bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.01.31.634947

Hepatic Arterial Flow-Induced Portal Tract Fibrosis in Portal Hypertension: The Role of VCAM-1 and Osteopontin-Expressing Macrophages

Ma, R.·Gong, L.·Dong, C.·Utsumi, T.·Qi, J.·Zhuang, Z.·Zhang, X.·Yang, Y.·McConnell, M. J.·Huang, H.-C.·Iwakiri, Y.
View original source ↗Export metadata ↓

Abstract

BackgroundThe liver undergoes significant hemodynamic changes during surgery, transplantation, or cirrhosis with portal hypertension(PH). The hepatic artery buffer response(HABR), which compensates for reduced portal venous flow by increasing hepatic artery(HA) flow, is hypothesized to induce pathological portal tract remodeling. This study investigates the molecular mechanisms underlying this process. MethodsPH was induced in Sprague-Dawley rats via partial portal vein ligation(PPVL). Structural evaluation(microCT), immune cell profiling, hemodynamic measurements, and transcriptomic analysis in macrophages(M{phi}) from sham or PPVL rats were conducted. ResultsMicroCT revealed decreased portal vein flow and increased HA flow correlated with portal pressure(r=0.799, p<0.01). A 2-fold increase in portal tract fibrosis(p<0.001) was observed with increased -SMA+ myofibroblasts in PPVL rats. CD68+ M{phi} peaked at 10 days post-PPVL, and their depletion significantly reduced fibrosis(p<0.001), indicating critical roles of M{phi} in portal tract remodeling. VCAM-1 was elevated in HA endothelium and portal fibroblasts (PFs); VCAM-1 neutralization reduced collagen accumulation(p<0.05), CD68+ M{phi}(46.3%, p<0.01), and CD3+ T cells(18%, p<0.05). M{phi}-conditioned medium increased VCAM-1 in PFs(8-fold, p<0.001) and enhanced PF migration, while VCAM-1 knockdown reduced this effect (p<0.01). Single-cell RNA sequencing data(GSE171904) and RNA-FISH revealed increased interactions between osteopontin (Spp1)+ M{phi} and PFs, with Spp1+ M{phi} driving fibrosis. Spp1 knockdown in M{phi} co-culture reduced PF fibrogenic markers, while recombinant Spp1 upregulated Col1a1, Fn1, and Acta2 expression in PFs. ConclusionIncreased VCAM-1 in arterial endothelial cells and PFs facilitates the recruitment of Spp1+ M{phi}, which drive HA flow-mediated vascular remodeling and portal tract fibrosis. These findings highlight arterial flow-induced fibrosis as a key mechanism in PH, potentially contributing to disease progression and decompensation. SynopsisLiver hemodynamic changes in portal hypertension drive extracellular matrix accumulation and portal tract remodeling via Spp1+ macrophages. This study highlights how altered blood flow induces fibrosis, and its potential role in decompensation, and identifies therapeutic targets for advanced liver disease.

Source connections

Explore related subjects

pathologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Ma, R., Gong, L., Dong, C., Utsumi, T., Qi, J., Zhuang, Z., Zhang, X., Yang, Y., McConnell, M. J., Huang, H.-C., Iwakiri, Y.. 2025-02-06. Hepatic Arterial Flow-Induced Portal Tract Fibrosis in Portal Hypertension: The Role of VCAM-1 and Osteopontin-Expressing Macrophages. https://doi.org/10.1101/2025.01.31.634947

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Negative association between nodular stromal fibrosis and large lipid droplets in human choroid plexus epithelial cells

