Regenerative therapeutics of bone diseases by means of in situ direct reprogramming

• Project/Area Number: 21K19577
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Mazda Osam 京都府立医科大学, 医学(系)研究科(研究院), 教授 (00271164)
• Co-Investigator(Kenkyū-buntansha): 山本 健太 京都府立医科大学, 医学(系)研究科(研究院), 助教 (00636160) ; 新井 祐志 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (50347449)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2022: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2021: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 再生医療 / 骨疾患 / ダイレクト・リプログラミンング / ダイレクト・リプログラミング

Outline of Research at the Start

骨粗鬆症や関節リウマチなどの骨吸収性疾患は、運動機能を著しく低下させて、健康寿命を短縮する疾患である。骨芽細胞は、骨形成を担い、骨組織再生に寄与する細胞である。そのため機能的な骨芽細胞を骨欠損部位に供給することが出来れば、失われた骨組織の再生を促進し、種々の骨吸収性疾患に対する効果的な治療法となり得る。そこで本研究では、骨吸収が起きている場で機能的な骨芽細胞を誘導しえる方法として、in situ ダイレクト・リプログラミングによる骨芽細胞の誘導を確立する。

Outline of Final Research Achievements

Bone regenerative therapy may be useful for treatment of patients with bone resorptive diseases including osteoporosis, rheumatoid arthritis, and osteoarthritis. We previously succeeded in directly converting human fibroblasts into functional osteoblasts that may be applicable to novel bone regenerative therapy in the future. To realize effective bone regenerative therapy using the direct conversion (DC) technologies, however, it is also needed to develop a suitable scaffold that can support formation of cultured 3D bone tissue in combination with reprogrammed osteoblasts, as well as a novel technology to induce DC at a bone resorptive lesion.
In this study, we have developed a novel transplantable scaffold that enable directly converted osteoblasts to form 3D bone tissue in culture, while we also tried to obtain data for basic technology that are needed to directly induce osteoblasts from other somatic cells at a bone resorptive tissue.

Academic Significance and Societal Importance of the Research Achievements

骨粗しょう症、関節リウマチ、変形性膝関節症などの骨吸収性疾患は、罹患者数が極めて多く、運動機能を著しく低下させて、健康寿命を短縮する疾患である。高齢化と相まって、医療資源の消費の観点からも大きな問題であり、有効な骨再生治療が求められている。機能的な骨芽細胞を骨欠損部位に直接供給することが出来れば、失われた骨組織の再生を促進し、種々の骨吸収性疾患に対する効果的な治療法となり得る。
本研究は、骨芽細胞の分化のエピジェネティック制御の分子レベルの理解につながり学術的な意義も大きいが、上記のように骨吸収性疾患の治療法の開発に直結する基盤技術を提供する可能性があり、社会的な意義も大きい。

