INVESTIGATING THE MECHANISMS GOVERNING THE INITIATION AND EXPANSION OF BILE CANALICULI

Abstract

Bile canaliculi (BC) are the structure basis for various liver functions. Abnormalities in the development of BC structure have been associated with diseases such as cholestasis and liver cancer. In this thesis, 3D single hepatocyte or doublets culture systems were created to precisely control the biophysical properties of external cues presented to cells. Individual hepatocyte developed a fully functional luminal domain when cultured with access to spatially segmented cadherin and ECM signaling. Combined with data from co-culture assay, I demonstrated that cell polarity is largely a cell-autonomous process, independent of the nature of neighboring cells and the polarity state of triggering signaling. Mechanistically, actin cortex rearrangements regulated by the biophysical properties and density of cadherins at the initial cell-cell junction is critical for the correct localization of polarity markers. Altogether, the reductionist approach demonstrated that single hepatocyte can be fooled into a functional polarized state by fine-tuning biomimetic microniches.