Fibrosis is an age-related change within the human choroid plexus that is likely to affect its function negatively. We systematically analyzed nodular stromal fibrosis present in postmortem tissue from a large repository encompassing the human lifespan. Following manual annotation of sampled images from 81 specimens of choroid plexus from the atrium of the lateral ventricle, a deep learning model was trained to assess stages of fibrosis (dense, hyalinized, and mineralized) occurring in papillae across whole slide images of hematoxylin and eosin-stained sections from 204 cases. The percentage of affected papillae and the relative area of fibrosis at all three stages of severity increased with age. Affected papillae were significantly clustered across the choroid plexus, with areas of high and low fibrotic density. Choroid plexus epithelial cells (CPECs) associated with fibrotic papillae were less likely to contain large lipid droplets than were non-fibrotic papillae, as assessed by another deep learning model. Across papillae within a case, the area of each stage of fibrosis was negatively correlated with the prevalence of CPECs containing large lipid droplets. Finally, individuals displaying more nodular fibrosis had significantly fewer CPECs containing large lipid droplets. Thus, age-related nodular stromal fibrosis may negatively impact lipid storage and homeostasis for the choroid plexus and brain.

pathology↗
bioRxiv2026

SilencioM: silencing connected interfering oligonucleotides against MAPT as a potential disease modifying therapeutic for tauopathies

Tauopathies are a diverse group of neurodegenerative diseases whose pathogenesis involves brain accumulation of misfolded, pathological tau (Microtubule Associated Protein Tau, MAPT). More than twenty tauopathies have been identified thus far that collectively impact millions of people worldwide, of which the most common is Alzheimer's disease (AD). Despite substantial efforts to develop drugs for tauopathies, no effective treatments currently exist, highlighting the urgent need for therapeutics to combat these prevalent and ruinous neurodegenerative diseases. Strategies that target tau are likely to have the greatest impact since tau is the proximal cause of their pathogenesis. Small interfering RNAs (siRNAs) have emerged as a powerful class of precision therapeutics that silence disease-causing genes through RNA interference with favorable safety profiles. Delivery challenges are rapidly being addressed, and siRNA-based approaches are poised to transform the therapeutic landscape of neurological diseases. In this study, we describe SilencioM (Silencing connected interfering oligonucleotides against MAPT) and show its efficacy in markedly reducing tau pathology after a single intracerebroventricular injection in PS19 mice, a mouse model of severe tauopathy. SilencioM targets human, primate, rat and mouse ortholog genes; thus, the same compound can proceed from efficacy studies to Investigational New Drug Application (IND)-enabling studies. SilencioM is simple to manufacture and is administered without encapsulation in lipid nanoparticles and without requirements for lipophilic conjugation, making it a promising candidate for further development as a novel therapeutic for tauopathies, including AD.

pathology↗
bioRxiv2026

SilencioMA: A single compound that targets both MAPT and APP as a potential disease modifying therapeutic for Alzheimer's Disease

Alzheimer's Disease (AD) is the most common age-related neurodegenerative disease and the leading cause of dementia worldwide. AD pathogenesis involves aggregation of amyloid-beta (A{beta}), produced from amyloidogenic proteolytic processing of Amyloid Precursor Protein (APP), and accumulation of misfolded, pathological tau (Microtubule Associated Protein Tau, MAPT). Current efforts focus on developing disease modifying therapeutics (DMTs) against single targets: A{beta} or tau. However, DMTs that concurrently target both tau and A{beta} are likely to have the greatest impact since they target both culprits of AD pathogenesis. Here we describe the development of SilencioMA, a single compound that targets both MAPT and APP messenger RNAs (mRNAs) based on silencing connected interfering oligonucleotides against MAPT and APP. Cerebrospinal fluid (CSF) administration of SilencioMA reduces A{beta} and tau and pathology after a single intracerebroventricular injection in 5XFAD/PS19 mice, an animal model of severe amyloidosis and tauopathy. SilencioMA does not rely on lipid nanoparticles or lipophilic conjugates for CSF administration. At the same time its modular design permits conjugation of ligands that facilitate transcytosis through the blood brain barrier, allowing systemic administration. Our findings provide proof-of-concept for a strategy that targets the dual A{beta} and tau pathologies of AD, and establishes a compelling foundation for further development of SilencioMA as a next-generation DMT for AD.

pathology↗