Abstract
Simple SummaryChronic 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.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.
Highlights
Chronic liver diseases affect over 35 million Americans with estimated health care costs of $10 billion per year [1,2,3,4]
This article explores how stiffness affects the phenotype of cultured hepatocytes in coculture with non-parenchymal cells
Primary hepatocytes cultured on softer polydimethyl siloxane (PDMS) gels with a modulus of 2 kPa were more functional than cells on stiffer substrates (55 kPa) as observed by albumin synthesis and E-cadherin expression
Summary
Chronic liver diseases affect over 35 million Americans with estimated health care costs of $10 billion per year [1,2,3,4]. Fibroscan measurements have indicated a graded change in liver stiffness (LS) at various stages of fibrosis (2–4 kPa: healthy liver, 8–10 kPa: fibrosis stage of F0–1, 12–25 kPa: F2–4 fibrotic liver, and >55 kPa: cirrhosis) [5,6]. Mechanical force across a tissue can change due to fluctuations in blood pressure, the behavior of contractile cells (e.g., hepatic stellate cells-HSCs), and changes in the extracellular matrix (ECM). Following liver injury changes in hepatic blood pressure occur rapidly [13,14], and hypertension in the context of liver disease appears to increase the risk of fibrosis [14,15]. The majority of the emphasis in understanding the role of stiffness during fibrotic liver disease has largely been on HSCs [16,17,18]. The impact and the molecular mechanisms that account for the stiffness predilection to hepatocytes dysfunction during fibrosis have been underexplored
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