Bone morphogenetic protein signaling governs biliary-driven liver regeneration in zebrafish through tbx2b and id2a.
Bone morphogenetic protein signaling governs biliary-driven liver regeneration in zebrafish through tbx2b and id2a.
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DOI：
10.1002/hep.29309
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Shin D
中科院分区：
文献类型：
--
作者：
Choi TY;Khaliq M;Tsurusaki S;Ninov N;Stainier DYR;Tanaka M;Shin D
在轻度肝损伤时，新的肝细胞来源于预先存在的肝细胞。然而，如果肝细胞增殖受损，严重肝损伤的表现，胆管上皮细胞（BEC）通过BEC去分化为肝祖细胞（LPC）（也称为卵圆细胞或成肝细胞样细胞（HB-LC））并随后分化为肝细胞而有助于新的肝细胞。尽管鉴定了几个调节BEC去分化和活化的因素，但对肝再生过程中LPC分化成肝细胞的调节因素知之甚少。使用斑马鱼模型的接近完全的肝细胞消融，我们在这里表明，BMP信号是必需的BEC转化为肝细胞，特别是LPC分化为肝细胞。我们发现，严重的肝损伤会导致肝脏中与Bmp信号相关的基因上调，包括smad 5，tbx 2b和id 2a。BMP的抑制并没有阻止BEC去分化成HB-LCs，然而，由于HB-LCs维持在未分化状态，HB-LCs向肝细胞的分化受损。随后BMP抑制不影响HB-LC分化，但通过增殖增加BEC数量。值得注意的是，smad 5，tbx 2b和id 2a突变体表现出类似的肝再生缺陷中观察到的BMP抑制的肝脏。此外，BMP 2的加入促进了小鼠LPC细胞系在体外分化为肝细胞。结论：BMP信号通过smad 5、tbx 2b和id 2a调节BEC驱动的肝再生：它通过tbx 2b调节HB-LC分化为肝细胞，通过id 2a调节BEC增殖。我们的研究结果为促进先天性肝再生作为一种新型疗法提供了见解。
Upon mild liver injury, new hepatocytes originate from pre-existing hepatocytes. However, if hepatocyte proliferation is impaired, a manifestation of severe liver injury, biliary epithelial cells (BECs) contribute to new hepatocytes through BEC dedifferentiation into liver progenitor cells (LPCs), also termed oval cells or hepatoblast-like cells (HB-LCs), and subsequent differentiation into hepatocytes. Despite the identification of several factors regulating BEC dedifferentiation and activation, little is known about factors involved in the regulation of LPC differentiation into hepatocytes during liver regeneration. Using a zebrafish model of near-complete hepatocyte ablation, we here show that Bmp signaling is required for BEC conversion to hepatocytes, particularly for LPC differentiation into hepatocytes. We found that severe liver injury led to the upregulation of genes involved in Bmp signaling, including smad5, tbx2b, and id2a, in the liver. Bmp suppression did not block BEC dedifferentiation into HB-LCs; however, the differentiation of HB-LCs into hepatocytes was impaired due to the maintenance of HB-LCs in an undifferentiated state. Later Bmp suppression did not affect HB-LC differentiation, but increased BEC number through proliferation. Notably, smad5, tbx2b, and id2a mutants exhibited similar liver regeneration defects as those observed in Bmp-suppressed livers. Moreover, BMP2 addition promoted the differentiation of a murine LPC cell line into hepatocytes in vitro. Conclusions: Bmp signaling regulates BEC-driven liver regeneration via smad5, tbx2b and id2a: it regulates HB-LC differentiation into hepatocytes via tbx2b and BEC proliferation via id2a. Our findings provide insights into promoting innate liver regeneration as a novel therapy.
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影响因子：
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