MiR-122 in hepatic function and liver diseases

As the most abundant liver-specific microRNA,mi-croRNA-122(miR-122)is involved in various physio-logical processes in hepatic function as well as in liver pathology.There is now compelling evidence that miR-122,as a regulator of gene networks and pathways in hepatocytes,plays a central role in diverse aspects of hepatic function and in the progress of liver diseases.This liver-enriched transcription factors-regulated miRNA promotes differentiation of hepatocytes and regulates lipid metabolism.With regard to liver diseases,miR-122 was shown to stimulate hepatitis C virus(HCV)replication through a unique and unusual interaction with two binding sites in the 5′-UTR of HCV genome to mediate the stability of the viral RNA,whereas inhibit the expression and replication of hepatitis B virus(HBV)by a miR-122-cylin G1/p53-HBV enhancer regulatory pathway.In addition,miR-122 acts as a suppressor of cell prolif-eration and malignant transformation of hepatocytes with remarkable tumor inhibition activity.Notably,a clinical trial targeting miR-122 with the anti-miR-122 oli-gonucleotides miravirsen,the first miRNA targeted drug,has been initiated for treatment of HCV infection.With further understanding of the comprehensive roles of miR-122 in hepatic functions and the mechanisms in-volved in miR-122 down-regulation in chronic hepatitis or hepatocellular carcinoma,miR-122 appears to be a promising candidate for effective therapeutic ap-proaches against tumor and infectious diseases.

Rapid generation of gene-targeted EPS-derived mouse models through tetraploid complementation

One major strategy to generate genetically modified mouse models is gene targeting in mouse embryonic stem(ES)cells,which is used to produce gene-targeted mice for wide applications in biomedicine.However,a major bottleneck in this approach is that the robustness of germiine transmission of gene-targeted ES cells can be significantly reduced by their genetic and epigenetic instability after long-term culturing,which impairs the efficiency and robustness of mouse model generation.Recently,we have established a new type of pluripotent cells termed extended pluripotent stem(EPS)cells,which have superior developmental potency and robust germline competence compared to conventional mouse ES cells.In this study,we demonstrate that mouse EPS cells well maintain developmental potency and genetic stability after long-term passage.Based on gene targeting in mouse EPS cells,we established a new approach to directly and rapidly generate gene-targeted mouse models through tetraploid complementation,Haibo Li and Chaoran Zhao contributed equally to this work.Electronic supplementary material The online version of this article(https://doi.org/10.1007/s13238-018-0556-1)contains supplementary material,which is available to authorized users.which could be accomplished in approximately 2 months.Importantly,using this approach,we successfully constructed mouse models in which the human interleukin 3(IL3)or interleukin 6(IL6)gene was knocked into its corresponding locus in the mouse genome.Our study demonstrates the feasibility of using mouse EPS cells to rapidly generate mouse models by gene targeting,which have great application potential in biomedical research.

Correction to:Efficient derivation of extended pluripotent stem cells from NOD-scid II2rg^-/-mice

Figure 1.Generation of NOD-scid II2rg^-1-extended pluripotent stem cells.(A)Schematic of two approaches used for generating NOD-scid II2rg^-1-extended pluripotent stem cells:de novo derivation from blastocysts(upper panels)and chemical reprogramming from embryonic fibroblasts(lower panels).(B)Phase-contrast images of de novo derived outgrowth and EPS colonies for 17 passages in LCDM medium.Scale bars,100 pm.(C)qRT-PCR analysis of XEN marker genes expression during the chemical induction process(day 16).Error bars indicate SEM(n=2).(D)Co-immunostaining of XEN marker genes during the chemical induction process(day 16).Upper panels:GATA6 and SALL4;lower panels:SOX17 and SALL4.Scale bars,100 pm.

Efficient derivation of extended pluripotent stem cells from NOD-scid II2rg-/-mice

Recently we have established a new culture condition enabling the derivation of extended pluripotent stem(EPS)cells,which,compared to conventional pluripotent stem cells,possess superior developmental potential and germline competence.However,it remains unclear whether this condition permits derivation of EPS cells from mouse strains that are refractory or non-permissive to pluripotent cell establishment.Here,we show that EPS cells can be robustly generated from non-permissive NOD-sc/d Il2rg 1 mice through de novo derivation from blastocysts.Furthermore,these cells can also be efficiently generated by chemical reprogramming from embryonic NOD-sc/d II2rg-/-fibroblasts.NOD-sc/d II2rg-/-EPS cells can be expanded for more than 20 passages with genomic stability and can be genetically modified through gene targeting.Notably,these cells contribute to both embryonic and extraembryonic lineages in vivo.More importantly,they can produce chimeras and integrate into the E13.5 genital ridge.Our study demonstrates the feasibility of generating EPS cells from refractory mouse strains,which could potentially be a general strategy for deriving mouse pluripotent cells.The generation of NOD-sc/d II2rg-/-Yaqin Du and Ting Wang contributed equally to this work.Electronic supplementary material The online version of this article(https://doi.org/10.1007/s13238-018-0558-z)contains supplementary material,which is available to authorized users.EPS cell lines permits sophisticated genetic modification in NOD-scid II2rg-/-mice,which may greatly advance the optimization of humanized mouse models for biomedical applications.