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Exploring Interactions between Primary Hepatocytes and Non-Parenchymal Cells on Physiological and Pathological Liver Stiffness

SIMPLE SUMMARY: Chronic liver disease is characterized by progressive hepatic fibrosis leading to the formation of cirrhosis irrespective of the etiology with no effective treatment currently available. Liver stiffness (LS) is currently the best clinical predictor of this fibrosis progression irresp...

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Autores principales: Natarajan, Vaishaali, Moeun, Youra, Kidambi, Srivatsan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147966/
https://www.ncbi.nlm.nih.gov/pubmed/34063016
http://dx.doi.org/10.3390/biology10050408
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author Natarajan, Vaishaali
Moeun, Youra
Kidambi, Srivatsan
author_facet Natarajan, Vaishaali
Moeun, Youra
Kidambi, Srivatsan
author_sort Natarajan, Vaishaali
collection PubMed
description SIMPLE SUMMARY: Chronic liver disease is characterized by progressive hepatic fibrosis leading to the formation of cirrhosis irrespective of the etiology with no effective treatment currently available. Liver stiffness (LS) is currently the best clinical predictor of this fibrosis progression irrespective of the cause of the disease. However, it is not well understood how does LS regulate the critical hepatocytes–non parenchymal cell interactions. We here present, to the best of our knowledge, the first analyses of the impact of physiological and pathological stiffness on hepatocytes–non parenchymal cell interaction. Our findings indicate the role of stiffness in regulating the hepatocytes interactions with NPCs necessary for maintenance of hepatocytes function. ABSTRACT: Chronic liver disease is characterized by progressive hepatic fibrosis leading to the formation of cirrhosis irrespective of the etiology with no effective treatment currently available. Liver stiffness (LS) is currently the best clinical predictor of this fibrosis progression irrespective of the etiology. LS and hepatocytes-nonparenchymal cells (NPC) interactions are two variables known to be important in regulating hepatic function during liver fibrosis, but little is known about the interplay of these cues. Here, we use polydimethyl siloxane (PDMS) based substrates with tunable mechanical properties to study how cell–cell interaction and stiffness regulates hepatocytes function. Specifically, primary rat hepatocytes were cocultured with NIH-3T3 fibroblasts on soft (2 kPa) and stiff substrates that recreates physiologic (2 kPa) and cirrhotic liver stiffness (55 kPa). Urea synthesis by primary hepatocytes depended on the presence of fibroblast and was independent of the substrate stiffness. However, albumin synthesis and Cytochrome P450 enzyme activity increased in hepatocytes on soft substrates and when in coculture with a fibroblast. Western blot analysis of hepatic markers, E-cadherin, confirmed that hepatocytes on soft substrates in coculture promoted better maintenance of the hepatic phenotype. These findings indicate the role of stiffness in regulating the hepatocytes interactions with NPCs necessary for maintenance of hepatocytes function.
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spelling pubmed-81479662021-05-26 Exploring Interactions between Primary Hepatocytes and Non-Parenchymal Cells on Physiological and Pathological Liver Stiffness Natarajan, Vaishaali Moeun, Youra Kidambi, Srivatsan Biology (Basel) Article SIMPLE SUMMARY: Chronic liver disease is characterized by progressive hepatic fibrosis leading to the formation of cirrhosis irrespective of the etiology with no effective treatment currently available. Liver stiffness (LS) is currently the best clinical predictor of this fibrosis progression irrespective of the cause of the disease. However, it is not well understood how does LS regulate the critical hepatocytes–non parenchymal cell interactions. We here present, to the best of our knowledge, the first analyses of the impact of physiological and pathological stiffness on hepatocytes–non parenchymal cell interaction. Our findings indicate the role of stiffness in regulating the hepatocytes interactions with NPCs necessary for maintenance of hepatocytes function. ABSTRACT: Chronic liver disease is characterized by progressive hepatic fibrosis leading to the formation of cirrhosis irrespective of the etiology with no effective treatment currently available. Liver stiffness (LS) is currently the best clinical predictor of this fibrosis progression irrespective of the etiology. LS and hepatocytes-nonparenchymal cells (NPC) interactions are two variables known to be important in regulating hepatic function during liver fibrosis, but little is known about the interplay of these cues. Here, we use polydimethyl siloxane (PDMS) based substrates with tunable mechanical properties to study how cell–cell interaction and stiffness regulates hepatocytes function. Specifically, primary rat hepatocytes were cocultured with NIH-3T3 fibroblasts on soft (2 kPa) and stiff substrates that recreates physiologic (2 kPa) and cirrhotic liver stiffness (55 kPa). Urea synthesis by primary hepatocytes depended on the presence of fibroblast and was independent of the substrate stiffness. However, albumin synthesis and Cytochrome P450 enzyme activity increased in hepatocytes on soft substrates and when in coculture with a fibroblast. Western blot analysis of hepatic markers, E-cadherin, confirmed that hepatocytes on soft substrates in coculture promoted better maintenance of the hepatic phenotype. These findings indicate the role of stiffness in regulating the hepatocytes interactions with NPCs necessary for maintenance of hepatocytes function. MDPI 2021-05-05 /pmc/articles/PMC8147966/ /pubmed/34063016 http://dx.doi.org/10.3390/biology10050408 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Natarajan, Vaishaali
Moeun, Youra
Kidambi, Srivatsan
Exploring Interactions between Primary Hepatocytes and Non-Parenchymal Cells on Physiological and Pathological Liver Stiffness
title Exploring Interactions between Primary Hepatocytes and Non-Parenchymal Cells on Physiological and Pathological Liver Stiffness
title_full Exploring Interactions between Primary Hepatocytes and Non-Parenchymal Cells on Physiological and Pathological Liver Stiffness
title_fullStr Exploring Interactions between Primary Hepatocytes and Non-Parenchymal Cells on Physiological and Pathological Liver Stiffness
title_full_unstemmed Exploring Interactions between Primary Hepatocytes and Non-Parenchymal Cells on Physiological and Pathological Liver Stiffness
title_short Exploring Interactions between Primary Hepatocytes and Non-Parenchymal Cells on Physiological and Pathological Liver Stiffness
title_sort exploring interactions between primary hepatocytes and non-parenchymal cells on physiological and pathological liver stiffness
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147966/
https://www.ncbi.nlm.nih.gov/pubmed/34063016
http://dx.doi.org/10.3390/biology10050408
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AT kidambisrivatsan exploringinteractionsbetweenprimaryhepatocytesandnonparenchymalcellsonphysiologicalandpathologicalliverstiffness