Therapy of non-alcoholic steatohepatitis by adipose tissue-derived mesenchymal stem cells and safety

• Project/Area Number: 19K08382
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Takanashi Masakatsu 東京医科大学, 医学部, 講師 (80312007)
• Co-Investigator(Kenkyū-buntansha): 村上 善基 東京医科大学, 医学部, 兼任教授 (00397556) ; 上田 しのぶ 東京医科大学, 医学部, 助手 (00521874) ; 須藤 カツ子 東京医科大学, 医学部, 兼任講師 (50126091) ; 梅澤 明弘 国立研究開発法人国立成育医療研究センター, 再生医療センター, 再生医療センター長 (70213486)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: NASH / 間葉系幹細胞 / エクソソーム / exosome

Outline of Research at the Start

NASHの進行は肝機能不全となり、移植療法が有効な治療であるが実施には支障がある。再生医療は問題を解決する手法として注目され、侵襲性の低い脂肪組織由来間葉系幹細胞(AMSC)が肝機能不全モデル動物を用いた前臨床試験が試されている。しかし、NASHでの炎症反応は肝臓以外の脂肪組織にも影響を与えることが予想され、これらの組織由来のAMSCが肝臓に与える影響は解明されていない。そこでNASHモデル動物を作成し、その個体からAMSCを樹立し、正常マウス由来の細胞と比較し安全性について検討する。さらに、再生肝の脂肪蓄積予防を脂肪代謝の活発な肝臓に改善するため脂肪分解酵素を導入したAMSCの樹立を目指す。

Outline of Final Research Achievements

Mesenchymal stem cells derived from adipose tissue are known to be less invasive to tissues and have higher stem cell content in tissues. Regenerating medicine using mesenchymal stem cells is expected to have a high potential for practical application as an effective therapeutic option after developing non-alcoholic steatohepatitis (NASH). We attempted to establish mesenchymal stem cells from adipose tissue of NASH by generating NASH model mice. Although there have been several reports on the creation of animal models of NASH, studies similar to those on human pathology are still needed. In this study, we succeeded in creating a model animal by administering streptozotocin to IL-1 receptor antagonist-deficient mice and feeding them a high-fat diet for a long period. We succeeded in establishing involved stem cells from the adipose tissue of these animals.

Academic Significance and Societal Importance of the Research Achievements

NASHモデル動物の作成とその動物由来の脂肪組織から間葉系幹細胞を樹立した。NASHの発症原因は様々な報告がある。NASHの発症機序や治療法の研究にはモデル動物は必要不可欠である。しかし、これまでに報告されいるモデル動物では、未だ開発する必要がある。本研究ではこれまでに報告のない、IL-1 receptor antagonist欠損したマウスを使用した。このマウスはIL-1のシグナル伝達系が恒常的に刺激され、炎症が誘導された状態にあるマウスである。この系統によるモデルマウスの作出は、安定的に高頻度に誘導することが可能である。今後のNASHの発症の解明や治療モデルに応用されることが期待される。

