The evolving microenvironment of the human hepatocyte: Healthy vs. cirrhotic liver vs. isolated cells

The study of the liver microenvironment and hepatocyte's response to this environment in the setting of healthy liver, cirrhotic liver or cultured primary human hepatocytes (PHHs) addresses key questions for the development of novel liver therapies and predicts relevance of ex vivo PHHs models in liver biology. This study compared quantitative gene and protein expression of the inflammatory profile, oxidative stress response, angiogenesis and homing mechanisms in the biopsies of healthy and cirrhotic human livers and isolated PHHs. These profiles were correlated with the metabolic health of liver and PHHs defined by albumin production. The analysis demonstrated that cirrhotic liver and PHHs exhibited a distinct upregulation of the pro-inflammatory, oxidative stress and homing mechanism markers when compared to normal liver. The upregulation of the oxidative stress markers in PHHs inversely correlated with the albumin production. PHHs had diverse secretion of matrix metalloproteinases and their inhibitors, reflective of the cellular response to non-physiological culture conditions. The current study suggests that ex vivo PHHs manifest adaptive behavior by upregulating stress mechanisms (similar to the cirrhotic liver), downregulating normal metabolic function and upregulating matrix turnover. The ex vivo profile of PHHs may limit their therapeutic functionality and metabolic capacity to serve as in vitro metabolism and toxicology models.