期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 14, 页码 3654-3659出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1621361114
关键词
liver; stem cells; regeneration; hepatocyte; lineage-restricted progenitors
资金
- Virginia and D. K. Ludwig Fund for Cancer Research
- National Heart, Lung, and Blood Institute [R01HL058770, U01HL099999]
- California Institute for Regenerative Medicine [RC1 00354]
- Human Frontier Science Program Career Development Award [CDA00017]
- German Research Foundation [RI 2787/1]
- Siebel Stem Cell Institute
- Thomas and Stacey Siebel Foundation [1119368-104-GHBJI]
- NIH [T32GM007365]
- National Research Service Award [1F30DK108561]
- Paul and Daisy Soros Fellowship for New Americans
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.
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