Circulating cell-free messenger RNA secretome characterization of primary sclerosing cholangitis

Naga Chalasani; Raj Vuppalanchi; Craig Lammert; Samer Gawrieh; Jerome V Braun; Jiali Zhuang; Arkaitz Ibarra; David A Ross; Michael Nerenberg; Stephen R Quake; John J Sninsky; Shusuke Toden

doi:10.1097/HC9.0000000000000140

Circulating cell-free messenger RNA secretome characterization of primary sclerosing cholangitis

Hepatol Commun. 2023 May 23;7(6):e0140. doi: 10.1097/HC9.0000000000000140. eCollection 2023 Jun 1.

Authors

Affiliations

¹ Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
² Molecular Stethoscope Inc., South San Francisco, California, USA.
³ Department of Bioengineering and Department of Applied Physics; Stanford University, Stanford, California, USA.
⁴ Chan Zuckerberg Biohub, San Francisco, California, USA.

Abstract

Background: Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease characterized by multifocal bile duct strictures. To date, underlying molecular mechanisms of PSC remain unclear, and therapeutic options are limited.

Methods: We performed cell-free messenger RNA (cf-mRNA) sequencing to characterize the circulating transcriptome of PSC and noninvasively investigate potentially bioactive signals that are associated with PSC. Serum cf-mRNA profiles were compared among 50 individuals with PSC, 20 healthy controls, and 235 individuals with NAFLD. Tissue and cell type-of-origin genes that are dysregulated in subjects with PSC were evaluated. Subsequently, diagnostic classifiers were developed using PSC dysregulated cf-mRNA genes.

Results: Differential expression analysis of the cf-mRNA transcriptomes of PSC and healthy controls resulted in identification of 1407 dysregulated genes. Furthermore, differentially expressed genes between PSC and healthy controls or NAFLD shared common genes known to be involved in liver pathophysiology. In particular, genes from liver- and specific cell type-origin, including hepatocyte, HSCs, and KCs, were highly abundant in cf-mRNA of subjects with PSC. Gene cluster analysis revealed that liver-specific genes dysregulated in PSC form a distinct cluster, which corresponded to a subset of the PSC subject population. Finally, we developed a cf-mRNA diagnostic classifier using liver-specific genes that discriminated PSC from healthy control subjects using gene transcripts of liver origin.

Conclusions: Blood-based whole-transcriptome cf-mRNA profiling revealed high abundance of liver-specific genes in sera of subjects with PSC, which may be used to diagnose patients with PSC. We identified several unique cf-mRNA profiles of subjects with PSC. These findings may also have utility for noninvasive molecular stratification of subjects with PSC for pharmacotherapy safety and response studies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell-Free Nucleic Acids*
Cholangitis, Sclerosing*
Cholestasis*
Humans
Non-alcoholic Fatty Liver Disease*
RNA, Messenger
Secretome

Substances

Cell-Free Nucleic Acids
RNA, Messenger