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Bioinformatics analysis to screen key genes implicated in the differentiation of induced pluripotent stem cells to hepatocytes.

ABSTRACT: Due to the lack of potential organs, hepatocellular transplantation has been considered for treating end-stage liver disease. Induced pluripotent stem cells (iPSCs) are reverted from somatic cells and are able to differentiate into hepatocytes. The present study aimed to investigate the mechanisms underlying iPSC differentiation to hepatocytes. GSE66076 was downloaded from the Gene Expression Omnibus; this database includes data from 3 undifferentiated (T0), 3 definitive endoderm (T5), and 3 early hepatocyte (T24) samples across hepatic?directed differentiation of iPSCs. Differentially expressed genes (DEGs) between T0 and T5 or T24 samples were identified using the linear models for microarray data package in Bioconductor, and enrichment analyses were performed. Using the weighted correlation network analysis package in R, clusters were identified for the merged DEGs. Cytoscape was used to construct protein?protein interaction (PPI) networks for DEGs identified to belong to significant clusters. Using the ReactomeFI plugin in Cytoscape, functional interaction (FI) networks were constructed for the common genes. A total of 433 and 1,342 DEGs were identified in the T5 and T24 samples respectively, compared with the T0 samples. Blue and turquoise clusters were identified as significant gene clusters. In the PPI network for DEGs in the blue cluster, the key node fibroblast growth factor 2 (FGF2) could interact with bone morphogenetic protein 2 (BMP2). Cyclin?dependent kinase 1 (CDK1) was demonstrated to have the highest degree (degree=71) in the PPI network for DEGs in the turquoise cluster. Enrichment analysis for the common genes, including hepatocyte nuclear factor 4? (HNF4A) and epidermal growth factor (EGF), in the FI network indicated that EGF and FGF2 were enriched in the Ras and Rap1 signaling pathways. The present results suggest that FGF2, BMP2, CDK1, HNF4A and EGF may participate in the differentiation of iPSCs into hepatocytes.

SUBMITTER: Lin R

PROVIDER: S-EPMC5802208 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Bioinformatics analysis to screen key genes implicated in the differentiation of induced pluripotent stem cells to hepatocytes.

Lin Rui R Wang Yufeng Y Ji Kun K Liu Zhongyan Z Xiao Shuai S Zhou Dehua D Chen Quanning Q Shi Baomin B

Molecular medicine reports 20180105 3

Due to the lack of potential organs, hepatocellular transplantation has been considered for treating end-stage liver disease. Induced pluripotent stem cells (iPSCs) are reverted from somatic cells and are able to differentiate into hepatocytes. The present study aimed to investigate the mechanisms underlying iPSC differentiation to hepatocytes. GSE66076 was downloaded from the Gene Expression Omnibus; this database includes data from 3 undifferentiated (T0), 3 definitive endoderm (T5), and 3 ear ...[more]

PMID: 29328449

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Project description:BackgroundThe regeneration of muscle cells from stem cells is an intricate process, and various genes are included in the process such as myoD, mf5, mf6, etc. The key genes and pathways in the differentiating stages are various. Therefore, the differential expression of key genes after 4?weeks of differentiation were investigated in our study.MethodThree published gene expression profiles, GSE131125, GSE148994, and GSE149055, about the comparisons of pluripotent stem cells to differentiated cells after 4?weeks were obtained from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (DEGs) were obtained for further analysis such as protein-protein interaction (PPI) network, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and GSEA analysis. After hub genes and key pathways were obtained, we manipulated in vitro cell research for substantiation such as immunohistochemical staining and semi-quantitative analysis and quantitative real-time PCR.ResultsA total of 824 DEGs including 350 upregulated genes and 474 downregulated genes were identified in the three GSEs. Nineteen hub genes were identified from the PPI network. The GO and KEGG pathway analyses confirmed that myogenic differentiation at 4?weeks was strongly associated with pathway in cancer, PI3K pathway, actin cytoskeleton regulation and metabolic pathway, biosynthesis of antibodies, and cell cycle. GSEA analysis indicated the differentiated cells were enriched in muscle cell development and myogenesis. Meanwhile, the core genes in each pathway were identified from the GSEA analysis. The in vitro cell research revealed that actin cytoskeleton and myoD were upregulated after 4-week differentiation.ConclusionsThe research revealed the potential hub genes and key pathways after 4-week differentiation of stem cells which contribute to further study about the molecular mechanism of myogenesis regeneration, paving a way for more accurate treatment for muscle dysfunction.

Project description:Background & aimsIncreased expression of IFN-stimulated gene 15 (ISG15) and subsequently increased ISGylation are key factors in the host response to viral infection. In this study, we sought to characterize the expression of ISG15, ISGylation, and associated enzymes at each stage of differentiation from induced pluripotent stem cells (iPSCs) to hepatocytes.MethodsTo study the regulation of ISGylation, we utilized patient samples and in vitro cell culture models including iPSCs, hepatocytes-like cells, immortalized cell lines, and primary human hepatocytes. Protein/mRNA expression were measured following treatment with poly(I:C), IFNα and HCV infection.ResultsWhen compared to HLCs, we observed several novel aspects of the ISGylation pathway in iPSCs. These include a lower baseline expression of the ISGylation-activating enzyme, UBE1L, a lack of IFN-induced expression of the ISGylation-conjugation enzyme UBE2L6, an attenuated activation of the transcription factor STAT1 and constitutive expression of SOCS1. ISGylation was observed in iPSCs following downregulation of SOCS1, which facilitated STAT1 activation and subsequently increased expression of UBE2L6. Intriguingly, HCV permissive transformed hepatoma cell lines demonstrated higher intrinsic expression of SOCS1 and weaker ISGylation following IFN treatment. SOCS1 downregulation in HCV-infected Huh 7.5.1 cells led to increased ISGylation.ConclusionsHerein, we show that high basal levels of SOCS1 inhibit STAT1 activation and subsequently IFN-induced UBE2L6 and ISGylation in iPSCs. Furthermore, as iPSCs differentiate into hepatocytes, epigenetic mechanisms regulate ISGylation by modifying UBE1L and SOCS1 expression levels. Overall, this study demonstrates that the development of cell-intrinsic innate immunity during the differentiation of iPSCs to hepatocytes provides insight into cell type-specific regulation of host defense responses and related oncogenic processes.Impact and implicationsTo elucidate the mechanism underlying regulation of ISGylation, a key process in the innate immune response, we studied changes in ISGylation-associated genes at the different stages of differentiation from iPSCs to hepatocytes. We found that high basal levels of SOCS1 inhibit STAT1 activation and subsequently IFN-induced UBE2L6 and ISGylation in iPSCs. Importantly, epigenetic regulation of SOCS1 and subsequently ISGylation may be important factors in the development of cell type-specific host defense responses in hepatocytes that should be considered when studying chronic infections and oncogenic processes in the liver.

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Bioinformatics analysis to screen key genes implicated in the differentiation of induced pluripotent stem cells to hepatocytes.

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Bioinformatics analysis to screen key genes implicated in the differentiation of induced pluripotent stem cells to hepatocytes.

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