Localized hepatic lobular regeneration by central-vein-associated lineage-restricted progenitors.
The regeneration of organ morphology and function following tissue loss is critical to restore normal physiology, yet few cases are documented in mammalian postnatal life. Partial hepatectomy of the adult mammalian liver activates compensatory hepatocyte hypertrophy and cell division across remaining lobes, resulting in restitution of organ mass but with permanent alteration of architecture. Here, we identify a time window in early postnatal life wherein partial amputation culminates in a localized regeneration instead of global hypertrophy and proliferation. Quantifications of liver mass, enzymatic activity, and immunohistochemistry demonstrate that damaged lobes underwent multilineage regeneration, reforming a lobe often indistinguishable from undamaged ones. Clonal analysis during regeneration reveals local clonal expansions of hepatocyte stem/progenitors at injured sites that are lineage but not fate restricted. Tetrachimeric mice show clonal selection occurs during development with further selections following injury. Surviving progenitors associate mainly with central veins, in a pattern of selection different from that of normal development. These results illuminate a previously unknown program of liver regeneration after acute injury and allow for exploration of latent regenerative programs with potential applications to adult liver regeneration.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.|Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305.
Jonathan M
JM
Tsai
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305.|Department of Computer Science, Stanford University, Stanford, CA 94305.
Pang Wei
PW
Koh
Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, 81377 Munich, Germany.
Ania
A
Stefanska
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Liujing
L
Xing
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Graham G
0000-0002-9706-8356
GG
Walmsley
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Nicolas
N
Poux
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; irv@stanford.edu yuval.rinkevich@helmholtz-muenchen.de.|Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305.|Ludwig Center for Cancer Stem Cell Biology and Medicine, Stanford University, Stanford, CA 94305.
Irving L
IL
Weissman
Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, 81377 Munich, Germany; irv@stanford.edu yuval.rinkevich@helmholtz-muenchen.de.
Yuval
Y
Rinkevich
D000818:Animals; D000831:Animals, Newborn; D002455:Cell Division; D019070:Cell Lineage; D002999:Clone Cells; D008099:Liver / Q000166:cytology* / Q000502:physiology / Q000601:surgery*; D008115:Liver Regeneration; D051379:Mice; D008954:Models, Biological; D013234:Stem Cells / Q000166:cytology*
hepatocyte; lineage-restricted progenitors; liver; regeneration; stem cells