Research Products

• [Journal Article] Cisplatin inducesdifferentiation in teratomas derived from pluripotent stem cells. (2021)
  • Author(s): Kurata A, Takanashi M, Ohno SI, Fujita K, Kuroda M.
  • Journal Title: Regen Ther. Volume: 18 Pages: 117-126
  • DOI: 10.1016/j.reth.2021.05.005
  • Peer Reviewed / Open Access
• [Journal Article] WAPL induces cervical intraepithelial neoplasia modulated with estrogen signaling without HPV E6/E7. Oncogene. (2021)
  • Author(s): Kumagai K, Takanashi M, Ohno SI, Harada Y, Fujita K, Oikawa K, Sudo K, Ikeda SI, Nishi H, Oikawa K, Kuroda M.
  • Journal Title: Oncogene Volume: 40(21) Issue: 21 Pages: 3695-3706
  • DOI: 10.1038/s41388-021-01787-5
  • Peer Reviewed / Open Access
• [Journal Article] Acerola exosome-like nanovesicles to systemically deliver nucleic acid medicine via oral administration. (2021)
  • Author(s): Umezu T, Takanashi M, Murakami Y, Ohno SI, Kanekura K, Sudo K, Nagamine K, Takeuchi S, Ochiya T, Kuroda M.
  • Journal Title: Molecular therapy. Methods & clinical development. Volume: 10;21 Pages: 199-208
  • DOI: 10.1016/j.omtm.2021.03.006
  • Peer Reviewed / Open Access
• [Journal Article] Expression of L-type amino acid transporter 1 is a poor prognostic factor for Non-Hodgkin's lymphoma. (2021)
  • Author(s): Jigjidkhorloo N, Kanekura K, Matsubayashi J, Akahane D, Fujita K, Oikawa K, Kurata A, Takanashi M, Endou H, Nagao T, Gotoh A, Norov O, Kuroda M.
  • Journal Title: Sci Rep. Volume: 11(1) Issue: 1 Pages: 21638-21638
  • DOI: 10.1038/s41598-021-00811-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comprehensive miRNA Analysis Using Serum From Patients With Noninfectious Uveitis. (2020)
  • Author(s): Asakage M, Usui Y, Nezu N, Shimizu H, Tsubota K, Yamakawa N, Takanashi M, Kuroda M, Goto H.
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: 61(11) Issue: 11 Pages: 4-4
  • DOI: 10.1167/iovs.61.11.4
  • Peer Reviewed / Open Access
• [Journal Article] Share Distinctive Tissue and Serum MicroRNA Profile of IgG4-Related Ophthalmic Disease and MALT Lymphoma. (2020)
  • Author(s): Nezu N, Usui Y, Asakage M, Shimizu H, Tsubota K, Narimatsu A, Umazume K, Yamakawa N, Ohno SI, Takanashi M, Kuroda M, Goto H.
  • Journal Title: J Clin Med. Volume: 9(8) Issue: 8 Pages: 2530-2530
  • DOI: 10.3390/jcm9082530
  • Peer Reviewed / Open Access
• [Journal Article] High-Throughput MicroRNA Profiling of Vitreoretinal Lymphoma: Vitreous and Serum MicroRNA Profiles Distinct from Uveitis. (2020)
  • Author(s): Minezaki T, Usui Y, Asakage M, Takanashi M, Shimizu H, Nezu N, Narimatsu A, Tsubota K, Umazume K, Yamakawa N, Kuroda M, Goto H.
  • Journal Title: J Clin Med. Volume: 9(6) Issue: 6 Pages: 1844-1844
  • DOI: 10.3390/jcm9061844
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular microvesicles that originated adipose tissue derived mesenchymal stem cells have the potential ability to improve rheumatoid arthritis on mice. (2020)
  • Author(s): Tsujimaru K, Takanashi M, Sudo K, Ishikawa A, Mineo S, Ueda S, Kumagai K, Kuroda M.
  • Journal Title: Regen Ther. Volume: 15 Pages: 305-311
  • DOI: 10.1016/j.reth.2020.08.004
  • Peer Reviewed / Open Access
• [Journal Article] miR-27a ameliorates chemoresistance of breast cancer cells by disruption of reactive oxygen species homeostasis and impairment of autophagy (2020)
  • Author(s): Ueda S, Takanashi M, Sudo K, Kanekura K, Kuroda M
  • Journal Title: Lab Invest. Volume: - Issue: 6 Pages: 863-873
  • DOI: 10.1038/s41374-020-0409-4
  • Peer Reviewed / Open Access
• [Journal Article] Fascin as a Useful Marker for Identifying Neural Components in Immature Teratomas of Human Ovary and Those Derived From Murine Embryonic Stem Cells (2018)
  • Author(s): Umehara R, Kurata A, Takanashi M, Hashimoto H, Fujita K, Nagao T, Kuroda M.
  • Journal Title: Int J Gynecol Pathol. Volume: - Issue: 4 Pages: 1-9
  • DOI: 10.1097/pgp.0000000000000528
  • Peer Reviewed / Open Access
• [Presentation] 樹状細胞由来エクソソームは内包因子をＴ細胞に伝達することで免疫系を活性化する (2021)
  • Author(s): 髙梨正勝 須藤カツ子 石川章夫 黒田雅彦
  • Organizer: 第8回日本細胞外小胞学会総会
• [Presentation] DC由来のexosomeによるT細胞の活性化機構について (2020)
  • Author(s): 高梨正勝 須藤カツ子 石川章夫 黒田雅彦
  • Organizer: 日本細胞外小胞学会
• [Presentation] Dendritic cell derived-exosomes activate immune systems by transferring exosome involved factors to T cell. (2019)
  • Author(s): Takanashi M, Ueda S, Sudo K, Kuroda M
  • Organizer: ANNUAL MEETING ISEV 2019
  • Int'l Joint Research