Hepatic Regeneration in Cirrhosis.

End-stage liver disease is characterized by massive hepatocyte death resulting in clinical decompensation and organ failures. Clinical consequences in cirrhosis are the results of the loss of functional hepatocytes and excessive scarring. The only curative therapy in advanced cirrhosis is orthotropic liver transplantation, but the clinical demand outweighs the availability of acceptable donor organs. Moreover, this also necessitates lifelong immunosuppression and carries associated risks. The liver has a huge capability for regeneration. Self-replication of quiescent differentiated hepatocytes and cholangiocytes occurs in patients with acute liver injury. Due to limited hepatocyte self-renewal capacity in advanced cirrhosis, great interest has therefore been shown in characterizing the possible role of hepatic progenitor cells and bone marrow-derived stem cells to therapeutically aid this process. Transplantation of cells from various sources that can be properly differentiated into functional liver cells or use of growth factors for ex-vivo expansion of progenitor cells is needed at utmost priority. Multiple researches over the last two decades have aided researchers in refining proliferation, differentiation, and storage techniques and understand the functionality of these cells for use in clinical practice. However, these cell-based therapies are still experimental and have to be used in trial settings.

Specific Labeling and Lineage Tracing of Periportal Hepatocytes Using Two-Step Genetic Recombination.

The liver is unmatched in regenerative capacity. However, when exhausted, the liver is predisposed to various diseases based on injury types and causal agents. Although hepatocytes have been proposed to be the main source of new hepatocytes during regeneration, the existence of specialized liver stem cells has been long debated. In mice, oval cells or ductal cells have been postulated as such stem/progenitor pool. Exhaustive works from different laboratories have shown that in genetically unmodified mice, oval cells, or by extension ductal cells, only contribute marginally in producing new hepatocytes during liver regeneration, thus indicating that hepatocytes are the main regenerative cell source. In this debated context, we identified a new population of periportal hepatocytes in the normal mouse liver. These cells we termed hybrid hepatocytes (HybHP) express low levels of the transcription factor Sox9. Using complementary lineage tracing tools, we demonstrated that HybHP regenerate the liver after chronic hepatocyte depleting injuries. Here, we describe the two-step genetic recombination method that allowed us to study HybHP's lineage in two established models of liver injury.

Yes-associated protein at the intersection of liver cell fate determination.

A recent publication highlights the importance of high yes-associated protein (YAP) expressing cells in liver regeneration following partial hepatectomy. Although the names of the cell populations described in these articles [hybrid periportal hepatocytes (HybHP) or epithelial-mesenchymal transition (EMT)-reprogrammed hepatocytes] are not identical, they all express high levels of YAP. We hypothesize that the HybHP and EMT-reprogrammed hepatocytes might be a similar cell population. Hippo signaling is the primary pathway that regulates YAP activity. According to the contribution of these two types of cells to liver regeneration and the high YAP expression, Hippo-YAP signaling activation may be a common regulatory pathway experienced by cells undergoing dedifferentiation and reactivating proliferative activity during liver regeneration. Although no evidence has shown that HybHP cells contribute to hepatocellular carcinoma in mouse models, we can not rule out the possibility that these highly regenerative cells can further develop into tumor cells when they acquire mutations caused by viral infection or other risk factors like alcohol. The detailed mechanistic insight of the regulation of YAP expression and activity in HybHP (or other types of cells contributing to liver regeneration) is unknown. We hypothesize that liver regeneration under various conditions will eventually lead to divergent consequences, likely due to the duration of YAP activation regulated by Hippo-large tumor suppressor 1 and 2 pathway in a context- and cell type-dependent manner.