PDF(Pubmed)
Abstract：
BACKGROUND: When massive necrosis occurs in acute liver failure (ALF), rapid expansion of HSCs called liver progenitor cells (LPCs) in a process called ductular reaction is required for survival. The underlying mechanisms governing this process are not entirely known to date. In ALF, high levels of retinoic acid (RA), a molecule known for its pleiotropic roles in embryonic development, are secreted by activated HSCs. We hypothesized that RA plays a key role in ductular reaction during ALF.
METHODS: RNAseq was performed to identify molecular signaling pathways affected by all-trans retinoid acid (atRA) treatment in HepaRG LPCs. Functional assays were performed in HepaRG cells treated with atRA or cocultured with LX-2 cells and in the liver tissue of patients suffering from ALF.
RESULTS: Under ALF conditions, activated HSCs secreted RA, inducing RARα nuclear translocation in LPCs. RNAseq data and investigations in HepaRG cells revealed that atRA treatment activated the WNT-β-Catenin pathway, enhanced stemness genes (SOX9, AFP, and others), increased energy storage, and elevated the expression of ATP-binding cassette transporters in a RARα nuclear translocation-dependent manner. Further, atRA treatment-induced pathways were confirmed in a coculture system of HepaRG with LX-2 cells. Patients suffering from ALF who displayed RARα nuclear translocation in the LPCs had significantly better MELD scores than those without.
CONCLUSIONS: During ALF, RA secreted by activated HSCs promotes LPC activation, a prerequisite for subsequent LPC-mediated liver regeneration.
METHODS: RNAseq was performed to identify molecular signaling pathways affected by all-trans retinoid acid (atRA) treatment in HepaRG LPCs. Functional assays were performed in HepaRG cells treated with atRA or cocultured with LX-2 cells and in the liver tissue of patients suffering from ALF.
RESULTS: Under ALF conditions, activated HSCs secreted RA, inducing RARα nuclear translocation in LPCs. RNAseq data and investigations in HepaRG cells revealed that atRA treatment activated the WNT-β-Catenin pathway, enhanced stemness genes (SOX9, AFP, and others), increased energy storage, and elevated the expression of ATP-binding cassette transporters in a RARα nuclear translocation-dependent manner. Further, atRA treatment-induced pathways were confirmed in a coculture system of HepaRG with LX-2 cells. Patients suffering from ALF who displayed RARα nuclear translocation in the LPCs had significantly better MELD scores than those without.
CONCLUSIONS: During ALF, RA secreted by activated HSCs promotes LPC activation, a prerequisite for subsequent LPC-mediated liver regeneration.
摘要：
背景：当急性肝衰竭（ALF）发生大面积坏死时，在称为导管反应的过程中，称为肝祖细胞（LPC）的HSC的快速扩增是存活所必需的。迄今为止，管理这一进程的基本机制尚不完全清楚。在ALF中,高水平的视黄酸（RA），一种以其在胚胎发育中多效作用而闻名的分子，由活化的HSC分泌。我们假设RA在ALF过程中的导管反应中起关键作用。
方法：进行RNAseq以鉴定HepaRGLPCs中全反式维甲酸（atRA）处理影响的分子信号通路。在用atRA处理或与LX-2细胞共培养的HepaRG细胞中以及患有ALF的患者的肝组织中进行功能测定。
结果：在ALF条件下，激活的HSC分泌RA，在LPCs中诱导RARα核易位。在HepaRG细胞中的RNAseq数据和研究表明，atRA治疗激活了WNT-β-Catenin通路，增强的干性基因(SOX9，AFP，和其他)，增加能量储存，并以RARα核易位依赖性方式提高了ATP结合盒转运蛋白的表达。Further,在HepaRG与LX-2细胞的共培养系统中证实了atRA治疗诱导的途径。在LPC中显示RARα核易位的患有ALF的患者的MELD评分明显优于没有的患者。
结论：在ALF期间，激活的HSC分泌的RA促进LPC激活，随后LPC介导的肝脏再生的先决条件。
方法：进行RNAseq以鉴定HepaRGLPCs中全反式维甲酸（atRA）处理影响的分子信号通路。在用atRA处理或与LX-2细胞共培养的HepaRG细胞中以及患有ALF的患者的肝组织中进行功能测定。
结果：在ALF条件下，激活的HSC分泌RA，在LPCs中诱导RARα核易位。在HepaRG细胞中的RNAseq数据和研究表明，atRA治疗激活了WNT-β-Catenin通路，增强的干性基因(SOX9，AFP，和其他)，增加能量储存，并以RARα核易位依赖性方式提高了ATP结合盒转运蛋白的表达。Further,在HepaRG与LX-2细胞的共培养系统中证实了atRA治疗诱导的途径。在LPC中显示RARα核易位的患有ALF的患者的MELD评分明显优于没有的患者。
结论：在ALF期间，激活的HSC分泌的RA促进LPC激活，随后LPC介导的肝脏再生的先决条件。
