Hepatic hypertension on-a-chip identifies GPR116 as a hydrostatic pressure mechanosensor to regulate vascular injury in cirrhosis

Cirrhosis-associated portal hypertension drives vascular injury, yet the pathogenesis mediated by abnormal hydrostatic pressure (HP) remains unclear due to the absence of in vitro models replicating the cirrhotic perivascular mechanical microenvironment. Here, we developed 2D static and 3D dynamic "hepatic hypertension on-a-chip" (HH chip) systems replicating cirrhotic hemodynamics and matrix properties. The HH chip realized integration and decoupled regulation of HP, shear stress, and matrix stiffness. Liver sinusoidal endothelial cells (LSECs) exhibited HP-induced damage exclusively on stiff matrices, recapitulating cirrhotic degeneration phenotypes and genotypes. Using the HH chip, we identified GPR116 as the key HP mechanosensor in LSECs and delineated its downstream mechanotransduction pathway driving cellular injury. Genetic silencing of GPR116 protected endothelial cells from HP-induced damage both in vitro and in cirrhotic murine models. Cell- and gene-based therapies targeting GPR116 significantly attenuated cirrhosis progression. The HH chip can accelerate pathological investigation, target identification, and therapeutic development for hypertension-associated diseases.

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Publication Details

Journal
Science Advances
Published
2025-11-14
DOI
https://doi.org/10.1126/sciadv.adu7596
Citations
3
Primary Topic
Liver physiology and pathology
Type
article
Field-Weighted Citation Impact
3.97
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article

Hepatic hypertension on-a-chip identifies GPR116 as a hydrostatic pressure mechanosensor to regulate vascular injury in cirrhosis

Xiaolong Qi, Yudi Niu, Kaini Liang, Yanxiao Ao et al.
3 citations
Science Advances
Liver physiology and pathology
3.97
article

Hepatic hypertension on-a-chip identifies GPR116 as a hydrostatic pressure mechanosensor to regulate vascular injury in cirrhosis

Xiaolong Qi, Yudi Niu, Kaini Liang, Yanxiao Ao, Bingjie Wu, Yanan Du, Ruiquan Liu, Yuhong Jin, Xiangyu Liu, Zhaozhao Wu, Yan Zhang, Zhi-Qiang Liu, Xin Zhang, Rui Wang, Bin Liu, Yi Long
article en
3 citations

Abstract

Cirrhosis-associated portal hypertension drives vascular injury, yet the pathogenesis mediated by abnormal hydrostatic pressure (HP) remains unclear due to the absence of in vitro models replicating the cirrhotic perivascular mechanical microenvironment. Here, we developed 2D static and 3D dynamic "hepatic hypertension on-a-chip" (HH chip) systems replicating cirrhotic hemodynamics and matrix properties. The HH chip realized integration and decoupled regulation of HP, shear stress, and matrix stiffness. Liver sinusoidal endothelial cells (LSECs) exhibited HP-induced damage exclusively on stiff matrices, recapitulating cirrhotic degeneration phenotypes and genotypes. Using the HH chip, we identified GPR116 as the key HP mechanosensor in LSECs and delineated its downstream mechanotransduction pathway driving cellular injury. Genetic silencing of GPR116 protected endothelial cells from HP-induced damage both in vitro and in cirrhotic murine models. Cell- and gene-based therapies targeting GPR116 significantly attenuated cirrhosis progression. The HH chip can accelerate pathological investigation, target identification, and therapeutic development for hypertension-associated diseases.

Science AdvancesVol. 11(46)
Sun Yat-sen University (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Kunming Medical University (CN), National Institute of Biological Sciences, Beijing (CN), Sun Yat-sen Memorial Hospital (CN), Zhongda Hospital Southeast University (CN), First Affiliated Hospital of Kunming Medical University (CN), Membrane Technology & Research (United States) (US), Center for Life Sciences (CN), State Key Laboratory of Digital Medical Engineering (CN), Tsinghua University (CN)
Openalex Percentile: Top 5%
Liver physiology and pathology
3.97
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