Synergistic Cooperation of Heterogeneous Stromal Cells for Wound Repair Priming

• Project/Area Number: 17K09559
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Dokkyo Medical University
• Principal Investigator: Kishimoto Satoko 獨協医科大学, 医学部, 講師 (10511488)
• Co-Investigator(Kenkyū-buntansha): 井上 健一 獨協医科大学, 医学部, 准教授 (90587974) ; 佐久間 理吏 獨協医科大学, 医学部, 准教授 (10530199) ; 井上 晃男 獨協医科大学, 医学部, 教授 (20168454)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 創傷治癒 / 間質細胞 / 傷害刺激 / 血管新生 / 脂肪由来間質細胞

Outline of Final Research Achievements

We show that surgical treatments for adipose tissue reproducibly increase and reorganize adipose-derived stromal vascular fractions (SVFs). We term this phenomenon “wound repair priming” and subsequently developed a method to reproduce this phenomenon and investigated its mechanisms. The primed SVFs required two surgical procedures: mincing fat parenchyma (injury) and ligating the subcutaneous fat-feeding artery (ischemia). The primed SVFs rapidly reorganize their cell components during wound repair. Residential stromal cells and mobilized immune cells collaborate to achieve effective angiogenesis in ischemic tissues.

Academic Significance and Societal Importance of the Research Achievements

我々は、異種雑多な間質細胞が創傷治癒というゴールを目指してチームとして機能するという新たな概念（創傷治癒プライミング）を提唱し、そのメカニズムについて研究することに学術的な意義があると考える。
臨床現場で移植細胞の品質を均一に確保することが難しいという問題を解決するには、将来的に、外科的なプライミングと同等の効果が得られるアプローチ、例えば自然免疫シグナルを刺激する化学物質を用いたプライミングなどが有望な代替手段となり得る。このような化学的・薬理学的なプライミングは、重症虚血肢などの虚血性心血管疾患に対する効果的な血管新生療法の開発に貢献すると考えられる。

Research Products

• [Journal Article] Surgical Injury and Ischemia Prime the Adipose Stromal Vascular Fraction and Increase Angiogenic Capacity in a Mouse Limb Ischemia Model (2020)
  • Author(s): Kishimoto S, Inoue KI, Sohma R, Toyoda S, Sakuma M, Inoue T, Yoshida K
  • Journal Title: Stem Cells International Volume: 7219149 Pages: 7219149-7219149
  • DOI: 10.1155/2020/7219149
  • Peer Reviewed / Open Access
• [Journal Article] Surgical Injury and Ischemia Prime the Adipose Stromal Vascular Fraction and Increases Angiogenic Capacity in a Mouse Limb Ischemia Model (2019)
  • Author(s): Kishimoto S, Inoue KI, Sohma R, Toyoda S, Sakuma M, Inoue T, Yoshida KI
  • Journal Title: Stem Cells International Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Cancer-associated fibroblasts show heterogeneous gene expression and induce vascular endothelial growth factor A (VEGFA) in response to environmental stimuli (2019)
  • Author(s): Inoue KI, Kishimoto S, Akimoto K, Sakuma M, Toyoda S, Inoue T, Yoshida KI, Shimoda M, Suzuki S
  • Journal Title: Ann Gastroenterol Surg Volume: 3 Issue: 4 Pages: 416-425
  • DOI: 10.1002/ags3.12249
  • Peer Reviewed / Open Access
• [Journal Article] Polyelectrolyte Complexes of natural polymers and their biomedical applications (2019)
  • Author(s): Ishihara M, Kishimoto S, Nakamura S, Sato Y, Hattori H
  • Journal Title: Polymers (Basel) Volume: 11 Issue: 4 Pages: 672-672
  • DOI: 10.3390/polym11040672
  • Peer Reviewed / Open Access
• [Journal Article] Low-Molecular Weight Heparin/Protamine Micro-Nanoparticles Augmented Viability of Human Adipose-Derived Regenerative Cells. (2018)
  • Author(s): Masashi Sakuma, Satoko Kishimoto, Ken-ichi Inoue, Ryoichi Sohma, Shigeru Toyoda, Hideki Iwaguro and Teruo Inoue
  • Journal Title: Biomedical Journal of Scientific and Technical Research Volume: 12 Issue: 3 Pages: 1-3
  • DOI: 10.26717/bjstr.2018.12.002265
  • Peer Reviewed / Open Access
• [Journal Article] Autologous and heterotopic transplantation of adipose stromal vascular fraction ameliorates stress urinary incontinence in rats with simulated childbirth trauma (2018)
  • Author(s): Ken-ichi Inoue, Satoko Kishimoto, Kanya Kaga, Miki Fuse, Akira Furuta, Tomonori Yamanishi
  • Journal Title: Regenerative Therapy Volume: 8 Pages: 9-14
  • DOI: 10.1016/j.reth.2017.11.003
  • Peer Reviewed / Open Access
• [Journal Article] Reproducible insulin secretion from isolated rat pancreas preparations using an organ bath (2018)
  • Author(s): Asuka Morita, Motoshi Ouchi, Misao Terada, Hiroe Kon, Satoko Kishimoto, Keitaro Satoh, Naoyuki Otani, Keitaro Hayashi, Tomoe Fujita, Ken-ichi Inoue, Naohiko Anzai
  • Journal Title: Experimental Animals Volume: 67 Issue: 1 Pages: 15-22
  • DOI: 10.1538/expanim.17-0059
  • NAID: 130006339985
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed / Open Access
• [Journal Article] Biomaterials as cell carriers for augmentation of adipose tissue-derived stromal cell transplantation. (2018)
  • Author(s): Masayuki Ishihara, Satoko Kishimoto, Shingo Nakamura, Koichi Fukuda, Yoko Sato, Hidemi Hattori
  • Journal Title: Bio-Medical Materials and Engineering Volume: 29 Issue: 5 Pages: 567-585
  • DOI: 10.3233/bme-181009
  • Peer Reviewed / Open Access
• [Presentation] 組織間質細胞の修復戦略を細胞社会の文脈で理解する (2018)
  • Author(s): 井上健一, 岸本聡子, 井上晃男, 吉田謙一郎
  • Organizer: 第17回日本再生医療学会総会
• [Presentation] 創傷治癒における間質細胞の傷害刺激感知と血管新生増強 (2017)
  • Author(s): 岸本聡子, 井上健一, 朝戸裕貴, 井上晃男, 吉田謙一郎
  • Organizer: 第47回日本創傷治癒学会