Nuclear deformation mediates liver cell mechanosensing in cirrhosis.

Guixé Muntet, Sergi; Ortega-Ribera, Martí; Wang, Cong; Selicean, Sonia; Andreu, Ion; Kechagia, Jenny Z; Fondevila, Constantino; Roca-Cusachs, Pere; Dufour, Jean-François; Bosch, Jaime; Berzigotti, Annalisa; Gracia Sancho, Jordi (2020). Nuclear deformation mediates liver cell mechanosensing in cirrhosis. JHEP reports, 2(5), p. 100145. Elsevier 10.1016/j.jhepr.2020.100145

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Background & Aims

Liver stiffness is increased in advanced chronic liver disease (ACLD) and accurately predicts prognosis in this population. Recent data suggest that extracellular matrix stiffness per se may modulate the phenotype of liver cells. We aimed at investigating the effect of matrix stiffness on the phenotype of liver cells of rats with cirrhosis, assessing its influence on their response to antifibrotic strategies and evaluating associated molecular mechanisms.

Methods

Hepatocytes, hepatic stellate cells, and liver sinusoidal endothelial cells were isolated from healthy rats or rats with cirrhosis (carbon tetrachloride or thioacetamide), and cultured on polyacrylamide gels with different physiologically relevant stiffness for 72 h.

Results

All cell types of rats with cirrhosis cultured at low stiffness showed a significant phenotype amelioration vs. rigid matrix (assessed by quantitative morphology, mRNA expression, protein synthesis, and electron microscopy imaging). Additionally, stiffness modified the antifibrotic effects of liraglutide in stellate cells of rats with cirrhosis. Finally, evaluation of nuclear morphology revealed that high stiffness induced nuclei deformation in all cell types, an observation confirmed in cells from human livers. Disconnecting the nucleus from the cytoskeleton by cytoskeleton disruption or a defective form of nesprin 1 significantly recovered spherical nuclear shape and quiescent phenotype of cells.

Conclusions

The environment's stiffness per se modulates the phenotype of healthy rats and liver cells of rats with cirrhosis by altering the nuclear morphology through cytoskeleton-derived mechanical forces. The reversibility of this mechanism suggests that targeting the stiffness-mediated intracellular mechanical tensions may represent a novel therapeutic strategy for ACLD.

Lay summary

During cirrhosis, the liver becomes scarred, stiff, and unable to perform its normal functions efficiently. In this study, we demonstrated that cells from diseased (stiff) livers recovered their functionality when placed in a soft environment (as that of a healthy liver). Furthermore, treatments aimed at tricking liver cells into believing they are in a healthy, soft liver improved their function and could potentially contribute to treat cirrhosis.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology

UniBE Contributor:

Guixé Muntet, Sergi; Wang, Cong; Selicean, Sonia-Emilia; Dufour, Jean-François; Bosch, Jaime; Berzigotti, Annalisa and Gracia Sancho, Jorge Sergio

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2589-5559

Publisher:

Elsevier

Language:

English

Submitter:

Thi Thao Anh Pham

Date Deposited:

09 Dec 2020 08:09

Last Modified:

27 Mar 2021 20:08

Publisher DOI:

10.1016/j.jhepr.2020.100145

PubMed ID:

32939447

Uncontrolled Keywords:

ACLD, advanced chronic liver disease Cd, cytoskeleton disruptor Chronic liver disease DN-KASH, dominant negative nesprin peptide containing a KASH domain ECM, extracellular matrix HNF4α, hepatocyte nuclear factor 4α HSC HSC, hepatic stellate cell Hepatocyte KASH, Klarsicht/abnormal nuclear anchorage-1/Syne homology LSEC LSEC, liver sinusoidal endothelial cell Lamb1, laminin b1 Stiffness TAA, thioacetamide eNOS, endothelial nitric oxide synthase α-SMA, α-smooth muscle actin

BORIS DOI:

10.7892/boris.148107

URI:

https://boris.unibe.ch/id/eprint/148107

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