Kamiya A, Kinoshita T, Ito Y, Matsui T, Morikawa Y, Senba E, Nakashima K, Taga T, Yoshida K, Kishimoto T, Miyajima A
Laboratory of Cellular Biosynthesis, Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, 113-0032 Tokyo.
EMBO J. 1999 Apr 15;18(8):2127-36. doi: 10.1093/emboj/18.8.2127.
Fetal liver, the major site of hematopoiesis during embryonic development, acquires additional various metabolic functions near birth. Although liver development has been characterized biologically as consisting of several distinct steps, the molecular events accompanying this process are just beginning to be characterized. In this study, we have established a novel culture system of fetal murine hepatocytes and investigated factors required for development of hepatocytes. We found that oncostatin M (OSM), an interleukin-6 family cytokine, in combination with glucocorticoid, induced maturation of hepatocytes as evidenced by morphological changes that closely resemble more differentiated hepatocytes, expression of hepatic differentiation markers and intracellular glycogen accumulation. Consistent with these in vitro observations, livers from mice deficient for gp130, an OSM receptor subunit, display defects in maturation of hepatocytes. Interestingly, OSM is expressed in CD45(+) hematopoietic cells in the developing liver, whereas the OSM receptor is expressed predominantly in hepatocytes. These results suggest a paracrine mechanism of hepatogenesis; blood cells, transiently expanding in the fetal liver, produce OSM to promote development of hepatocytes in vivo.
胎儿肝脏是胚胎发育过程中的主要造血部位，在临近出生时获得了多种额外的代谢功能。尽管肝脏发育在生物学上已被描述为由几个不同阶段组成，但其伴随这一过程的分子事件才刚刚开始被阐明。在本研究中，我们建立了一种新型的胎鼠肝细胞培养系统，并研究了肝细胞发育所需的因子。我们发现，抑瘤素M（OSM），一种白细胞介素-6家族细胞因子，与糖皮质激素联合使用时，可诱导肝细胞成熟，这表现为形态学变化与更分化的肝细胞非常相似、肝分化标志物的表达以及细胞内糖原积累。与这些体外观察结果一致，缺乏OSM受体亚基gp130的小鼠肝脏显示出肝细胞成熟缺陷。有趣的是，OSM在发育中的肝脏中的CD45(+)造血细胞中表达，而OSM受体主要在肝细胞中表达。这些结果提示了一种肝脏发生的旁分泌机制；在胎儿肝脏中短暂增殖的血细胞产生OSM以促进体内肝细胞的发育。
