Role of calcium integrin-binding protein 1 in the mechanobiology of the liver endothelium.

Wang, Cong; Felli, Eric; Selicean, Sonia; Yeliduosi, Nulan; Lozano, Juan José; Guixé-Muntet, Sergi; Bosch, Jaume; Berzigotti, Annalisa; Gracia-Sancho, Jordi (2024). Role of calcium integrin-binding protein 1 in the mechanobiology of the liver endothelium. Journal of cellular physiology, 239(5), e31198. Wiley 10.1002/jcp.31198

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Liver sinusoidal endothelial cells (LSECs) dysfunction is a key process in the development of chronic liver disease (CLD). Progressive scarring increases liver stiffness in a winch-like loop stimulating a dysfunctional liver cell phenotype. Cellular stretching is supported by biomechanically modulated molecular factors (BMMFs) that can translocate into the cytoplasm to support mechanotransduction through cytoskeleton remodeling and gene transcription. Currently, the molecular mechanisms of stiffness-induced LSECs dysfunction remain largely unclear. Here we propose calcium- and integrin-binding protein 1 (CIB1) as BMMF with crucial role in LSECs mechanobiology in CLD. CIB1 expression and translocation was characterized in healthy and cirrhotic human livers and in LSECs cultured on polyacrylamide gels with healthy and cirrhotic-like stiffnesses. Following the modulation of CIB1 with siRNA, the transcriptome was scrutinized to understand downstream effects of CIB1 downregulation. CIB1 expression is increased in LSECs in human cirrhosis. In vitro, CIB1 emerges as an endothelial BMMF. In human umbilical vein endothelial cells and LSECs, CIB1 expression and localization are modulated by stiffness-induced trafficking across the nuclear membrane. LSECs from cirrhotic liver tissue both in animal model and human disease exhibit an increased amount of CIB1 in cytoplasm. Knockdown of CIB1 in LSECs exposed to high stiffness improves LSECs phenotype by regulating the intracellular tension as well as the inflammatory response. Our results demonstrate that CIB1 is a key factor in sustaining cellular tension and stretching in response to high stiffness. CIB1 downregulation ameliorates LSECs dysfunction, enhancing their redifferentiation, and reducing the inflammatory response.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology
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 > 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

UniBE Contributor:

Wang, Cong, Felli, Eric, Selicean, Sonia-Emilia, Yeliduosi, Nulan, Bosch Genover, Jaime, Berzigotti, Annalisa, Jordi, Gracia

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0021-9541

Publisher:

Wiley

Language:

English

Submitter:

Pubmed Import

Date Deposited:

14 Mar 2024 13:14

Last Modified:

16 May 2024 00:14

Publisher DOI:

10.1002/jcp.31198

PubMed ID:

38451745

Uncontrolled Keywords:

chronic liver disease liver sinusoidal endothelial cells mechanotransduction stiffness

BORIS DOI:

10.48350/194022

URI:

https://boris.unibe.ch/id/eprint/194022

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