Expression of hepatic transcription factors during liver development and oval cell differentiation.
Expression of hepatic transcription factors during liver development and oval cell differentiation.
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DOI：
10.1083/jcb.126.1.223
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发表时间：
1994-07
期刊：
影响因子：
--
通讯作者：
Thorgeirsson SS
中科院分区：
文献类型：
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作者：
Nagy P;Bisgaard HC;Thorgeirsson SS
卵圆细胞被认为是肝干细胞隔室的后代，并且现在存在强有力的证据表明这些细胞可以通过分化成不同的肝谱系来参与肝再生。为了更好地理解这一过程的调节，我们研究了肝富集转录因子（HNF 1 α和HNF 1 β，HNF 3 α，HNF 3 β和HNF 3 γ，HNF 4，C/EBP，C/EBP β和DBP）在卵圆细胞增殖和分化的实验模型中的表达，并将这些因子的表达与肝个体发育晚期观察到的表达进行了比较。在胚胎肝脏发育的后期，四种“肝脏富集”转录因子（HNF 1 α、HNF 3 α、HNF 4和C/EBP β）的稳态mRNA水平逐渐下降，而三种因子（HNF 1 β、HNF 3 β和DBP）则增加。在正常成年大鼠肝脏中，所有转录因子的表达仅限于肝细胞。然而，在卵圆细胞增殖的早期阶段，小胆管和大胆管都开始表达HNF 1 α和HNF 1 β、HNF 3 γ、C/EBP和DBP，但不表达HNF 4。在后期阶段，所有这些因子也在增殖的卵圆细胞中高度表达。当卵圆细胞在形态和功能上分化为肝细胞并形成嗜碱性灶时，首先观察到HNF 4的表达。此时，其他一些因素的表达也进一步增加。基于这些数据，我们认为“建立”因子（HNF 1和-3）的上调可能是卵圆细胞活化的重要步骤。这些因子在卵圆细胞和胚胎成肝细胞中的高水平进一步证实了两个细胞室之间的相似性。此外，这些数据表明，HNF 4可能是负责一小部分卵圆细胞的最终承诺，分化成肝细胞，形成嗜碱性灶，并最终再生肝实质。
The oval cells are thought to be the progeny of a liver stem cell compartment and strong evidence now exists indicating that these cells can participate in liver regeneration by differentiating into different hepatic lineages. To better understand the regulation of this process we have studied the expression of liver-enriched transcriptional factors (HNF1 alpha and HNF1 beta, HNF3 alpha, HNF3 beta, and HNF3 gamma, HNF4, C/EBP, C/EBP beta, and DBP) in an experimental model of oval cell proliferation and differentiation and compared the expression of these factors to that observed during late stages of hepatic ontogenesis. The steady-state mRNA levels of four (HNF1 alpha, HNF3 alpha, HNF4, and C/EBP beta) "liver-enriched" transcriptional factors gradually decrease during the late period of embryonic liver development while three factors (HNF1 beta, HNF3 beta, and DBP) increase. In the normal adult rat liver the expression of all the transcription factors are restricted to the hepatocytes. However, during early stages of oval cell proliferation both small and large bile ducts start to express HNF1 alpha and HNF1 beta, HNF3 gamma, C/EBP, and DBP but not HNF4. At the later stages all of these factors are also highly expressed in the proliferating oval cells. Expression of HNF4 is first observed when the oval cells differentiate morphologically and functionally into hepatocytes and form basophilic foci. At that time the expression of some of the other factors is also further increased. Based on these data we suggest that the upregulation of the "establishment" factors (HNF1 and -3) may be an important step in oval cell activation. The high levels of these factors in the oval cells and embryonic hepatoblasts further substantiates the similarity between the two cell compartments. Furthermore, the data suggest that HNF4 may be responsible for the final commitment of a small portion of the oval cells to differentiate into hepatocytes which form the basophilic foci and eventually regenerate the liver parenchyma.