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ZNF469 is a novel pro-fibrotic regulator of extracellular matrix in hepatic stellate cells

ABSTRACT: Activation of quiescent hepatic stellate cells (HSCs) into proliferative myofibroblasts drives extracellular cellular matrix (ECM) accumulation and liver fibrosis; nevertheless, transcriptional network that promotes such the process remains elusive. ZNF469, a putative C2H2 zinc finger protein, is found to be upregulated upon HSC activation; however, the molecular function of ZNF469 is completely unknown. Here, we show that knockdown of ZNF469 in primary human HSCs impaired proliferation, migration, and collagen production. Conversely, overexpression of ZNF469 in HSCs yielded the opposite results. TGFb promoted expression of ZNF469 in a Smad3-dependent manner where the binding of Smad3 was confirmed at the ZNF469 promoter. RNA-seq data of ZNF469-knockdown HSCs revealed the ECM-receptor interaction as the top affected pathway, and significant downregulation of various collagen and proteoglycan genes was observed. To explore the function of ZNF469, we cloned a full-length open reading frae (ORF) of ZNF469 with an epitope tag and identified a nuclear localization of the protein. ChIP assays revealed the presence of ZNF469 at the promoter of ECM genes, supporting its function as a transcription factor. Analysis of human fibrotic and cirrhotic tissues showed increased expression of ZNF469 and a positive correlation between expression levels of ZNF469 and ECM genes. Moreover, this observation was similar in other fibrotic organs, including heart, lung, and skin. Together, this study is the first to reveal the roles of ZNF469 as a pro-fibrotic factor in HSCs and suggests ZNF469 as a novel target for antifibrotic therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252958 | GEO | 2024/03/15

REPOSITORIES: GEO

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Project description:Background: Fibrosis is a pathological scarring process characterized by persistent myofibroblasts activation with excessive accumulation of extracellular matrix (ECM). Fibrotic disorders represent an increasing burden of disease-associated morbidity and mortality worldwide for which there are limited therapeutic options. Reversing fibrosis requires the elimination of myofibroblasts, remodeling of the ECM, and regeneration of functional tissue. Multipotent mesenchymal stromal cells (MSC) have antifibrotic properties mediated by secreted factors present in their conditioned medium (MSC-CM). However, there are no standardized in vitro assays to predict the antifibrotic effects of human MSC, and, as a consequence, we lack evidence on the effect of cytokine priming on MSC’s antifibrotic effects. We hypothesize that the MSC-CM promotes fibrosis resolution in vitro and that this effect is enhanced following MSC cytokine priming. Methods: We tested the antifibrotic effects of resting and interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) primed MSC-CM in three in vitro assays: prevention of fibroblast activation, myofibroblasts deactivation and ECM degradation. Furthermore, we performed transcriptomic analysis of myofibroblasts treated or not with resting- or primed-MSC-CM and proteomic characterization of resting- and primed-MSC-CM. Results: We report that MSC-CM treatment prevented TGF-β induced fibroblast activation and reduced fibrogenic myofibroblasts (i.e. transcriptomic upregulation of apoptosis, senescence, and inflammatory pathways). These effects were higher when primed rather than resting MSC-CM was used. Priming increased the ability of MSC-CM to remodel the extracellular matrix reducing its content of collagen I and fibronectin. Priming increased the following antifibrotic proteins in MSC-CM: DKK1, MMP-1, MMP-3, follistatin and cathepsin S. DKK1 inhibition reduced the anti-fibrotic effects of MSC-CM. Thus, cytokine priming increases antifibrotic factors in the MSC-CM which in turn amplify the anti-fibrotic effects of MSC-CM. Conclusions: In a pro-fibrotic in vitro environment MSC-CM promote fibrosis resolution, an effect enhanced following MSC cytokine priming. Specifically, MSC-CM reduces fibrogenic myofibroblasts through apoptosis, senescence, and inflammatory signals, as well as by enhancing ECM degradation. Future studies will establish the in vivo relevance of MSC priming to fibrosis resolution

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ZNF469 is a novel pro-fibrotic regulator of extracellular matrix in hepatic stellate cells

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