Basic studies for the development of efficient liver regenerative therapy using bone marrow cells

利用骨髓细胞开发高效肝脏再生疗法的基础研究

• 批准号: 18590737
• 负责人: TERAI Shuji
• 金额: $ 2.57万
• 依托单位: Yamaguchi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590737/
• 关键词: Regenerative medicine; Cell and regenerative therapy; Cells and tissues; Development and differentiation

We have developed an in vivo mouse model, the GFP/CC14 model, and have reported that transplanted GFP-positive bone marrow cells (BMCs) differentiate into hepatocytes and improve /CC14-induced cirrhosis. We have also reported that fibroblast growth factor 2 (FGF2) facilitated the differentiation of transplanted BMCs into hepatocytes. However, it is unclear the mechanism(s) of the differentiation from transplanted BMCs into hepatocytes. In 2006, our studies demonstrated that administration of FGF2 in combination with bone marrow transplantation (BMT) synergistically activated tumor necrosis factor-alpha signaling and significantly improved liver function and prognosis more than BMC infusion alone, suggesting that FGF2 had an important role in liver regeneration. Next, in 2007, we analyzed why the injected BMC are resistant to /CC14 damage and subsequently improve the local microenvironment in damaged liver. To analyze the cellular phenomena involved in this process, we studied the damag … More ed liver using electron microscopy. We found that /CC14 caused rough endoplasmic reticule to swell in hepatocytes. To analyze the gene expression patterns associated with this process, we conducted PCR-selected suppressive subtractive hybridization. We found that expression levels of HSP84, HSP40, and XBPI differed markedly between control liver and liver infused with BMC. Immunohistochemical staining revealed that expression levels of HSP84 and HSP40 were markedly higher in the early phase of differentiation immediately after BMC infusion, but decreased over time. XBPI expression remained high during the late phase, and GRP78 expression increased with XBPI activation. We also found that GFP-positive BMC expressed XBPI and GRP78. XBP1 and GRP78 are associated with ER stress. Thus, continuous high XBPI and GRP78 expression might be essential for the survival and proliferation of BMC in a CC14-induced persistent liver damage environment. These basic studies are important for the development of an effective autologous bone marrow cell infusion (ABMI) therapy for patients with liver cirrhosis. Less

我们开发了一种体内小鼠模型，GFP/CC14模型，并报道了移植的GFP阳性骨髓细胞（BMCs）分化为肝细胞并改善/CC14诱导的肝硬化。我们也报道了成纤维细胞生长因子2 （FGF2）促进移植骨髓干细胞向肝细胞的分化。然而，移植骨髓干细胞向肝细胞分化的机制尚不清楚。2006年，我们的研究表明，与单独输注BMC相比，FGF2联合骨髓移植（BMT）可协同激活肿瘤坏死因子- α信号，显著改善肝功能和预后，表明FGF2在肝脏再生中具有重要作用。接下来，在2007年，我们分析了为什么注射的BMC能够抵抗/CC14损伤，并随后改善受损肝脏的局部微环境。为了分析这一过程中涉及的细胞现象，我们用电子显微镜研究了损伤的…我们发现/CC14引起肝细胞粗面内质网肿胀。为了分析与这一过程相关的基因表达模式，我们进行了pcr选择的抑制性减法杂交。我们发现HSP84、HSP40和XBPI的表达水平在对照肝和BMC灌注肝中有显著差异。免疫组化染色显示，HSP84和HSP40的表达水平在BMC输注后立即分化早期明显升高，但随着时间的推移而降低。XBPI在后期保持高表达，GRP78表达随XBPI激活而增加。我们还发现gfp阳性BMC表达XBPI和GRP78。XBP1和GRP78与内质网应激有关。因此，在cc14诱导的持续性肝损伤环境中，XBPI和GRP78的持续高表达可能对BMC的存活和增殖至关重要。这些基础研究对于开发有效的自体骨髓细胞输注（ABMI）治疗肝硬化患者具有重要意义。少

项目成果

Administration of fibroblast growth factor 2 in combination with bone marrow transplantation synergistically improves carbon-tetrachloride-induced liver fibrosis in mice

• DOI: 10.1007/s00441-006-0334-x
• 发表时间: 2007-03-01
• 期刊: CELL AND TISSUE RESEARCH
• 影响因子: 3.6
• 作者: Ishikawa, Tsuyoshi;Terai, Shuji;Sakaida, Isao
• 通讯作者: Sakaida, Isao

Current status of ABMI therapy for liver cirrhosis patient.

肝硬化患者ABMI治疗现状

• 发表时间: 2007
• 作者: Obika M;Shinji T;Fujioka SI;Terada R;Ryuko H;Lwin AA;Shiraha H;Koide N;Terai S
• 通讯作者: Terai S

自己骨髄細胞を用いた肝臓再生療法の開発 -基礎研究から臨床研究へ 実験医学

自体骨髓细胞肝再生疗法的进展 - 从基础研究到临床研究 实验医学

• 发表时间: 2006
• 作者: Shojima;N.;石川 剛
• 通讯作者: 石川 剛

多施設臨床研究:肝硬変症に対するABMI療法の開発

多中心临床研究：ABMI治疗肝硬化的进展

• 发表时间: 2006
• 期刊: 日本再生医療学会誌、再生医療 5
• 作者: Koda S;Date Y;Murakami N;Shimbara T;Hanada T;Toshinai K;Niiji A;Furuya M;Inomata N;Osuye K;Nakazato M;寺井 崇二
• 通讯作者: 寺井 崇二

Elevated levels of circulating cell-free DNA in the blood of patients with hepatitis C virus-associated hepatocellular carcinoma.

• 发表时间: 2006-11
• 期刊: Anticancer research
• 影响因子: 2
• 作者: N. Iizuka;I. Sakaida;T. Moribe;N. Fujita;T. Miura;M. Stark;S. Tamatsukuri;H. Ishitsuka;K. Uchida;S. Terai;Kazuhiko Sakamoto;T. Tamesa;M. Oka