FGF2 mediates hepatic progenitor cell formation during human pluripotent stem cell differentiation by inducing the WNT antagonist NKD1

Twaroski, Kirk; Mallanna, Sunil K.; Jing, Ran; DiFurio, Francesca; Urick, Amanda; Duncan, Stephen A.

doi:10.1101/gad.268961.115

Cited by 34 publications

(20 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, it is important to note that cell death per se should not be considered a criterion for exclusion because disruption of many developmentally important pathways can manifest in a cell death phenotype. For example, acute inhibition of FGF signaling blocks specification, but when the FGFR is chronically repressed it diminishes cell viability (Twaroski et al, 2015). With this in mind, if we avoid exclusion based solely on viability, several additional small molecules could be considered provocative.…”

Section: Discussionmentioning

confidence: 99%

“…In our screen, treatment with such small molecules usually resulted in a detrimental effect on cell viability as evidenced by loss of DAPI staining. We also identified small molecules targeting signaling pathways that are necessary for hepatic progenitor cell formation from pluripotent stem cells, including the FGF (PD161570) and WNT (XAV939) pathways (Twaroski et al, 2015). In addition to the known pathways, several of the small molecules that affected HNF4A protein levels were agonists or antagonists of kinases or signaling receptors.…”

Section: −26mentioning

confidence: 99%

“…We first considered the possibility that HSP90β interfered with HNF4A mRNA expression by repressing the FGF signaling pathway. FGF is crucial for hepatic specification and tissue growth through the activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathways (Jung et al, 1999;Calmont et al, 2006;Twaroski et al, 2015). It has been reported that HSP90β inhibition blocks MAPK1/3 (ERK1/2) and v-akt murine thymoma viral oncogene homolog 1 (AKT) activation, which are downstream effectors of the FGFR (Hackl et al, 2010).…”

Section: −26mentioning

confidence: 99%

See 2 more Smart Citations

A small-molecule screen reveals that HSP90β promotes the conversion of induced pluripotent stem cell-derived endoderm to a hepatic fate and regulates HNF4A turnover

Jing

Duncan

2017

Development

Self Cite

View full text Add to dashboard Cite

We have previously shown that the transcription factor HNF4A is required for the formation of hepatic progenitor cells from endoderm that has been derived from human induced pluripotent stem cells (iPSCs). We reasoned that we could uncover regulatory pathways with new roles in hepatocyte differentiation by identifying cellular processes that regulate HNF4A. We therefore performed a screen of 1120 small molecules with well-characterized mechanisms of action to detect those that affect the abundance of HNF4A in iPSC-derived hepatic progenitor cells. This approach uncovered several small molecules that depleted HNF4A. Of those, we chose to focus on an inhibitor of heat shock protein 90 beta (HSP90β). We show that mutation of the gene encoding HSP90β represses hepatocyte differentiation during the formation of hepatocytes from iPSCs. We reveal that HSP90β, although dispensable for expression of HNF4A mRNA, directly interacts with HNF4A protein to regulate its half-life. Our results demonstrate that HSP90β has an unappreciated role in controlling hepatic progenitor cell formation and highlight the efficiency of using small-molecule screens during the differentiation of iPSCs to reveal new molecular mechanisms that control hepatocyte formation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: −26mentioning

confidence: 99%

Section: −26mentioning

confidence: 99%

See 1 more Smart Citation

A small-molecule screen reveals that HSP90β promotes the conversion of induced pluripotent stem cell-derived endoderm to a hepatic fate and regulates HNF4A turnover

Jing

Duncan

2017

Development

Self Cite

View full text Add to dashboard Cite

show abstract

“…Using this approach, numerous novel FGF‐dependent immediate early genes whose expression was elevated during the specification of hepatic cells from the endoderm were identified. These studies revealed that the WNT signaling inhibitor naked cuticle homolog 1 was an FGFR immediate early gene that was essential for the transition of the endoderm to a hepatic fate …”

Section: Pscs As a Model Of Liver Developmentmentioning

confidence: 99%

The Use of Human Pluripotent Stem Cells for Modeling Liver Development and Disease

