Suksaweang Sanong, Lin Chih-Min, Jiang Ting-Xin, Hughes Michael W, Widelitz Randall B, Chuong Cheng-Ming
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Dev Biol. 2004 Feb 1;266(1):109-22. doi: 10.1016/j.ydbio.2003.10.010.
During development and regeneration, new cells are added and incorporated to the liver parenchyma. Regulation of this process contributes to the final size and shape of the particular organs, including the liver. We identified the distribution of liver growth zones using an embryonic chicken model because of its accessibility to experimentation. Hepatocyte precursors were first generated all over the primordia surrounding the vitelline blood vessel at embryonic day 2 (E2), then became limited to the peripheral growth zones around E6. Differentiating daughter cells of the peripheral hepatocyte precursors were shown by DiI microinjection to be laid inward and were subsequently organized to form the hepatic architecture. At E8, hepatocyte precursor cells were further restricted to limited segments of the periphery, called localized growth zones (LoGZ). Adhesion and signaling molecules in the growth zone were studied. Among them, beta-catenin and Wnt 3a were highly enriched. We overexpressed constitutively active beta-catenin using replication competent avian sarcoma (RCAS) virus. Liver size increased about 3-fold with an expanded hepatocyte precursor cell population. In addition, blocking beta-catenin activity by either overexpression of dominant-negative LEF1 or overexpression of a secreted Wnt inhibitor Dickkopf (DKK) resulted in decreased liver size with altered liver shape. Our data suggest that (1) the duration of active growth zone activity modulates the size of the liver; (2) a shift in the position of the localized growth zone helps to shape the liver; and (3) beta-catenin/Wnt are involved in regulating growth zone activities during liver development.
在发育和再生过程中，新细胞不断添加并整合到肝实质中。这一过程的调控有助于特定器官（包括肝脏）最终的大小和形状的形成。由于易于进行实验，我们利用胚胎鸡模型确定了肝脏生长区的分布。在胚胎第2天（E2）时，肝细胞前体首先在围绕卵黄血管的原基各处产生，然后在E6左右局限于外周生长区。通过DiI显微注射显示，外周肝细胞前体的分化子细胞向内排列，随后组织形成肝脏结构。在E8时，肝细胞前体细胞进一步局限于外周的有限节段，即局部生长区（LoGZ）。我们研究了生长区中的黏附分子和信号分子。其中，β-连环蛋白和Wnt 3a高度富集。我们使用具有复制能力的禽肉瘤（RCAS）病毒组成性过表达活性β-连环蛋白。随着肝细胞前体细胞群体的扩大，肝脏大小增加了约3倍。此外，通过过表达显性负性LEF1或过表达分泌型Wnt抑制剂Dickkopf（DKK）来阻断β-连环蛋白活性，会导致肝脏大小减小且肝脏形状改变。我们的数据表明：（1）活跃生长区活动的持续时间调节肝脏大小；（2）局部生长区位置的改变有助于塑造肝脏形状；（3）β-连环蛋白/Wnt参与肝脏发育过程中生长区活动的调节。
