Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Molecular Stethoscope Inc., South San Francisco, California, USA.
Hepatol Commun. 2023 May 23;7(6). doi: 10.1097/HC9.0000000000000140. eCollection 2023 Jun 1.
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.
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.
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.
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.
原发性硬化性胆管炎（PSC）是一种罕见的慢性胆汁淤积性肝病，其特征为多发性胆管狭窄。迄今为止，PSC 的潜在分子机制尚不清楚，治疗选择有限。
我们进行了无细胞信使 RNA（cf-mRNA）测序，以描述 PSC 的循环转录组，并无创性研究与 PSC 相关的潜在生物活性信号。比较了 50 名 PSC 患者、20 名健康对照者和 235 名非酒精性脂肪性肝病（NAFLD）患者的血清 cf-mRNA 谱。评估了 PSC 患者中失调的组织和细胞来源基因。随后，使用 PSC 失调的 cf-mRNA 基因开发了诊断分类器。
PSC 和健康对照者 cf-mRNA 转录组的差异表达分析导致鉴定出 1407 个失调基因。此外，PSC 和健康对照者或 NAFLD 之间差异表达的基因共享已知参与肝病理生理学的共同基因。特别是，来自肝和特定细胞来源的基因，包括肝细胞、HSCs 和 KCs，在 PSC 患者的 cf-mRNA 中高度丰富。基因聚类分析显示，PSC 中失调的肝特异性基因形成一个独特的簇，与 PSC 患者的一部分人群相对应。最后，我们使用来自肝的基因转录本，使用肝特异性基因开发了一种 cf-mRNA 诊断分类器，该分类器可将 PSC 与健康对照者区分开来。
基于血液的全转录组 cf-mRNA 分析显示，PSC 患者血清中存在大量肝特异性基因，可用于诊断 PSC 患者。我们确定了 PSC 患者的几种独特 cf-mRNA 谱。这些发现也可能对 PSC 患者进行非侵入性分子分层，以进行药物治疗安全性和反应研究具有实用性。
