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Designing in vitro liver microenvironment models to regulate hepatocellular phenotype
The liver is a complex multicellular organ that performs vital metabolic, synthetic and clearance-related functions. Elements of the liver microenvironment such as mechanical cues, cell-cell communication, and cell-ECM interactions are essential in maintaining organ function. Chronic stress to the organ could result in altered liver microenvironment which leads to the onset and progression of liver fibrosis. Clinical and animal studies have contributed significantly to our understanding of liver biology but there exists a need for in vitro models to investigate the essential biochemical mechanistic pathways in isolation. The field of liver bioengineering attempts to design functional hepatic tissue in vitro to investigate the complex mechanisms that regulate the functional maintenance, drug metabolism and disease progression in the organ. The goal of this dissertation was to employ bioengineering principles to design physiologically relevant in vitro models of the liver to understand the role of liver microenvironmental elements such as 1) matrix stiffness, 2) heterotypic cell-cell interactions, and 3) cell-ECM interactions on the functional maintenance of hepatocytes and liver sinusoidal endothelial cells (LSECs). These models were also utilized to understand the role of changing microenvironment in liver fibrosis progression. Our findings demonstrate that mimicking the healthy liver mechanical cues results in the maintenance of phenotypic stability in hepatocytes and LSECs whereas, fibrotic tissue mechanics triggers a fibrogenic response in both cell types. Our studies also demonstrate that the nature of cross-talk between hepatocytes and non-parenchymal cells drastically alters between healthy and fibrotic livers. Overall, this work advances our understanding of the microenvironment-based regulation of hepatocellular phenotype through design and employment of novel in vitro liver models.
Cellular biology|Biomedical engineering|Chemical engineering
Natarajan, Vaishaali, "Designing in vitro liver microenvironment models to regulate hepatocellular phenotype" (2016). ETD collection for University of Nebraska-Lincoln. AAI10124334.