SOX9 contributes to the progression of ductular reaction for the protection from chronic liver injury
SOX9 contributes to the progression of ductular reaction for the protection from chronic liver injury
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DOI：
10.1007/s13577-022-00683-8
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发表时间：
2022-02
期刊：
影响因子：
4.3
通讯作者：
D. Yoshii;K. Shimata;Y. Yokouchi;Y. Komohara;H. Suda;M. Honda;K. Yamamura;T. Hibi;Y. Inomata
中科院分区：
文献类型：
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作者：
D. Yoshii;K. Shimata;Y. Yokouchi;Y. Komohara;H. Suda;M. Honda;K. Yamamura;T. Hibi;Y. Inomata
转录因子性别决定区 Y-box 9 (SOX9) 是在肝细胞 (SOX9 + 肝细胞) 中异位表达的胆道上皮标记物。 SOX9 + 肝细胞被认为在导管反应（DR）中发挥作用，被认为是与肝脏再生相关的重要现象；然而，SOX9 的功能作用以及 SOX9 + 肝细胞在 DR 进展中的临床意义尚不清楚。对人和小鼠肝脏样本进行免疫组织化学和基因功能分析，以研究 SOX9 的功能作用以及 SOX9 + 肝细胞的临床意义。在胆管结扎 (BDL) 小鼠模型中观察到 SOX9++ 肝细胞。通过流体动力注射在小鼠肝细胞中强制表达 Sox9，将其转化为胆管细胞样细胞。肝上皮特异性 Sox9 敲除 BDL 小鼠的 DR 进展比野生型 BDL 小鼠慢。 SOX9 + 肝细胞也在罕见的儿童肝病胆道闭锁（BA）中观察到。在接受肝移植（LT）的BA患者中，LT时SOX9 + 肝细胞的中位数显着低于LT前进行的Kasai门肠造口术（KP）（P<0.001）。在 KP 处的高 SOX9 + 肝细胞组表现出比低 SOX9 + 肝细胞组在 390 个细胞/mm2 截止值时显着更高的天然肝脏存活率（P= 0.019，对数秩检验）。 SOX9 在慢性损伤肝脏的肝细胞中异位表达可能对 DR 进展发挥保护作用。据我们所知，这是第一项研究表明 KP 时的 SOX9 + 肝细胞计数可以成为预测 BA 患者 KP 后天然肝脏存活的有前景的生物标志物。
The transcription factor sex-determining region Y-box 9 (SOX9)is a biliary epithelial marker ectopically expressed in hepatocytes (SOX9 + hepatocytes). SOX9 + hepatocytes are believed to function in ductular reaction (DR), recognized as an essential phenomenon related to liver regeneration; however, the functional role of SOX9 and clinical implications of SOX9 + hepatocytes in DR progression are unclear. Human and mouse liver samples were subjected to immunohistochemical and gene functional analyses to investigate the functional role of SOX9 and the clinical significance of SOX9 + hepatocytes. SOX9 + hepatocytes were observed in a bile duct ligation (BDL) mouse model. ForcedSox9expression in mouse hepatocytes by hydrodynamic injection converted them into cholangiocyte-like cells. DR progression was slower in liver epithelium-specificSox9-knockout BDL mice than in wild-type BDL mice. SOX9 + hepatocytes were also observed in rare pediatric liver disease biliary atresia (BA). In patients with BA who underwent liver transplantation (LT), the median number of SOX9 + hepatocytes at LT was significantly lower than that at Kasai portoenterostomy (KP) performed prior to LT (P< 0.001). The high SOX9 + hepatocyte group at KP demonstrated significantly better native liver survival rates than the low SOX9 + hepatocyte group at a cut-off of 390 cells/mm2(P= 0.019, log-rank test). Ectopic expression of SOX9 in hepatocytes of chronically injured livers may exert protective effects in DR progression. To our knowledge, this is the first study showing that SOX9 + hepatocyte count at KP can be a promising biomarker to predict native liver survival after KP in patients with BA.