Biliary fibrosis drives liver repopulation and phenotype transition of transplanted hepatocytes.
Biliary fibrosis drives liver repopulation and phenotype transition of transplanted hepatocytes.
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DOI：
10.1016/j.jhep.2016.01.036
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发表时间：
2016-06
影响因子：
25.7
通讯作者：
Oertel M
中科院分区：
文献类型：
--
作者：
Yovchev MI;Locker J;Oertel M
目前的研究重点是开发替代策略，在终末期肝病发生之前恢复减少的肝脏质量。细胞植入/再生需要在正常肝脏中再生，但我们已经证明，严重的肝损伤可以刺激再生，而不需要肝部分切除(PH)。我们现在已经调查了不太严重的损伤，继发性胆管纤维化，是否会促使异位移植的成熟肝细胞植入/再生。采用胆总管结扎法诱导−F344大鼠胆管增生和进行性纤维化。将纯化的DPPIV+/GFP+肝细胞在不含PH的情况下注入BDL大鼠的脾内，并与无BDL的大鼠进行比较。1周内，在肝门管区和扩张的门管区周边可检测到移植肝细胞。在BDL大鼠体内观察到DPPIV+/GFP+重新填充大小不等的细胞团，但未观察到未经处理的正常受体。令人惊讶的是，一些移植的肝细胞在重新填充的簇内形成了表达CK-19/claudin-7的上皮细胞，类似于胆管细胞。此外，大量移植于脾内注射部位的肝细胞聚集成多细胞群。这些结果还显示，接受BDL治疗的大鼠脾内注射部位的大部分胆汁“转分化”，但未接受治疗的受体大鼠则没有。基因芯片分析显示骨桥蛋白(SPP1)表达上调。细胞培养结果显示，在骨桥蛋白作用下，肝细胞ITGβ4、hNF1β、hNF6、SOX-9和CK-19mRNA表达增加，提示该分泌蛋白促进肝细胞去分化。我们的研究表明，胆道纤维化通过异位移植的肝细胞刺激肝脏再生，也刺激肝细胞向胆管上皮表型转变。字数：249
Current research focuses on developing alternative strategies to restore decreased liver mass prior to the onset of endstage liver disease. Cell engraftment/repopulation requires regeneration in normal liver, but we have shown that severe liver injury stimulates repopulation without partial hepatectomy (PH). We have now investigated whether a less severe injury, secondary biliary fibrosis, would drive engraftment/repopulation of ectopically transplanted mature hepatocytes. Ductular proliferation and progressive fibrosis in DPPIV− F344 rats was induced by common bile duct ligation (BDL). Purified DPPIV+/GFP+ hepatocytes were infused without PH into the spleen of BDL rats and compared to rats without BDL. Within one week, transplanted hepatocytes were detected in hepatic portal areas and at the periphery of expanding portal regions. DPPIV+/GFP+ repopulating cell clusters of different sizes were observed in BDL rats but not untreated normal recipients. Surprisingly, some engrafted hepatocytes formed CK-19/claudin-7 expressing epithelial cells resembling cholangiocytes within repopulating clusters. In addition, substantial numbers of hepatocytes engrafted at the intrasplenic injection site assembled into multicellular groups. These also showed biliary “transdifferentiation” in the majority of intrasplenic injection sites of rats that received BDL but not in untreated recipients. PCR array analysis showed up-regulation of osteopontin (SPP1). Cell culture studies demonstrated increased Itgβ4, HNF1β, HNF6, Sox-9, and CK-19 mRNA expression in hepatocytes incubated with osteopontin, suggesting that this secreted protein promotes dedifferentiation of hepatocytes. Our studies show that biliary fibrosis stimulates liver repopulation by ectopically transplanted hepatocytes and also stimulates hepatocyte transition towards a biliary epithelial phenotype. Words: 249