Journal Title

      Journal of Comparative Neurology

      Volume: 528 Issue: 9 Pages: 1486-1501

    • DOI

      10.1002/cne.24837

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effective Differentiation of Induced Pluripotent Stem Cells Into Dental Cells.2019

    • Author(s)
      Kim EJ, Yoon KS, Arakaki M, Otsu K, Fukumoto S, Harada H, Green DW, Lee JM, Jung HS.
    • Journal Title

      Dev Dyn

      Volume: Jan;248(1) Issue: 1 Pages: 129-139

    • DOI

      10.1002/dvdy.24663

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] 歯の発生,萌出,乳歯歯根吸収および関連するトピックス2019

    • Author(s)
      原田英光、大津 圭史
    • Journal Title

      小児歯科臨床

      Volume: 24 Pages: 14-19

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Microdissection and Isolation of Mouse Dental Epithelial Cells of Continuously Growing Mouse Incisors.2019

    • Author(s)
      Harada H, Otsu K.
    • Journal Title

      Methods Mol Biol.

      Volume: 1922 Pages: 3-11

    • DOI

      10.1007/978-1-4939-9012-2_1

    • ISBN
      9781493990115, 9781493990122
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Craniofacial Bone Regeneration using iPS Cell-Derived Neural Crest Like Cells2018

    • Author(s)
      Kikuchi K, Masuda T, Fujiwara N, Kuji A, Miura H, Jung H-S, Harada H, Otsu K.
    • Journal Title

      Journal of Hard Tissue Biology

      Volume: 27 Issue: 1 Pages: 1-10

    • DOI

      10.2485/jhtb.27.1

    • NAID

      130006301954

    • ISSN
      1341-7649, 1880-828X
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Loss of Stemness, EMT, and Supernumerary Tooth Formation in Cebpb-/-Runx2+/- Murine Incisors.2018

    • Author(s)
      Saito K, Takahashi K, Huang B, Asahara M, Kiso H, Togo Y, Tsukamoto H, Mishima S, Nagata M, Iida M, Tokita Y, Asai M, Shimizu A, Komori T, Harada H, MacDougall M, Sugai M, Bessho K.
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 5169-5169

    • DOI

      10.1038/s41598-018-23515-y

    • NAID

      120006545187

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] エナメル上皮細胞が担うエナメル質形成と多様な役割2021

    • Author(s)
      原田英光
    • Organizer
      福岡歯科大学学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Regulatory mechanism of dental epithelial stem cells by microenvironmental oxygen-RhoA-YAP/TAZ signal in mouse incisor2021

    • Author(s)
      Keishi Otsu, Hiroko Ida-Yonemochi, Shojiro Ikezaki, Hayato Ohshima, Hidemitsu Harada
    • Organizer
      ISSCR
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] エナメル質形成におけるカルシウムトランスポーター局在制御メカニズ2021

    • Author(s)
      大津圭史, 稲葉 陽, 池崎晶二郎, 森川和政, 原田英光
    • Organizer
      日本解剖学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] マウス付着上皮細胞培養法と細胞株樹立2021

    • Author(s)
      池崎昌二郎, 熊上-坂野深香 大津圭史, 原田英光
    • Organizer
      岩手歯学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 成熟期エナメル芽細胞のプロトンポンプの新規機能2020

    • Author(s)
      大津圭史, 池崎晶二郎, 原田英光
    • Organizer
      第62回歯科基礎医学会学術大会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Oxygen regulates dental epithelial stem cell proliferation via RhoA-actomyosin-YAP/TAZ signal2020

    • Author(s)
      Keishi Otsu, Hiroko Ida-Yonemochi, Shojiro Ikezaki, Hayato Ohshima, Hidemitsu Harada
    • Organizer
      2020 ISSCR
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] エナメル芽細胞におけるLPAシグナルの機能的役割2020

    • Author(s)
      稲葉陽, 池崎昌二郎, 原田英光, 大津圭史
    • Organizer
      第125回日本解剖学会総会・全国学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] エナメル芽細胞におけるプロトンポンプはナノモーターとして分泌小胞の輸送を担っているか?2020

    • Author(s)
      原田英光、池崎晶二郎、後藤(松元)奈緒美,中西(松井)真弓,和田洋、孫(和田)戈虹、大津圭史
    • Organizer
      第15回ナノバイオメディカル学会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Role of vacuolar proton-pumps (V-ATPase) at maturation stage of amalogenesis2019

