Development of bone regeneration methods based on understanding of tissue remodeling

• Project/Area Number: 21K19883
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 90:Biomedical engineering and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Tei Yuichi 東京大学, 大学院工学系研究科(工学部), 教授 (30345053)
• Co-Investigator(Kenkyū-buntansha): 岡田 寛之 東京大学, 大学院医学系研究科(医学部), 助教 (10883481) ; 大庭 伸介 大阪大学, 大学院歯学研究科, 教授 (20466733) ; 酒井 崇匡 東京大学, 大学院工学系研究科(工学部), 教授 (70456151) ; 北條 宏徳 東京大学, 大学院医学系研究科(医学部), 准教授 (80788422)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2022: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 組織リモデリング / バイオマテリアル / 骨再生 / 線維化 / 一細胞解析 / 骨欠損

Outline of Research at the Start

組織修復の理解には、組織リモデリングと呼ばれる、組織損傷部位における炎症・免疫反応の制御と、体制幹細胞の増殖・分化を介する組織再生の制御の両方が必要です。本研究では、この両制御機構を包括的に理解し、適切なバイオマテリアルと統合することで、組織リモデリングの制御に基づく新しい骨再生戦略の確立を目指します。

Outline of Final Research Achievements

In this study, by focusing on skeletal progenitors, we performed the lineage tracing analysis and single cell RNA-seq (scRNA-seq) analysis to understand behavior of the progenitors and the mechanism of cell fate determination to osteoblasts at bone repair sites. As a result, we confirmed that Gli1-positive cells were activated at bone repair sites and contributed to bone repair and fibrosis. scRNA-seq analysis provided candidate signaling factors involved in the fate determination to osteoblasts. We also developed a new hydrogel with drug-loading ability and demonstrated its contribution to bone regeneration in cell experiments and animal models.

Academic Significance and Societal Importance of the Research Achievements

本研究により、骨の修復過程におけるGli1陽性の骨格系前駆細胞の振る舞いと、骨修復・線維化における制御機構の一端が明らかになった。一細胞解析により、骨再生への関与が推定される候補因子群が見つかった。さらに、新規ハイドロゲルの開発を通して、成長因子を保持・遊離可能な機構を有する足場材料の開発に成功した。今後、これらの因子・材料を組み合わせることで、安全で効率的な骨再生医療の実現に寄与することが期待される。