Research Products

• [Journal Article] Three-Dimensional Culture of Cartilage Tissue on Nanogel-Cross-Linked Porous Freeze-Dried Gel Scaffold for Regenerative Cartilage Therapy: A Vibrational Spectroscopy Evaluation (2022)
  • Author(s): Adachi Tetsuya、Miyamoto Nao、Imamura Hayata、Yamamoto Toshiro、Marin Elia、Zhu Wenliang、Kobara Miyuki、Sowa Yoshihiro、Tahara Yoshiro、Kanamura Narisato、Akiyoshi Kazunari、Mazda Osam、Nishimura Ichiro、Pezzotti Giuseppe
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 15 Pages: 8099-8099
  • DOI: 10.3390/ijms23158099
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hypoxia promotes differentiation of pure cartilage from human induced pluripotent stem cells. (2022)
  • Author(s): Shimomura S, Inoue H, Arai Y, Nakagawa S, Fujii Y, Kishida T, Shin-Ya M, Ichimaru S, Tsuchida S, Mazda O, Kubo T.
  • Journal Title: Mol Med Rep Volume: 26 Issue: 1 Pages: 229-229
  • DOI: 10.3892/mmr.2022.12745
  • Peer Reviewed / Open Access
• [Journal Article] Injectable Prevascularized Mature Adipose Tissues (iPAT) to Achieve Long‐Term Survival in Soft Tissue Regeneration (2022)
  • Author(s): Louis Fiona、Sowa Yoshihiro、Irie Shinji、Higuchi Yuriko、Kitano Shiro、Mazda Osam、Matsusaki Michiya
  • Journal Title: Advanced Healthcare Materials Volume: 11 Issue: 23 Pages: 2201440-2201440
  • DOI: 10.1002/adhm.202201440
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Micronized cellular adipose matrix (MCAM) promotes the therapeutic effect of an artificial nerve conduit in peripheral nerve gap injury (2022)
  • Author(s): Sawai Seiji、Sowa Yoshihiro、Kishida Tsunao、Inokawa Hitoshi、Inafuku Naoki、Tsuchida Shinji、Oda Ryo、Fujiwara Hiroyoshi、Mazda Osam、Yoshimura Kotaro、Takahashi Kenji
  • Journal Title: Plastic and Reconstructive Surgery Volume: -
  • DOI: 10.1097/prs.0000000000010136
  • Peer Reviewed / Open Access
• [Journal Article] ALK5 i II Accelerates Induction of Adipose-Derived Stem Cells toward Schwann Cells through a Non-Smad Signaling Pathway (2021)
  • Author(s): Seiji Sawai 1, Tsunao Kishida , Shin-Ichiro Kotani , Shinji Tsuchida , Ryo Oda , Hiroyoshi Fujiwara, Kenji Takahashi , Osam Mazda , Yoshihiro Sowa
  • Journal Title: Stem Cells Int . Volume: Oct. 15 Pages: 1-11
  • DOI: 10.1155/2021/8307797
  • Peer Reviewed / Open Access
• [Journal Article] Direct Conversion of Human Fibroblasts into Adipocytes Using a Novel Small Molecular Compound: Implications for Regenerative Therapy for Adipose Tissue Defects. (2021)
  • Author(s): Sowa Y, Kishida T, Louis F, Sawai S, Seki M, Numajiri T, Takahashi K, Mazda O
  • Journal Title: Cells Volume: 10 Issue: 3 Pages: 65-76
  • DOI: 10.3390/cells10030605
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Osteogenic Response to Polysaccharide Nanogel Sheets of Human Fibroblasts After Conversion Into Functional Osteoblasts by Direct Phenotypic Cell Reprogramming (2021)
  • Author(s): Nakai K, Yamamoto K, Kishida T, Kotani SI, Sato Y, Horiguchi S, Yamanobe H, Adachi T, Boschetto F, Marin E, Zhu W, Akiyoshi K, Yamamoto T, Kanamura N, Pezzotti G, Mazda O.
  • Journal Title: Front Bioeng Biotechnol . Volume: Sep 3;9:713932 Pages: 713932-713932
  • DOI: 10.3389/fbioe.2021.713932
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Treadmill running prevents atrophy differently in fast- versus slow-twitch muscles in a rat model of rheumatoid arthritis (2021)
  • Author(s): Yoichiro Kamada , Shogo Toyama , Yuji Arai , Hiroaki Inoue , Shuji Nakagawa , Yuta Fujii Kenta Kaihara , Tsunao Kishida , Osam Mazda , Kenji Takahashi
  • Journal Title: J Muscle Res Cell Motil . Volume: Dec;42(3-4) Issue: 3-4 Pages: 429-441
  • DOI: 10.1007/s10974-021-09610-0
  • Peer Reviewed / Open Access
• [Journal Article] Mechanical stimulation of chondrocytes regulates HIF-1α under hypoxic conditions (2021)
  • Author(s): Shimomura S, Inoue H, Arai Y, Nakagawa S, Fujii Y, Kishida T, Shin-Ya M, Ichimaru S, Tsuchida S, Mazda O, Takahashi K.
  • Journal Title: Tissue Cell . Volume: Aug;71:101574. Pages: 101574-101574
  • DOI: 10.1016/j.tice.2021.101574
  • Peer Reviewed / Open Access