Heslop

Duncan

2019

Hepatology

Self Cite

View full text Add to dashboard Cite

The use of pluripotent stem cells (PSCs) has transformed the investigation of liver development and disease. Clinical observations and animal models have provided the foundations of our understanding in these fields. While animal models remain essential research tools, long experimental lead times and low throughput limit the scope of investigations. The ability of PSCs to produce large numbers of human hepatocyte‐like cells, with a given or modified genetic background, allows investigators to use previously incompatible experimental techniques, such as high‐throughput screens, to enhance our understanding of liver development and disease. In this review, we explore how PSCs have expedited our understanding of developmental mechanisms and have been used to identify new therapeutic options for numerous hepatic diseases. We discuss the future directions of the field, including how to further unlock the potential of the PSC model to make it amenable for use with a broader range of assays and a greater repertoire of diseases. Furthermore, we evaluate the current weaknesses of the PSC model and the directions open to researchers to address these limitations. Conclusion: The use of PSCs to model human liver disease and development has and will continue to have substantial impact, which is likely to further expand as protocols used to generate hepatic cells are improved.

show abstract

“…The JAK2 gene has been implicated in cytokine receptor signaling pathways and was identified to be associated with the reactions to human interferon-γ (29). The FGF2 protein is a member of the FGF family and is involved in wound healing, limb and nervous system development, and carcinoma growth (30). POLR2A encodes the largest subunit of RNA polymerase II, the product of this gene includes a carboxy-terminal domain composed of heptapeptide repeats, which are required for polymerase activity (31).…”

Section: Ppi Network and Module Constructionmentioning

confidence: 99%

Analysis of the function of microRNA-375 in humans using bioinformatics

Chen

Luo

et al. 2017

Biomedical Reports

View full text Add to dashboard Cite

Abstract. ) is expressed at low levels in many types of solid tumor, particularly in gastrointestinal tumors. It is considered to be important in the development of cancer and certain diseases. Thus, more detailed knowledge is required on the particular functions of miR-375. miRs function by regulating target genes. Therefore, in the current study, miRWalk (which includes the data from 10 prediction software programs) was used to predict the target genes of miR-375. The genes, which were co-predicted using five different software programs were further analyzed using Database for Annotation, Visualization and Integrated Discovery online software [including gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis]. Subsequently, the online tool, Search Tool for the Retrieval of Interacting Genes, was used to analyze the protein-protein interaction and construct modules using Cytoscape. The result demonstrated 6,574 predicted genes, 1,325 of which were co-predicted. The GO analysis result indicated that, in biological processes, the co-predicted genes were significantly enriched in the regulation of nervous system development and cell differentiation, and the highest enrichment of molecular function was ion binding. In KEGG analysis, the genes were enriched in the Hippo signaling pathway, glutamatergic synapse, circadian entrainment and the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway. The top 10 hub proteins were mechanistic target of rapamycin, PH domain and leucine rich repeat protein phosphatase 1, ubiquitously transcribed tetratricopeptide repeat containing, Y-linked, histone deacetylase 2, F-box and leucine rich repeat protein 19, KIT proto-oncogene receptor tyrosine kinase, angiotensinogen, Janus kinase 2, fibroblast growth factor 2 and RNA polymerase II subunit A. These proteins predominantly regulate the development and progression of cancer, hypertension, essential thrombocythemia and inflammation. The genes in the top seven modules selected were identified to be primarily enriched in chemokines, extracellular matrix-receptor interaction, focal adhesion, the PI3K-Akt signaling pathway, amoebiasis and protein processing signaling pathway. Thus, the target genes and hub proteins that were predicted in the current study were identified to be important in regulating the development and progression of cancer and certain diseases. Furthermore, they present potential novel biomarkers for tumor diagnosis and candidate targets for treatment, and indicate that further research is required to establish the functions of miR-375.

show abstract

FGF2 mediates hepatic progenitor cell formation during human pluripotent stem cell differentiation by inducing the WNT antagonist NKD1

Cited by 34 publications

References 68 publications

A small-molecule screen reveals that HSP90β promotes the conversion of induced pluripotent stem cell-derived endoderm to a hepatic fate and regulates HNF4A turnover

A small-molecule screen reveals that HSP90β promotes the conversion of induced pluripotent stem cell-derived endoderm to a hepatic fate and regulates HNF4A turnover

The Use of Human Pluripotent Stem Cells for Modeling Liver Development and Disease

Analysis of the function of microRNA-375 in humans using bioinformatics

Contact Info

Product

Resources

About