Global gene expression profiling reveals a key role of CD44 in hepatic oval-cell reaction after 2-AAF/CCl4 injury in rodents
Global gene expression profiling reveals a key role of CD44 in hepatic oval-cell reaction after 2-AAF/CCl4 injury in rodents
复制标题
DOI：
10.1007/s00418-009-0634-9
复制
发表时间：
2009-11-01
影响因子：
2.3
通讯作者：
Lee, Hsuan-Shu
中科院分区：
文献类型：
--
作者：
Chiu, Chien-Chang;Sheu, Jin-Chuan;Lee, Hsuan-Shu
肝祖细胞，即所谓的卵圆细胞，在严重肝损伤后肝细胞再生受损时从门静脉周围区域显著增殖。这些细胞侵入肝实质很深。卵圆细胞这些行为的分子机制仍然知之甚少。在这项研究中，我们用2-乙酰氨基芴/四氯化碳诱导大鼠肝卵圆细胞。通过表达微阵列分析，我们研究了肝组织中的全球基因表达谱，重点是粘附分子，细胞外基质蛋白，基质金属蛋白酶（MMPs），生长因子/细胞因子和受体，可能有助于卵圆细胞的独特行为。选择上调至少两倍的基因。然后，我们进行免疫染色，以验证微阵列的结果，并确定MMP-7和CD 44在卵圆细胞的表达。细胞角蛋白（CK）-19，一个卵圆细胞标记物，染色之间的卵圆细胞位于门静脉周围地区和那些位于远离实质。与此相反，CD 44染色更强烈的实质比在门静脉周围地区，表明CD 44的作用，卵圆细胞的侵袭。此外，病灶内新分化的CK-19（+）肝细胞未显示CD 44染色，表明CD 44与未分化的卵圆细胞表型相关。然后，我们研究了在CD 44缺陷小鼠的卵圆细胞诱导饮食的3，5-二乙氧羰基-1，4-二氢可力丁的卵圆细胞反应。结果显示，CD 44缺陷小鼠卵圆细胞反应性显著降低。因此，卵圆细胞表达MMP-7和CD 44，并且CD 44似乎在啮齿动物肝卵圆细胞的增殖、侵袭和分化中起关键作用。
Liver progenitors, so-called oval cells, proliferate remarkably from periportal areas after severe liver injury when hepatocyte regeneration is compromised. These cells invade far into the liver parenchyma. Molecular mechanisms underlying these behaviors of oval cells remain poorly understood. In this study, we treated rats with 2-acetylaminofluorene/carbon tetrachloride to induce hepatic oval cells. By expression microarray analysis, we investigated global gene expression profiles in liver tissue, with an emphasis on adhesion molecules, extracellular matrix proteins, matrix metalloproteinases (MMPs), growth factors/cytokines, and receptors that might contribute to the distinct behaviors of oval cells. Genes upregulated at least twofold were selected. We then performed immunostaining to verify the microarray results and identified expression of MMP-7 and CD44 in oval cells. Staining of cytokeratin (CK)-19, an oval-cell marker, was similar between oval cells located next to periportal areas and those located far within the parenchyma. In contrast, CD44 staining was more intense in the parenchyma than in periportal areas, suggesting a role of CD44 in oval-cell invasion. Moreover, newly differentiated CK-19(+) hepatocytes within foci did not show CD44 staining, suggesting that CD44 is related to the undifferentiated oval-cell phenotype. We then investigated oval-cell reactivity in CD44-deficient mice fed an oval cell-inducing diet of 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Results showed significantly reduced oval-cell reactivity in CD44-deficient mice. Thus, oval cells express MMP-7 and CD44, and CD44 appears to play critical roles in the proliferation, invasion, and differentiation of hepatic oval cells in rodents.