RNA Binding Proteins Control Transdifferentiation of Hepatic Stellate Cells into Myofibroblasts

Abstract

Background/Aims: 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.

TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019

“…Recently, insulin-like growth factor 2 binding protein 3 (IGF2BP3) was identified as an RBP and to be an effector and target of TGF-β signaling. Igf2bp3 knockdown decreased the effects of TGF-β on HSC activation, whereas TGF-β signaling inhibition induced Igf2bp3 expression in a miRNA dependent mechanism, therewith revealing an interesting positive feedback loop between TGF-β and IGF2BP3 [197].…”

RNA-Binding Proteins as Regulators of Migration, Invasion and Metastasis in Oral Squamous Cell Carcinoma

“…Over the past decade, RBPs have been increasingly recognized as important regulators of molecular and cellular homeostasis. RBPs regulate diverse cellular processes such as cell survival, pluripotency of embryonic stem cells, and immune cell function, as well as aid in the transition between cellular states in response to stimuli, e.g., during differentiation, cellular stress, or viral infection [51][52][53][54][55][56][57][58]. Nearly 7.5% of all human protein-coding genes have been assigned to the class of RBPs (1542).…”

Metabolic Reprogramming of Liver Fibrosis

“…The understanding of all of the factors that are involved, as well as the mechanisms governing the metabolic interactions in HSCs and in fibrosis in general, have been a huge effort in the scientific liver community in their attempts to develop new therapies [ 35 ]. In this regard, while the transcriptional networks that regulate fibrogenesis and HSCs transdifferentiation are extensively studied ([ 9 , 115 , 116 ] among others), how RNA regulatory processes control the metabolic rewiring of fibrogenesis remains less understood [ 117 ].…”