Hepatocyte-to-cholangiocyte conversion occurs through transdifferentiation independently of proliferation in zebrafish.
Hepatocyte-to-cholangiocyte conversion occurs through transdifferentiation independently of proliferation in zebrafish.
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DOI：
10.1097/hep.0000000000000016
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发表时间：
2023-04-01
期刊：
影响因子：
13.5
通讯作者：
Shin, Donghun
中科院分区：
文献类型：
--
作者：
Lee, Seung-Hoon;So, Juhoon;Shin, Donghun
肝胆管胆上皮细胞（BECs）损伤可导致胆汁淤积性肝病。在严重的胆道损伤时，肝细胞可以转化为BECs，从而有助于肝脏的恢复。考虑到增加这种肝细胞到bec的转化作为胆汁淤积性肝病的治疗选择的潜力，彻底了解转化过程的细胞和分子机制将是重要的。为此，我们利用Tg（fabp10a:CFP-NTR）斑马鱼在再生过程中暂时抑制Notch信号，建立了肝细胞向bec转化的斑马鱼模型。Cre/ loxp介导的永久和h2b - mcherry介导的短期谱系追踪显示，在模型中，所有BECs都起源于肝细胞。在转化过程中，BEC标记按照Sox9b、Yap/Taz、Notch活性/epcam、Alcama/krt18的顺序依次诱导；肝细胞标志物Bhmt的表达在Sox9b和Yap/Taz诱导之间消失。重要的是，实时延时成像明确地揭示了肝细胞向BECs的转分化：肝细胞转化为BECs而不经过增殖中间状态的过渡。此外，利用化合物和转基因和突变系调节Notch和Yap信号，我们发现即使在Notch和Yap过度激活的情况下，转换也需要Notch和Yap信号。肝细胞到bec的转化是通过独立于增殖的转分化发生的，Notch和Yap信号通过相互积极的相互作用并行地控制着这一过程。新的斑马鱼模型将进一步有助于彻底了解转化过程的机制。
Injury to biliary epithelial cells (BECs) lining the hepatic bile ducts leads to cholestatic liver diseases. Upon severe biliary damage, hepatocytes can convert to BECs, thereby contributing to liver recovery. Given a potential of augmenting this hepatocyte-to-BEC conversion as a therapeutic option for cholestatic liver diseases, it will be important to thoroughly understand the cellular and molecular mechanisms of the conversion process. Towards this aim, we have established a zebrafish model for hepatocyte-to-BEC conversion by employing Tg(fabp10a:CFP-NTR) zebrafish with a temporal inhibition of Notch signaling during regeneration. Cre/loxP-mediated permanent and H2B-mCherry-mediated short-term lineage tracing revealed that in the model, all BECs originate from hepatocytes. During the conversion, BEC markers are sequentially induced in the order of Sox9b, Yap/Taz, Notch activity/epcam, and Alcama/krt18; the expression of the hepatocyte marker Bhmt disappears between the Sox9b and Yap/Taz induction. Importantly, live time-lapse imaging unambiguously revealed transdifferentiation of hepatocytes into BECs: hepatocytes convert to BECs without transitioning through a proliferative intermediate state. In addition, using compounds and transgenic and mutant lines that modulate Notch and Yap signaling, we found that both Notch and Yap signaling are required for the conversion even in Notch- and Yap-overactivating settings. Hepatocyte-to-BEC conversion occurs through transdifferentiation independently of proliferation, and Notch and Yap signaling control the process in parallel with a mutually positive interaction. The new zebrafish model will further contribute to a thorough understanding of the mechanisms of the conversion process.