Human liver stem cells improve liver injury in a model of fulminant liver failure
Human liver stem cells improve liver injury in a model of fulminant liver failure
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DOI：
10.1002/hep.25986
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发表时间：
2013-01-01
期刊：
影响因子：
13.5
通讯作者：
Camussi, Giovanni
中科院分区：
文献类型：
--
作者：
Herrera, Maria Beatriz;Fonsato, Valentina;Camussi, Giovanni
肝移植是目前唯一有效的治疗暴发性肝功能衰竭的方法，但其使用受到移植器官稀缺，高成本和终身免疫抑制的限制。在这里，我们研究了人肝干细胞（HLSC）是否保护死亡的致命模型中的暴发性肝衰竭诱导的D-半乳糖胺和脂多糖腹腔注射在SCID小鼠。我们表明，在这个模型中，HLSC和HLSC条件培养基（CM）的注射显著减弱小鼠死亡率。肝组织病理学分析显示肝细胞凋亡减少，肝再生增强。通过光学成像，我们观察到标记的HLSC在肝脏内的优先定位。通过免疫组织化学在肝大血管（在24小时）和肝实质（在第3天之后）中检测HLSC。荧光原位杂交分析显示，阳性细胞在24小时时细胞角蛋白阴性。细胞角蛋白和人类染色体的共表达，观察到在7，在较小程度上，在21天。HLSC衍生的CM在体内模拟HLSC的作用。HLSC-CM的组成分析揭示了具有肝再生特性的生长因子和细胞因子的存在。体外实验表明，HLSC-CM保护人肝细胞免于凋亡，并促进其增殖。结论：这些数据表明，暴发性肝功能衰竭可能从HLSC或HLSC-CM治疗中获益。（肝脏病学2013;57：311-319）
Liver transplantation is currently the only effective therapy for fulminant liver failure, but its use is limited by the scarcity of organs for transplantation, high costs, and lifelong immunosuppression. Here we investigated whether human liver stem cells (HLSCs) protect from death in a lethal model of fulminant liver failure induced by intraperitoneal injection of D-galactosamine and lipopolysaccharide in SCID mice. We show that injection of HLSCs and of HLSC-conditioned medium (CM) significantly attenuates mouse mortality in this model. Histopathological analysis of liver tissue showed reduction of liver apoptosis and enhancement of liver regeneration. By optical imaging we observed a preferential localization of labeled HLSCs within the liver. HLSCs were detected by immunohistochemistry in large liver vessels (at 24 hours) and in the liver parenchyma (after day 3). Fluorescence in situ hybridization analysis with the human pan-centromeric probe showed that positive cells were cytokeratin-negative at 24 hours. Coexpression of cytokeratin and human chromosome was observed at 7 and, to a lesser extent, at 21 days. HLSC-derived CM mimicked the effect of HLSCs in vivo. Composition analysis of the HLSC-CM revealed the presence of growth factors and cytokines with liver regenerative properties. In vitro experiments showed that HLSC-CM protected human hepatocytes from apoptosis and enhanced their proliferation. Conclusion: These data suggest that fulminant liver failure may potentially benefit from treatment with HLSCs or HLSC-CM. (HEPATOLOGY 2013;57:311-319)