成体肝细胞的可塑性和细胞命运的重新调整：一种新的肝病

StephenW

Plasticity of adult hepatocytes and readjustment of cell fate: a novel dogma in liver disease

    Francisco Javier Cubero1,2, Maria Luz Martinez-Chantar3

Author affiliations

    Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
    Department of Immunology, Complutense University School of Medicine, Madrid, Spain
    Liver Disease Lab, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain

    Correspondence to Maria Luz Martinez-Chantar, Department of Metabolomic Unit, CICbioGUNE, Derio 48160, Spain; [email protected]

http://dx.doi.org/10.1136/gutjnl-2019-318218

   
Acute liver failure (ALF) is a life-threatening syndrome characterised by rapid hepatocellular necrosis due to various types of insults including drugs, autoimmune disorders or viral infections, and thus represents a disease with high mortality and elevated societal costs. At present, most ALF treatment strategies are rather aimed at simply preventing complications and decelerating disease progression. Unfortunately, the only curative treatment for ALF at present is liver transplantation, an option which is limited due to financial constraints, shortage of donor livers and immunosuppression-related complications.1 Therefore, novel therapeutic avenues for patients with ALF are urgently needed.

Normally, mature hepatocytes can orchestrate liver regeneration on loss of liver mass. When severe liver insult occurs, however, hepatocytes are unable to differentiate and hepatic progenitor cells (HPCs) are activated. HPCs, embryonic stem cells (ES) and induced pluripotent stem cells (iPS) have been considered a potential source for cell replacement in the injured liver since they possess hepatic differentiation capacity.2 However, their clinical applicability remains still controversial. For long, it has been widely assumed that hepatocytes do not contribute directly to the progenitor or stem cell compartment. Recently, Chen and colleagues2 reported the dedifferentiation of progenitor cells from isolated mature hepatocytes, refuting the current dogma.

Yet to be explored was the identification of molecular cascades that specifically dedifferentiate mature hepatocytes and activate a ‘fetal programme’. The Hippo/Yes-associated protein (YAP)-signalling pathway plays an essential role by determining cellular fates in the mammalian liver. Hippo signalling controls the phosphorylation of the transcriptional co-activator YAP whose constitutive activation in …

StephenW

成体肝细胞的可塑性和细胞命运的重新调整：一种新的肝病教条

    Francisco Javier Cubero1,2，Maria Luz Martinez-Chantar3

作者隶属关系

    德国亚琛亚琛工业大学医学院III
    西班牙马德里康普顿斯大学医学院免疫学系
    肝病实验室，CIC bioGUNE，CentrodeInvestigaciónBiomédicaenRed deEnfermedadesHepáticasyDigestivas（CIBERehd），Derio，Bizkaia，Spain

    与西班牙德里奥48160 CICbioGUNE代谢组科Maria Luz Martinez-Chantar的通信; [email protected]

http://dx.doi.org/10.1136/gutjnl-2019-318218

   
急性肝衰竭（ALF）是一种威胁生命的综合征，其特征在于由于各种类型的损伤（包括药物，自身免疫性疾病或病毒感染）导致的快速肝细胞坏死，因此代表具有高死亡率和高社会成本的疾病。目前，大多数ALF治疗策略旨在简单地预防并发症和减缓疾病进展。不幸的是，目前对ALF唯一的治疗方法是肝移植，由于经济上的限制，供体肝脏缺乏和免疫抑制相关的并发症，这一选择受到限制。因此，迫切需要为ALF患者提供新的治疗途径。

通常，成熟的肝细胞可以在肝脏质量损失时协调肝脏再生。然而，当发生严重的肝脏损伤时，肝细胞不能分化并且肝祖细胞（HPC）被激活。 HPC，胚胎干细胞（ES）和诱导多能干细胞（iPS）被认为是受损肝脏细胞替代的潜在来源，因为它们具有肝分化能力.2但是，它们的临床适用性仍然存在争议。长期以来，人们普遍认为肝细胞不直接贡献于祖细胞或干细胞区室。最近，陈和他的同事们报道了来自孤立的成熟肝细胞的祖细胞的去分化，驳斥了目前的教条。

尚待探索的是鉴定特异性去分化成熟肝细胞并激活“胎儿程序”的分子级联反应。 Hippo / Yes相关蛋白（YAP） - 信号通路通过测定哺乳动物肝脏中的细胞命运起着重要作用。 Hippo信号控制转录共激活因子YAP的磷酸化，其在...中的组成型激活