FGF7 is a functional niche signal required for stimulation of adult liver progenitor cells that support liver regeneration
FGF7 is a functional niche signal required for stimulation of adult liver progenitor cells that support liver regeneration
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DOI：
10.1101/gad.204776.112
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发表时间：
2013-01-15
影响因子：
10.5
通讯作者：
Miyajima, Atsushi
中科院分区：
文献类型：
--
作者：
Takase, Hinako M.;Itoh, Tohru;Miyajima, Atsushi
肝脏是一个独特的器官，在受伤后具有极高的再生潜力。在肝细胞增殖受损的严重受损的肝脏中，兼性肝祖细胞(LPC)增殖，并被认为有助于再生。在各种类型的肝病患者中常可观察到LPCS的扩张。然而，LPC激活的潜在机制在很大程度上仍不清楚。在这里，我们发现成纤维细胞生长因子家族的一个成员，Fgf7，是LPCS的关键调节因子。在小鼠模型的肝脏和急性肝衰竭患者的血清中，它的表达与LPC反应同时被诱导。FGF7基因缺陷小鼠在毒素诱导的肝损伤中表现出明显的LPC扩张抑制和较高的死亡率。体内转基因表达Fgf7可诱导出具有LPCS特征的细胞，改善肝功能障碍。我们发现，Thy1(+)间充质细胞产生Fgf7，并与LPCs紧密相连，暗示这些细胞在再生肝脏中扮演着LPC功能生态位的角色。这些发现为LPC调节的细胞和分子基础提供了新的见解，并确定Fgf7是肝病的潜在治疗靶点。
The liver is a unique organ with a remarkably high potential to regenerate upon injuries. In severely damaged livers where hepatocyte proliferation is impaired, facultative liver progenitor cells (LPCs) proliferate and are assumed to contribute to regeneration. An expansion of LPCs is often observed in patients with various types of liver diseases. However, the underlying mechanism of LPC activation still remains largely unknown. Here we show that a member of the fibroblast growth factor (FGF) family, FGF7, is a critical regulator of LPCs. Its expression was induced concomitantly with LPC response in the liver of mouse models as well as in the serum of patients with acute liver failure. Fgf7-deficient mice exhibited markedly depressed LPC expansion and higher mortality upon toxin-induced hepatic injury. Transgenic expression of FGF7 in vivo led to the induction of cells with characteristics of LPCs and ameliorated hepatic dysfunction. We revealed that Thy1(+) mesenchymal cells produced FGF7 and appeared in close proximity to LPCs, implicating a role for those cells as the functional LPC niche in the regenerating liver. These findings provide new insights into the cellular and molecular basis for LPC regulation and identify FGF7 as a potential therapeutic target for liver diseases.