Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene

Cell. 1991 Jul 26;66(2):245-56. doi: 10.1016/0092-8674(91)90615-6.

Abstract

We previously demonstrated that expression of an albumin-urokinase-type plasminogen activator (Alb-uPA) fusion construct in transgenic mice resulted in elevated plasma uPA concentration, hypofibrinogenemia, and neonatal hemorrhaging. Two lines of Alb-uPA mice were established in which only one half of the transgenic pups died at birth; surprisingly, plasma uPA concentrations in survivors gradually returned to normal by 2 months of age. The basis for this phenomenon is DNA rearrangement within hepatocytes that affects the transgene tandem array and abolishes transgene expression. Transgene-deficient cells selectively proliferate relative to surrounding liver, and this process culminates in replacement of the entire liver by clonal hepatic nodules derived from transgene-deficient progenitor cells. In some cases as few as two nodules can reconstitute over 90% of liver mass, highlighting the remarkable regenerative capacity of individual liver cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Cell Nucleus / ultrastructure
  • Chromosome Deletion*
  • DNA Replication
  • Enzyme Precursors / physiology
  • Gene Expression
  • Liver / pathology
  • Liver / physiology
  • Liver / ultrastructure
  • Liver Regeneration*
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron
  • Molecular Sequence Data
  • Oligonucleotide Probes
  • Plasminogen Activators / analysis
  • Plasminogen Activators / genetics*
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Serum Albumin / analysis
  • Serum Albumin / genetics*
  • Urokinase-Type Plasminogen Activator / analysis
  • Urokinase-Type Plasminogen Activator / genetics*
  • alpha-Fetoproteins / analysis
  • alpha-Fetoproteins / genetics

Substances

  • Enzyme Precursors
  • Oligonucleotide Probes
  • RNA, Messenger
  • Serum Albumin
  • alpha-Fetoproteins
  • Plasminogen Activators
  • Urokinase-Type Plasminogen Activator