title: Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes.
abstract: Adult liver progenitor cells are biliary-like epithelial cells that emerge only under injury conditions in the periportal region of the liver. They exhibit phenotypes of both hepatocytes and bile ducts. However, their origin and their significance to injury repair remain unclear. Here, we used a chimeric lineage tracing system to demonstrate that hepatocytes contribute to the progenitor pool. RNA-sequencing, ultrastructural analysis, and in vitro progenitor assays revealed that hepatocyte-derived progenitors were distinct from their biliary-derived counterparts. In vivo lineage tracing and serial transplantation assays showed that hepatocyte-derived proliferative ducts retained a memory of their origin and differentiated back into hepatocytes upon cessation of injury. Similarly, human hepatocytes in chimeric mice also gave rise to biliary progenitors in vivo. We conclude that human and mouse hepatocytes can undergo reversible ductal metaplasia in response to injury, expand as ducts, and subsequently contribute to restoration of the hepatocyte mass.
authors.affiliation: Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Department of Pediatrics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. Electronic address: tarlowb@ohsu.edu.
authors.forename: Branden D
authors.initials: BD
authors.lastname: Tarlow
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Pelz
authors.affiliation: Department of Gastroenterology & Hepatology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Willscott E
authors.initials: WE
authors.lastname: Naugler
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Wakefield
authors.affiliation: Yecuris Corporation, P.O. box 4645, Tualatin, OR 97062, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Wilson
authors.affiliation: Department of Pathology, Baylor College of Medicine, 6621 Fannin Street, Houston, TX 77030, USA.
authors.forename: Milton J
authors.initials: MJ
authors.lastname: Finegold
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002469:Cell Separation; D060833:Cellular Microenvironment; D002999:Clone Cells; D005786:Gene Expression Regulation; D006500:Hepatic Duct, Common / Q000166:cytology; D022781:Hepatocytes / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D008099:Liver / Q000473:pathology*; D008648:Mesoderm / Q000378:metabolism; D008810:Mice, Inbred C57BL; D055758:SOX9 Transcription Factor / Q000378:metabolism
chemical_list: D015415:Biomarkers; D055758:SOX9 Transcription Factor