Research Products

• [Int'l Joint Research] マサチューセッツ総合病院/米国衛生研究所(米国)
• [Journal Article] Single-cell RNA sequencing unravels heterogeneity of skeletal progenitors and cell-cell interactions underlying the bone repair process (2022)
  • Author(s): Nakayama Mika、Okada Hiroyuki、Seki Masahide、Suzuki Yutaka、Chung Ung-il、Ohba Shinsuke、Hojo Hironori
  • Journal Title: Regenerative Therapy Volume: 21 Pages: 9-18
  • DOI: 10.1016/j.reth.2022.05.001
  • Peer Reviewed / Open Access
• [Journal Article] Orally administrable peptides derived from egg yolk promote skeletal repair and ameliorate degenerative skeletal disorders in mouse models (2022)
  • Author(s): Kitaura Yoshiaki、Nakamura Utano、Awada Chihiro、Yamaguchi Motonori、Kim Mujo、Ikeda Yuki、Matsuo Yuki、Moriishi Takeshi、Sawase Takashi、Chung Ung-il、Hojo Hironori、Ohba Shinsuke
  • Journal Title: Regenerative Therapy Volume: 21 Pages: 584-595
  • DOI: 10.1016/j.reth.2022.11.002
  • Peer Reviewed / Open Access
• [Journal Article] Runx2 regulates chromatin accessibility to direct the osteoblast program at neonatal stages (2022)
  • Author(s): Hojo Hironori, Saito Taku, He Xinjun, Guo Qiuyu, Onodera Shoko, Azuma Toshifumi, Koebis Michinori, Nakao Kazuki, Aiba Atsu, Seki Masahide, Suzuki Yutaka, Okada Hiroyuki, Tanaka Sakae, Chung Ung-il, McMahon Andrew P., Ohba Shinsuke
  • Journal Title: Cell Reports Volume: 40 Issue: 10 Pages: 111315-111315
  • DOI: 10.1016/j.celrep.2022.111315
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Runx2 and Runx3 differentially regulate articular chondrocytes during surgically induced osteoarthritis development (2022)
  • Author(s): Nagata K, Hojo H, Chang SH, Okada H, Chijimatsu R, Omata Y, Mori D, Makii Y, Kawata M, Kaneko T, Iwanaga Y, Nakamoto H, Maenohara Y, Tachibana N, Ishikura H, Higuchi J, Taniguchi Y, Ohba S, Chung Ul, Tanaka S, Saito T
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 6187-6204
  • DOI: 10.1038/s41467-022-33744-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Simple Preparation of Injectable Hydrogels with Phase-Separated Structures That Can Encapsulate Live Cells (2022)
  • Author(s): Ishikawa Shohei、Yoshikawa Yuki、Kamata Hiroyuki、Chung Ung-il、Sakai Takamasa
  • Journal Title: ACS Applied Materials & Interfaces Volume: 14 Issue: 31 Pages: 35444-35453
  • DOI: 10.1021/acsami.2c09906
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of activator protein-1 family members in β-catenin and p300 association on the genome of PANC-1 cells (2022)
  • Author(s): Doi Tomomitsu、Hojo Hironori、Ohba Shinsuke、Obayashi Kunie、Endo Motoyoshi、Ishizaki Toshimasa、Katoh Akira、Kouji Hiroyuki
  • Journal Title: Heliyon Volume: 8 Issue: 2 Pages: e08890-e08890
  • DOI: 10.1016/j.heliyon.2022.e08890
  • Peer Reviewed / Open Access
• [Journal Article] A neomorphic variant in SP7 alters sequence specificity and causes a high-turnover bone disorder (2022)
  • Author(s): Lui Julian C.、Raimann Adalbert、Hojo Hironori、Dong Lijin、Roschger Paul、Kikani Bijal、Wintergerst Uwe、Fratzl-Zelman Nadja、Jee Youn Hee、Haeusler Gabriele、Baron Jeffrey
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 700-700
  • DOI: 10.1038/s41467-022-28318-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Star-Polymer-DNA Gels Showing Highly Predictable and Tunable Mechanical Responses (2022)
  • Author(s): Ohira Masashi、Katashima Takuya、Naito Mitsuru、Aoki Daisuke、Yoshikawa Yusuke、Iwase Hiroki、Takata Shin‐ichi、Miyata Kanjiro、Chung Ung‐il、Sakai Takamasa、Shibayama Mitsuhiro、Li Xiang
  • Journal Title: Advanced Materials Volume: 34 Issue: 13 Pages: 2108818-2108818
  • DOI: 10.1002/adma.202108818
  • Peer Reviewed
• [Journal Article] Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin (2021)
  • Author(s): Wang JS, Kamath T, Mazur CM, Mirzamohammadi F, Rotter D, Hojo H, Castro CD, Tokavanich N, Patel R, Govea N, Enishi T, Wu Y, da Silva Martins J, Bruce M, Brooks DJ, Bouxsein ML, Tokarz D, Lin CP, Abdul A, Macosko EZ, Fiscaletti M, Munns CF, Ryder P, Kost-Alimova M, Byrne P, Cimini B, Fujiwara M, Kronenberg HM, Wein MN.
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 6271-6271
  • DOI: 10.1038/s41467-021-26571-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Induction and expansion of human PRRX1+ limb-bud-like mesenchymal cells from pluripotent stem cells (2021)
  • Author(s): Yamada Daisuke、Nakamura Masahiro、Takao Tomoka、Takihira Shota、Yoshida Aki、Kawai Shunsuke、Miura Akihiro、Ming Lu、Yoshitomi Hiroyuki、Gozu Mai、Okamoto Kumi、Hojo Hironori、Kusaka Naoyuki、Iwai Ryosuke、Nakata Eiji、Ozaki Toshifumi、Toguchida Junya、Takarada Takeshi
  • Journal Title: Nature Biomedical Engineering Volume: 5 Issue: 8 Pages: 926-940
  • DOI: 10.1038/s41551-021-00778-x
  • Peer Reviewed
• [Journal Article] Mesenchymal stromal cells in the bone marrow niche consist of multi-populations with distinct transcriptional and epigenetic properties (2021)
  • Author(s): Kanazawa Sanshiro、Okada Hiroyuki、Hojo Hironori、Ohba Shinsuke、Iwata Junichi、Komura Makoto、Hikita Atsuhiko、Hoshi Kazuto
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 15811-15811
  • DOI: 10.1038/s41598-021-94186-5
  • Peer Reviewed / Open Access
• [Presentation] Elucidating Gene Regulatory Networks Underlying Human Skeletal Development by Integrating a Model of Human Endochondral Bones and Single-cell Multiomics (2022)
  • Author(s): Shoichiro Tani, Hiroyuki Okada, Masahide Seki, Yutaka Suzuki, Taku Saito, Sakae Tanaka, Ung-il Chung, Hironori Hojo and Shinsuke Ohba
  • Organizer: ASBMR 2022
  • Int'l Joint Research
• [Presentation] "Gene regulatory networks underlying human endochondral bone formation " (2022)
  • Author(s): Shoichiro Tani, Hiroyuki Okada, Taku Saito, Sakae Tanaka, Ung-il Chung, Hironori Hojo and Shinsuke Ohba
  • Organizer: ICORS 2022
  • Int'l Joint Research
• [Presentation] EXPLORING HUMAN SKELETAL DEVELOPMENT USING AN INDUCED HUMAN BONE TISSUE DERIVED FROM HUMAN PLURIPOTENT STEM CELLS (2021)
  • Author(s): Shoichiro Tani, Hiroyuki Okada, Masahide Seki, Yutaka Suzuki, Ung-il Chung, Hironori Hojo and Shinsuke Ohba
  • Organizer: ISSCR 2021
  • Int'l Joint Research
• [Presentation] Understanding a Mechanism Underlying Bone Repair Process by Combinational Analysis of Lineage Tracing and Single-Cell RNA Sequencing (2021)
  • Author(s): Mika Nakayama, Hiroyuki Okada, Masahide Seki, Yutaka Suzuki, Ung-il Chung, Shinsuke Ohba, Hironori Hojo
  • Organizer: ISSCR 2021
  • Int'l Joint Research
• [Presentation] Understanding a mechanism underlying bone repair process and application for bone regeneration (2021)
  • Author(s): Hironori Hojo
  • Organizer: SICEM 2021
  • Int'l Joint Research / Invited