Wang, Zhongyi, Keogh, Adrian, Waldt, Annick, Cuttat-Theurillat, Rachel, Neri, Marilisa, Zhu, Shanshan, Schuierer, Sven, Ruchti, Alexandra, Crochemore, Christophe, Knehr, Judith, Jourdain, Marie, Weber, Delphine, Bastien, Julie, Roma, Guglielmo, Ksiazek, Iwona, Ge, Hui, Wu, Jing, Sánchez-Taltavull, Daniel , Helliwell , Stephen , Stroka , Deborah and Nigsch, Florian (2021) Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis. Scientific reports, 11. ISSN 2045-2322

Abstract

Fibrosis is characterized by the excessive production of collagen and other extracellular matrix (ECM) components and represents a leading cause of morbidity and mortality worldwide. Previous studies of nonalcoholic steatohepatitis (NASH) with fibrosis were largely restricted to bulk transcriptome profiles. Thus, our understanding of this disease is limited by an incomplete characterization of liver cell types in general and hepatic stellate cells (HSCs) in particular, given that activated HSCs are the major fibrogenic population during liver fibrosis development. To help fill this gap, we profiled 17,810 non-parenchymal cells derived from six healthy human liver tissues. In conjunction with public single-cell data of fibrotic/cirrhotic human liver, it enables the assessment and identification of potential intercellular communications (e.g., ITGAV–LAMC1, TNFRSF11B–VWF and NOTCH2–DLL4 signaling axes) and regulons (e.g., RUNX1 and CREB3L1) responsible for the activation of HSCs during fibrogenesis. Bulk RNA-seq data of NASH patient livers and rodent models for liver fibrosis of diverse etiologies allowed us to evaluate the translatability of candidate therapeutic targets for NASH with fibrosis. We identified 61 liver fibrosis-associated genes (e.g., AEBP1, PRRX1 and LARP6) that may serve as a repertoire of translatable drug target candidates. Consistent with the above regulon results, gene regulatory network analysis allowed the identification of CREB3L1 as a master regulator of many of the 61 genes. Together, this study sheds light on potential cell-cell interactions and regulons that underlie HSC activation and reveals genes that may represent prospective hallmark signatures for liver fibrosis.

Item Type:	Article
Date Deposited:	15 Oct 2021 00:45
Last Modified:	15 Oct 2021 00:45
URI:	https://oak.novartis.com/id/eprint/44768