Abstract
It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes. However, the signaling pathways implicated in the differentiation of LPCs are still incompletely understood. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is known to be involved in osteoblast and myeloid differentiation, but its role in lineage commitment in the liver has not been investigated. Here we show that during development and upon regeneration TFEB drives the differentiation status of murine LPCs into the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation. Genetic interaction studies show that Sox9, a marker of precursor and biliary cells, is a direct transcriptional target of TFEB and a primary mediator of its effects on liver cell fate. In summary, our findings identify an unexplored pathway that controls liver cell lineage commitment and whose dysregulation may play a role in biliary cancer.
Highlights
It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes
Liver stem/progenitor cells (LPCs) have capacity to differentiate into hepatocytes and biliary cells in vitro and to form hepatocyte buds repopulating the liver in vivo, their ability to participate to liver regeneration in human clinical setting is still unclear[17]
To investigate whether Transcription Factor EB (TFEB) plays a role in liver development, we examined its expression during liver specification
Summary
It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes. Liver stem/progenitor cells (LPCs) may appear in chronic liver damage when hepatocyte proliferation is compromised and differentiate in both hepatocytes and bile ducts[11]. LPCs have capacity to differentiate into hepatocytes and biliary cells in vitro and to form hepatocyte buds repopulating the liver in vivo, their ability to participate to liver regeneration in human clinical setting is still unclear[17]. HybHPs are located at the periportal region of normal liver and are efficient in liver repair when non-centrilobular hepatocytes are damaged. It appears that liver injury triggers several regenerative responses depending on the size and the proliferative capacity of the remaining liver tissue[19]
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