INSERM, Université de Rennes, INRAE, Institut NuMeCan (Nutrition, Metabolisms and Cancer), F-35000 Rennes, France.
Department of Genetics, University of Saarland (UdS), 66123 Saarbrücken, Germany.
Cells. 2022 Jul 26;11(15):2298. doi: 10.3390/cells11152298.
Dimethyl sulfoxide (DMSO) is used to sustain or favor hepatocyte differentiation in vitro. Thus, DMSO is used in the differentiation protocol of the HepaRG cells that present the closest drug-metabolizing enzyme activities to primary human hepatocytes in culture. The aim of our study is to clarify its influence on liver-specific gene expression. For that purpose, we performed a large-scale analysis (gene expression and histone modification) to determine the global role of DMSO exposure during the differentiation process of the HepaRG cells. The addition of DMSO drives the upregulation of genes mainly regulated by PXR and PPARα whereas genes not affected by this addition are regulated by HNF1α, HNF4α, and PPARα. DMSO-differentiated-HepaRG cells show a differential expression for genes regulated by histone acetylation, while differentiated-HepaRG cells without DMSO show gene signatures associated with histone deacetylases. In addition, we observed an interplay between cytoskeleton organization and EMC remodeling with hepatocyte maturation.
二甲基亚砜（DMSO）用于体外维持或促进肝细胞分化。因此，DMSO 被用于 HepaRG 细胞的分化方案中，该方案在培养物中呈现出最接近原发性人肝细胞的药物代谢酶活性。我们的研究目的是阐明其对肝脏特异性基因表达的影响。为此，我们进行了大规模分析（基因表达和组蛋白修饰），以确定 DMSO 在 HepaRG 细胞分化过程中的全局作用。添加 DMSO 驱动主要由 PXR 和 PPARα 调节的基因上调，而不受此添加影响的基因则由 HNF1α、HNF4α 和 PPARα 调节。用 DMSO 分化的 HepaRG 细胞显示出受组蛋白乙酰化调节的基因的差异表达，而没有 DMSO 的分化 HepaRG 细胞则显示与组蛋白去乙酰化酶相关的基因特征。此外，我们观察到细胞骨架组织和 EMC 重塑与肝成熟之间的相互作用。
