The liver is thought to utilize facultative stem cells, also known as "oval cells" or "atypical ductal cells" (ADCs), for regeneration following various types of injury. However, this notion has been based largely on in vitro studies and transplantation models; where lineage tracing has been used, results have been conflicting and effect sizes have been small. Here, we used genetic and nucleoside analog-based tools to mark and track the origin and contribution of various cell populations to liver regeneration in vivo following several ADC-inducing insults. We report that, contrary to prevailing stem-cell-based models of regeneration, virtually all new hepatocytes come from preexisting hepatocytes.
Bibliographical noteFunding Information:
We thank V. Factor and D. Melton for providing A6 and Krt19 antibodies, respectively. We are grateful to A. Panikkar and C. Yang for technical assistance and the Abramson Family Center Research Institute histology core for sample processing. We are indebted to F. Camargo, K. Kaestner, K. Zaret, J. Rajagopal, and L. Greenbaum for helpful discussions and especially grateful to A. Penzo-Mendez for insightful comments on the manuscript. This work was supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases Center for Molecular Studies in Digestive and Liver Diseases (P30DK050306) and its core facilities (Molecular Pathology and Imaging Core, Molecular Biology/Gene Expression Core, Transgenic and Chimeric Mouse Core, and Cell Culture Core), as well as by Public Health Service grant DK083355 (to B.Z.S.), a grant from the European Research Council within the FP-7 (281738 LIVERMICROENV to E.P.), and an award from the Pew Charitable Trusts (to B.Z.S.).
© 2014 Elsevier Inc.