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RNA Binding Proteins Control Transdifferentiation of Hepatic Stellate Cells into Myofibroblasts. 2018

Sihyung Wang, and Youngmi Jung, and Jeongeun Hyun, and Matthew Friedersdorf, and Seh-Hoon Oh, and Jieun Kim, and Richard T Premont, and Jack D Keene, and Anna Mae Diehl
Department of Medicine, Duke University, Durham, North Carolina, USA.

OBJECTIVE Myofibroblasts (MF) derived from quiescent nonfibrogenic hepatic stellate cells (HSC) are the major sources of fibrous matrix in cirrhosis. Because many factors interact to regulate expansion and regression of MF-HSC populations, efforts to prevent cirrhosis by targeting any one factor have had limited success, motivating research to identify mechanisms that integrate these diverse inputs. As key components of RNA regulons, RNA binding proteins (RBPs) may fulfill this function by orchestrating changes in the expression of multiple genes that must be coordinately regulated to affect the complex phenotypic modifications required for HSC transdifferentiation. METHODS We profiled the transcriptomes of quiescent and MF-HSC to identify RBPs that were differentially-expressed during HSC transdifferentiation, manipulated the expression of the most significantly induced RBP, insulin like growth factor 2 binding protein 3 (Igf2bp3), and evaluated transcriptomic and phenotypic effects. RESULTS Depleting Igf2bp3 changed the expression of thousands of HSC genes, including multiple targets of TGF-β signaling, and caused HSCs to reacquire a less proliferative, less myofibroblastic phenotype. RNA immunoprecipitation assays demonstrated that some of these effects were mediated by direct physical interactions between Igf2bp3 and mRNAs that control proliferative activity and mesenchymal traits. Inhibiting TGF-β receptor-1 signaling revealed a microRNA-dependent mechanism that induces Igf2bp3. CONCLUSIONS The aggregate results indicate that HSC transdifferentiation is ultimately dictated by Igf2bp3-dependent RNA regulons and thus, can be controlled simply by manipulating Igf2bp3.

UI MeSH Term Description Entries
D008297 Male Males
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D016601 RNA-Binding Proteins Proteins that bind to RNA molecules. Included here are RIBONUCLEOPROTEINS and other proteins whose function is to bind specifically to RNA. Double-Stranded RNA-Binding Protein,Double-Stranded RNA-Binding Proteins,ds RNA-Binding Protein,RNA-Binding Protein,ds RNA-Binding Proteins,Double Stranded RNA Binding Protein,Double Stranded RNA Binding Proteins,Protein, Double-Stranded RNA-Binding,Protein, ds RNA-Binding,RNA Binding Protein,RNA Binding Proteins,RNA-Binding Protein, Double-Stranded,RNA-Binding Protein, ds,RNA-Binding Proteins, Double-Stranded,ds RNA Binding Protein
D054338 Cell Transdifferentiation A naturally occurring phenomenon where terminally differentiated cells dedifferentiate to the point where they can switch CELL LINEAGES. The cells then differentiate into other cell types. Transdifferentiation, Cell,Cell Transdifferentiations,Transdifferentiations, Cell
D055166 Hepatic Stellate Cells Perisinusoidal cells of the liver, located in the space of Disse between HEPATOCYTES and sinusoidal endothelial cells. Ito Cells,Cell, Hepatic Stellate,Cells, Hepatic Stellate,Cells, Ito,Hepatic Stellate Cell,Stellate Cell, Hepatic,Stellate Cells, Hepatic
D058628 Myofibroblasts Spindle-shaped cells with characteristic CONTRACTILE PROTEINS and structures that contribute to the WOUND HEALING process. They occur in GRANULATION TISSUE and also in pathological processes such as FIBROSIS. Myofibroblast

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