Secreted Factors of Human Liver-Derived Mesenchymal Stem Cells Promote Liver Regeneration Early After Partial Hepatectomy
Secreted Factors of Human Liver-Derived Mesenchymal Stem Cells Promote Liver Regeneration Early After Partial Hepatectomy
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DOI：
10.1089/scd.2011.0560
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发表时间：
2012-09-01
影响因子：
4
通讯作者：
van der Laan, Luc J. W.
中科院分区：
文献类型：
--
作者：
Fouraschen, Suomi M. G.;Pan, Qiuwei;van der Laan, Luc J. W.
活体供肝移植和肿瘤性肝切除后需要快速的肝脏再生，以保证足够的肝功能和防止小体积综合征。最近的证据显示间充质干细胞(MSC)治疗中毒性肝损伤的潜力，但MSC及其分泌的因子是否能刺激手术损伤后的肝再生尚不清楚。因此，本研究的目的是研究人肝源性MSC分泌因子在实验性肝切除模型中的作用。C57BL/6小鼠接受70%肝部分切除，给予MSC条件培养液(MSC-CM)或溶剂对照。对动物进行肝脏和体重、肝细胞增殖和肝脏基因表达的分析。利用全基因组基因表达芯片分析了MSC-CM对人肝细胞样细胞系Huh7细胞基因表达的影响。MSC-CM可显著促进肝再生，表现为肝/体重比增加和肝细胞增殖。MSC-CM上调了与细胞增殖、血管生成和抗炎反应相关的细胞因子和生长因子的基因表达。在体外，用MSC-CM处理Huh7细胞显著改变了类似3000个基因的表达水平。功能分析显示，与蛋白质合成、细胞存活和细胞增殖相关的网络具有很强的影响。本研究表明，在手术切除后早期应用MSC衍生因子治疗可以促进肝细胞的增殖和再生反应。MSC-CM可能是促进大范围肝切除或小肝移植后肝再生的一种可行的新策略。
Rapid liver regeneration is required after living-donor liver transplantation and oncologic liver resections to warrant sufficient liver function and prevent small-for-size syndrome. Recent evidence highlights the therapeutic potential of mesenchymal stem cells (MSC) for treatment of toxic liver injury, but whether MSC and their secreted factors stimulate liver regeneration after surgical injury remains unknown. Therefore, the aim of this study is to investigate the effect of human liver-derived MSC-secreted factors in an experimental liver resection model. C57BL/6 mice were subjected to a 70% partial hepatectomy and treated with either concentrated MSC-conditioned culture medium (MSC-CM) or vehicle control. Animals were analyzed for liver and body weight, hepatocyte proliferation, and hepatic gene expression. Effects of MSC-CM on gene expression in a human hepatocyte-like cell line (Huh7 cells) were analyzed using genome-wide gene expression arrays. Liver regeneration was significantly stimulated by MSC-CM as shown by an increase in liver to body weight ratio and hepatocyte proliferation. MSC-CM upregulated hepatic gene expression of cytokines and growth factors relevant for cell proliferation, angiogenesis, and anti-inflammatory responses. In vitro, treatment of Huh7 cells with MSC-CM significantly altered expression levels of similar to 3,000 genes. Functional analysis revealed strong effects on networks associated with protein synthesis, cell survival, and cell proliferation. This study shows that treatment with MSC-derived factors can promote hepatocyte proliferation and regenerative responses in the early phase after surgical resection. MSC-CM may represent a feasible new strategy to promote liver regeneration in patients undergoing extensive liver resection or after transplantation of small liver grafts.