ABSTRACT CELLULAR MECHANISMS OF MAMMALIAN LIVER REGENERATION Kilangsungla Yanger Ben Z. Stanger The liver is an essential organ that aids in metabolic processes, protein synthesis and detoxification of harmful substances. As the centre for detoxification, the liver is able to compensate for this routine damage with its robust regenerative ability. All vertebrate livers, for example, can make up for tissue mass loss (via surgical excision of a portion of the liver) by replication of their differentiated cells within the remnant lobes. These differentiated cells include parenchymal cells such as the hepatocytes and biliary epithelial cells (BECs) and also non-parenchymal cells. Despite the proliferative capacity exhibited by hepatocytes, the mechanism for how the liver regenerates after toxin injuries is debated. The liver is thought to utilize facultative stem cells (FSCs) originating from the BECs, often referred to as "oval cells," for regeneration following toxin-based injury. However, the notion that oval cells act as stem cells has been based largely on in vitro studies and transplantation models; where lineage tracing has been employed, results have been conflicting. This thesis work employs multiple genetic tools to lineage trace the origin and contribution of various cell populations to liver regeneration in vivo. The findings reveal that contrary to stem cell-based models of regeneration, virtually all new hepatocytes come from pre-existing hepatocytes with no evidence of BECs functioning as FSCs. Instead, hepatocyte lineage tracing reveals in addition to replication, they can function as FSCs. Upon perturbations including toxin injuries, they undergo a hepatocyte-to-BEC reprogramming process in vivo. Cellular reprogramming is the ability to interconvert distinct cell types with defined factors. This phenomenon has rarely been observed in vivo without exogenous factors. However, a detailed in vivo analysis reveals hepatocytes undergoing this cellular reprogramming process in a robust and step-wise manner involving both morphological and transcriptional changes. This hepatocyte-to-BEC reprogramming requires Notch signalling, similar to how the pathway functions in BEC-specification during liver development. These results provide direct evidence that mammalian regeneration prompts extensive and dramatic changes in cellular identity under various perturbations and thus can also serve as a cellular source for various diseases and potentially for therapy involving BEC paucity and dysfunction.