Analysis of immunoregulation and mechanism of liver regeneration in cell transplantation

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08765
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Sapporo Medical University
• Principal Investigator: Ichinohe Norihisa 札幌医科大学, 医学部, 助教 (80452978)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 細胞・組織 / 再生医学 / 肝幹・前駆細胞 / 細胞移植 / 生体組織工学

Outline of Final Research Achievements

Small hepatocyte-like progenitor cells (SHPCs) transiently appear in rat livers treated with retrorsine (Ret)/70% partial hepatectomy (PH). We reported that transplantation of Thy1+ cells derived from galactosamine-treated liver accelerated the growth of SHPCs in Ret/PH-treated rat livers. Extracellular vesicles (EVs) produced by Thy1+ donor cells activated SHPCs. As bone marrow-derived mesenchymal cells (BM-MCs) also express Thy1, we investigated whether BM-MCs could promote the growth of SHPCs as well as hepatic Thy1+ cells. EVs isolated from conditioned medium of cultured BM-MCs were administrated into Ret/PH-treated rat livers, resulting in the growth of SHPCs. Soluble factors contained in EVs were examined and we identified that miRNA146a is the most important factor for enhancing the proliferation of cultured small hepatocytes (SHs). EVs derived from BM-MCs carry miR146a into SHPCs for activating their growth capacity.

Free Research Field

医師薬学

Academic Significance and Societal Importance of the Research Achievements

現在、骨髄間葉系幹細胞を用いた脳疾患や脊髄疾患、肝硬変に対する臨床治験が行われている。その治療効果への期待は大きいが、その再生メカニズムはまだよくわかっていない。本研究は骨髄間葉系細胞移植の有効性を基礎的に裏付ける研究であり、細胞移植治療の再生メカニズムの検討から液性因子を同定し、内科的肝再生誘導治療へ繋げることが出来れば、ドナー細胞の確保を必要とせずに薬剤投与による治療が可能になる。また今回の再生誘導因子の同定は、新治療薬の開発のほか、より効率的に肝前駆細胞を体外増幅することが期待でき、肝細胞のドナー細胞不足の解消にも繋がることが期待できる。