TFEB regulates murine liver cell fate during development and regeneration

• DOI: 10.1038/s41467-020-16300-x
• Publication Date: 2020-05-18T10:02:50Z
• Authors: Nunzia Pastore; Tuong Huynh; Niculin J. Herz; Alessia Calcagni’; Tiemo J. Klisch; Lorenzo Brunetti; Kangho Ho Kim; Marco De Giorgi; Ayrea Hurley; Annamaria Carissimo; Margherita Mutarelli; Niya Aleksieva; Luca D’Orsi; William R. Lagor; David D. Moore; Carmine Settembre; Milton J. Finegold; Stuart J. Forbes; Andrea Ballabio
• Keywords: 0301 basic medicine; Medical Sciences; Regenerative Medicine; Inbred C57BL; Biochemistry; Oral and gastrointestinal; Transgenic; Cholangiocarcinoma; Mice; Stem Cell Research - Nonembryonic - Human; Models; Medical Specialties; 2.1 Biological and endogenous factors; Aetiology; Promoter Regions, Genetic; Biological Phenomena; Cancer; Pediatric; Transdifferentiation; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Phenomena; Liver Disease; Stem Cells; Q; Life Sciences; Cell Differentiation; SOX9 Transcription Factor; Up-Regulation; Phenotype; Liver; Medical Anatomy; Stem Cell Research - Nonembryonic - Non-Human; Protein Binding; Liver Cancer; 570; 1.1 Normal biological development and functioning; Science; Chronic Liver Disease and Cirrhosis; Biophysics; 610; Down-Regulation; Mice, Transgenic; Models, Biological; Article; Promoter Regions; 03 medical and health sciences; Rare Diseases; Genetic; Underpinning research; Spheroids, Cellular; Genetics; and Immunity; Animals; Regeneration; Cell Lineage; Biology; Cell Proliferation; TFEB; Stem Cell Research; Biological; Mice, Inbred C57BL; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Bile Duct Neoplasms; Bile Ducts; Cell Differentiation; Cell Proliferation; Cholangiocarcinoma; Down-Regulation; Hepatocytes; Liver; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Phenotype; Promoter Regions, Genetic; Protein Binding; Regeneration; SOX9 Transcription Factor; Spheroids, Cellular; Stem Cells; Up-Regulation; Cell Lineage; Bile Duct Neoplasms; and Structural Biology; Hepatocytes; Cellular; Bile Ducts; Spheroids; Digestive Diseases

AbstractIt 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 thatSox9, 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.