Contribution of mature hepatocytes to small hepatocyte-like progenitor cells in retrorsine-exposed rats with chimeric livers
Contribution of mature hepatocytes to small hepatocyte-like progenitor cells in retrorsine-exposed rats with chimeric livers
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DOI：
10.1002/hep.26104
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发表时间：
2013-03-01
期刊：
影响因子：
13.5
通讯作者：
Chen, Hui-Ling
中科院分区：
文献类型：
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作者：
Chen, Ya-Hui;Chang, Mei-Hwei;Chen, Hui-Ling
肝卵圆细胞、小肝细胞样祖细胞(SHPC)和肝细胞在肝再生中的潜在谱系关系一直存在争议。为检测成熟肝细胞能否产生SHPC，将内源性DPPIV缺陷肝细胞与DPPIV阳性肝细胞移植后，行逆转录激素治疗后行肝部分切除(PH)。DPPIV阳性肝细胞约占DPPIV嵌合肝质量的一半。经逆转录病毒/PH处理后的DPPIV嵌合肝组织显示大量SHPC簇。在任何分析样本中，SHPC簇均未显示DPPIV阳性。此外，GGT(胎肝母细胞标志)和葡萄糖-6-磷酸酶(G6Pase，成熟肝细胞标志)染色的连续切片显示，这两种酶的表达相反，并且染色模式与单个SHPC簇中从GGT(+)/G6Pase()到GGT()/G6Pase(+)的谱系一致。连续切片免疫荧光双标记法显示，CK-19(+)/laminin(+)和OV-6(+)/C/EBP-(+)的卵圆细胞从汇管区向SPHC簇内延伸，逐渐丧失CK-19/laminin表达，向簇侧出现C/EBP-表达，分化为肝细胞系。上皮细胞黏附分子(EpCAM(+))SHPC簇中的细胞呈膜性EpCAM(+)/HNF-4(+)(肝细胞核因子-4)染色，与周围胞质EpCAM(+)/HNF-4()导管状卵圆细胞毗邻。重复给予4，4-亚甲基二苯胺(DAPM)可广泛消除反式维甲酸暴露大鼠的卵圆细胞反应，削弱SHPC簇的出现。结论：这些发现高度提示反式维甲酸暴露的大鼠肝卵圆细胞而不是成熟肝细胞是SHPC簇的来源。(2013年《国际肝病》)
The potential lineage relationship between hepatic oval cells, small hepatocyte-like progenitor cells (SHPCs), and hepatocytes in liver regeneration is debated. To test whether mature hepatocytes can give rise to SHPCs, rats with dipeptidyl peptidase IV (DPPIV) chimeric livers, which harbored endogenous DPPIV-deficient hepatocytes and transplanted DPPIV-positive hepatocytes, were subjected to retrorsine treatment followed by partial hepatectomy (PH). DPPIV-positive hepatocytes comprised about half of the DPPIV chimeric liver mass. Tissues from DPPIV chimeric livers after retrorsine/PH treatment showed large numbers of SHPC clusters. None of the SHPC clusters were stained positive for DPPIV in any analyzed samples. Furthermore, serial sections stained for gamma-glutamyl-transpeptidase (GGT, a marker of fetal hepatoblasts) and glucose-6-phosphatase (G6Pase, a marker of mature hepatocytes) showed inverse expression of the two enzymes and a staining pattern consistent with a lineage that begins with GGT(+)/G6Pase() to GGT()/G6Pase(+) within a single SHPC cluster. Using double immunofluorescence staining for markers specific for hepatic oval cells and hepatocytes in serial sections, oval cell proliferations with CK-19(+)/laminin(+) and OV-6(+)/C/EBP-() were shown to extend from periportal areas into the SPHC clusters, differentiating into hepatic lineage by progressive loss of CK-19/laminin expression and appearance of C/EBP- expression towards the cluster side. Cells in the epithelial cell adhesion molecule (EpCAM(+)) SHPC clusters showed membranous EpCAM(+)/HNF-4(+) (hepatocyte nuclear factor-4) staining and were contiguous to the surrounding cytoplasmic EpCAM(+)/HNF-4() ductular oval cells. Extensive elimination of oval cell response by repeated administration of 4,4-methylenedianiline (DAPM) to retrorsine-exposed rats impaired the emergence of SHPC clusters. Conclusion: These findings highly suggest the hepatic oval cells but not mature hepatocytes as the origin of SHPC clusters in retrorsine-exposed rats. (HEPATOLOGY 2013)