Journal Article

TFEB regulates murine liver cell fate during development and regeneration

Carissimo, Annamaria, Hurley, Ayrea, Pastore, Nunzia, Settembre, Carmine, De Giorgi, Marco, Forbes, Stuart J., Calcagni’, Alessia, Brunetti, Lorenzo, Klisch, Tiemo J., Moore, David D., Finegold, Milton J., Ballabio, Andrea, Mutarelli, Margherita, Huynh, Tuong, Herz, Niculin J., Aleksieva, Niya, D’Orsi, Luca, Lagor, William R., Kim, Kangho Ho

2020

Overview

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. The Transcription Factor EB (TFEB) is known to regulate cellular homeostasis and energy metabolism, but its role in cell fate determination in the liver is unknown. Here, the authors show that TFEB regulates the progenitor/cholangiocyte lineage and that its depletion prevents tissue recovery upon injury.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/100 / 13/31 / 13/44 / 13/51 / 14 / 14/32 / 14/34 / 14/35 / 14/63 / 45 / 45/15 / 45/41 / 45/61 / 45/91 / 631/136/532/2128 / 631/532/489 / 64/110 / 64/60 / Animals / Autophagy / Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism / Bile Duct Neoplasms - pathology / Bile Ducts - metabolism / Biomedical materials / Cell Differentiation / Cell fate / Cell Lineage / Cell Proliferation / Cholangiocarcinoma - pathology / Depletion / Differentiation / Down-Regulation - genetics / Energy metabolism / Fetuses / Hepatocytes / Hepatocytes - cytology / Homeostasis / Humanities and Social Sciences / Injury prevention / Liver / Liver - cytology / Liver - physiology / Mice, Inbred C57BL / Mice, Transgenic / Models, Biological / multidisciplinary / Osteoblastogenesis / Phagocytosis / Phenotype / Pluripotency / Promoter Regions, Genetic - genetics / Protein Binding / Regeneration / Regeneration - physiology / Science / Science (multidisciplinary) / Sox9 protein / SOX9 Transcription Factor - genetics / SOX9 Transcription Factor - metabolism / Spheroids, Cellular - cytology / Stem cell transplantation / Stem cells / Stem Cells - cytology / Stem Cells - metabolism / Transcription factors / Up-Regulation - genetics