    • Author(s)
      Shojiro Ikezaki, Keishi Ots, Naomi Matsumoto, Mayumi Nakanishi-Matsui, Hidemitsu Harada
    • Organizer
      The 2019 TMD (Tooth Morphogenesis & Differentiation) meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] THE HYPOXIC MICROENVIRONMENT MAINTAIN DENTAL EPITHELIAL STEM CELLS VIA RHOA-YAP/TAZ SIGNAL.2019

    • Author(s)
      Keishi Otsu, Shojiro Ikezaki, Hayato Ohshima, Hidemitsu Harada
    • Organizer
      2019 ISSCR/KSSCR International Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Craniofacial Bone Regeneration using iPS Cell-Derived Neural Crest Like Cells2019

    • Author(s)
      Kazuko Kikuchi, Tomoyuki Masuda, Naoki Fujiwara, Akiyoshi Kuji, Hiroyuki Miura, Han-Sung Jung, Hidemitsu Harada, Keishi Otsu
    • Organizer
      第28回硬組織再生生物学会 学術大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Nobel role of vacuolar type proton-pump (V-ATPase) at maturation stage of amelogenesis2019

    • Author(s)
      Hidemitsu Harada, Shojiro Ikezaki Keishi Otsu, Naomi Matsumoto, Ge-Hong Sun-Wada, Yoh Wada, Mayumi Nakanishi-Matsui
    • Organizer
      The 7th Tripartite Conference on Tooth and Bone in Development & Regeneration
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dental epithelial stem cells are maintained under condition of low oxygen level.2019

    • Author(s)
      Keishi Otsu, Shojiro Ikezaki, Hayato Ohshima, Hidemitsu Harada
    • Organizer
      The 2019 TMD (Tooth Morphogenesis & Differentiation) meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] エナメル上皮幹細胞運命決定機構における低酸素―細胞内シグナル連間2019

    • Author(s)
      大津 圭史, 池崎 昌二郎, 大島勇人, 原田 英光
    • Organizer
      第60回歯科基礎医学会学術大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] iPS細胞を用いた象牙質・歯髄再生へのアプローチ2019

    • Author(s)
      原田英光
    • Organizer
      日本歯科保存学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 成熟期エナメル芽細胞におけるLPAシグナルの役割2018

    • Author(s)
      Keishi Otsu, Mika Kumakami-Sakano, Akira Inaba, Hidemitsu Harada
    • Organizer
      第60回歯科基礎医学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] LPA6-RhoA signal contributes to ameloblasts differentiation by regulating cell polarity2018

    • Author(s)
      Keishi Otsu, Yoshinori Sahara, Naoyuki Nishiya, Hidemitsu Harada
    • Organizer
      The 6th Tripartite Conference on Tooth and Bone in Development & Regeneration
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Oxygen levels regulate cell fate of mouse dental epithelial stem cells via RhoA signaling2018

    • Author(s)
      Keishi Otsu, Hidemitsu Harada
    • Organizer
      International society for stem cell research (ISSCR) 2018 annual meeting
    • Related Report
      2018 Annual Research Report
  • [Presentation] 組織内酸素濃度応答性RhoA-Sox2シグナルによるエナメル上皮幹細胞制御2018

    • Author(s)
      大津圭史、依田浩子、藤原尚樹、大島勇人、原田英光
    • Organizer
      第123回日本解剖学会総会・全国学術集会
    • Related Report
      2018 Annual Research Report
  • [Book] Methods Mol Biol.2019

    • Author(s)
      Harada H, Otsu K.
    • Total Pages
      565
    • Publisher
      Humana Press
    • ISBN
      9781493990115
    • Related Report
      2019 Annual Research Report
  • [Remarks] 岩手医科大学解剖学講座発生生物再生医学分野

    • URL

      http://oralhist.iwate-med.ac.jp/link.html

    • Related Report
      2019 Annual Research Report
  • [Remarks] 岩手医科大学解剖学講座発生生物再生医学分野ホームページ

    • URL

      http://oralhist.iwate-med.ac.jp/works.html

    • Related Report
      2018 Annual Research Report
  • [Funded Workshop] Japan-Korea joint seminar & Frontier meeting2020

    • Related Report
      2020 Annual Research Report

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Published: 2018-04-23   Modified: 2023-01-30  

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