Statin-polymer nanoparticles enhance the anti-inflammatory and anti-fibrotic effects of adipose-derived stem cell transplantation in a mouse model of bleomycin-induced scleroderma

• Project/Area Number: 17K15761
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: Osaka Medical College
• Principal Investigator: Nagai Koji 大阪医科大学, 医学部, 非常勤医師 (30572458)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 強皮症 / 脂肪幹細胞 / 間質性肺炎 / スタチン / 脂肪組織由来幹細胞 / 間葉系幹細胞 / 内科 / 免疫学 / 再生医学

Outline of Final Research Achievements

This study investigated the effects of simvastatin-conjugated nanoparticles (SimNPs) on the functions of adipose-derived mesenchymal stem cells (AdSCs) and the therapeutic effect of SimNP-AdSCs in mice models of scleroderma. The cellular functions of AdSCs from Balb/c mice conjugated with different concentrations of statins was observed, and the optimum simvastatin dose was selected. Mice were assigned to four groups: bleomycin (BLM) alone group, NP-AdSC group, SimNP group, and SimNP-AdSC group, and the treatments were performed on day 7. SimNPs significantly promoted migration activity, viability, and up-regulated immunomodulatory factors in in vitro assays. Inflammation and fibrosis in skin were significantly supressed in the SimNP-AdSC group. The gene expression levels of TNF-alpha and IL-4 were significantly lower and the MMP-9/TIMP-1 ratio was higher in the SimNP-AdSC group than the NP-AdSC group.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果から、SimNP-AdSCsはAdSCs単独より高い抗炎症効果と抗線維化効果が得られたことから、強皮症や合併する臓器病変である間質性肺炎に対する将来的に有望な治療候補になり得る可能性がある。この結果は、AdSCsの投与細胞数を減らし肺塞栓のリスク低減につながるという点で、より臨床応用に近づいたと言えるのではないか。AdSCsの細胞機能を更に高める方法の開発が今後も求められる。

Research Products

• [Presentation] シンバスタチンPLGA粒子抱合脂肪組織由来幹細胞の間質性肺炎モデルマウスに対する治療効果の検討 (2019)
  • Author(s): 小谷 卓矢，鈴鹿隆保, 永井孝治, 和田祐美子, 武内 徹, 荒若 繁樹，伊井 正明
  • Organizer: 第18回日本再生医療学会
• [Presentation] Simvastatin-conjugated nanoparticle enhances the therapeutic effect of adipose-derived stem cells on interstitial lung disease (2019)
  • Author(s): Takuya Kotani1, Masaaki Ii, Takayasu Suzuka, Yumiko Wada, Koji Nagai, Tohru Takeuchi, Shigeki Arawaka.
  • Organizer: 欧州リウマチ学会 (EULAR 2019)
  • Int'l Joint Research
• [Presentation] Anti-inflammatory and anti-fibrotic effects of intravenous adipose-derived stem cell transplantation in a mouse model of bleomycin-induced scleroderma (2019)
  • Author(s): Takayasu Suzuka, Takuya Kotani, Koji Nagai, Yumiko Wada, Masaaki Ii, Tohru Takeuchi, Shigeki Arawaka
  • Organizer: 欧州リウマチ学会 (EULAR 2019)
  • Int'l Joint Research