Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish.
Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish.
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DOI：
10.1053/j.gastro.2013.10.019
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发表时间：
2014-03
期刊：
影响因子：
29.4
通讯作者：
Shin D
中科院分区：
文献类型：
--
作者：
Choi TY;Ninov N;Stainier DY;Shin D
当肝细胞增殖受损时，胆管上皮细胞（BEC）被认为是再生肝细胞的来源。然而，对于BEC在多大程度上可以促进再生肝细胞群体，从而促进肝脏恢复，仍然存在争议。为了研究这个问题，我们建立了一个斑马鱼肝再生模型，其中肝细胞消融的程度可以控制。通过对Tg（fabp 10a：CFP-NTR）动物给予甲硝唑来消耗肝细胞。我们使用短期谱系追踪实验以及诱导型Cre/loxP系统追踪再生肝细胞的起源;具体而言，我们利用BEC示踪线Tg（Tp 1：CreERT 2）和肝细胞示踪线Tg（fabp 10a：CreERT 2）。我们还研究了BEC和肝细胞增殖以及肝再生过程中肝标志物基因的表达。在严重的肝细胞耗竭后，BEC在斑马鱼幼体和成体中产生了大部分的再生肝细胞。肝细胞丧失后，BEC增殖，因为它们去分化成成肝细胞样细胞;它们随后分化成高度增殖的肝细胞，恢复肝脏质量。这一过程在斑马鱼wnt 2bb突变体中受损;在这些动物中，肝细胞再生，但它们的增殖大大减少。BEC有助于斑马鱼肝细胞大量耗竭后肝细胞的再生，从而导致严重肝损伤的恢复。
Biliary epithelial cells (BECs) are considered to be a source of regenerating hepatocytes when hepatocyte proliferation is compromised. However, there is still controversy about the extent to which BECs can contribute to the regenerating hepatocyte population, and thereby to liver recovery. To investigate this issue, we established a zebrafish model of liver regeneration in which the extent of hepatocyte ablation can be controlled. Hepatocytes were depleted by administration of metronidazole to Tg(fabp10a:CFP-NTR) animals. We traced the origin of regenerating hepatocytes using short-term lineage tracing experiments as well as the inducible Cre/loxP system; specifically, we utilized both a BEC tracer lineTg(Tp1:CreERT2) and a hepatocyte tracer line Tg(fabp10a:CreERT2). We also examined BEC and hepatocyte proliferation as well as liver marker gene expression during liver regeneration. BECs gave rise to most of the regenerating hepatocytes in larval and adult zebrafish after severe hepatocyte depletion. Following hepatocyte loss, BECs proliferated as they dedifferentiated into hepatoblast-like cells; they subsequently differentiated into highly proliferative hepatocytes that restored the liver mass. This process was impaired in zebrafish wnt2bb mutants; in these animals, hepatocytes regenerated but their proliferation was greatly reduced. BECs contribute to regenerating hepatocytes following substantial hepatocyte depletion in zebrafish, thereby leading to recovery from severe liver damage.
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