The sources of parenchymal regeneration after chronic hepatocellular liver injury in mice.
After liver injury, parenchymal regeneration occurs through hepatocyte replication. However, during regenerative stress, oval cells (OCs) and small hepatocyte like progenitor cells (SHPCs) contribute to the process. We systematically studied the intra-hepatic and extra-hepatic sources of liver cell replacement in the hepatitis B surface antigen (HBsAg-tg) mouse model of chronic liver injury. Female HBsAg-tg mice received a bone marrow (BM) transplant from male HBsAg-negative mice, and half of these animals received retrorsine to block indigenous hepatocyte proliferation. Livers were examined 3 and 6 months post-BM transplantation for evidence of BM-derived hepatocytes, OCs, and SHPCs. In animals that did not receive retrorsine, parenchymal regeneration occurred through hepatocyte replication, and the BM very rarely contributed to hepatocyte regeneration. In mice receiving retrorsine, 4.8% of hepatocytes were Y chromosome positive at 3 months, but this was frequently attributable to cell fusion between indigenous hepatocytes and donor BM, and their frequency decreased to 1.6% by 6 months, as florid OC reactions and nodules of SHPCs developed. By analyzing serial sections and reconstructing a 3-dimensional map, continuous streams of OCs could be seen that surrounded and entered deep into the nodules of SHPCs, connecting directly with SHPCs, suggesting a conversion of OCs into SHPCs. In conclusion, during regenerative stress, the contribution to parenchymal regeneration from the BM is minor and frequently attributable to cell fusion. OCs and SHPCs are of intrinsic hepatic origin, and OCs can form SHPC nodules.
Vig
Pamela
P
Hepatology Section, Imperial College London, United Kingdom.
Russo
Francesco P
FP
Edwards
Robert J
RJ
Tadrous
Paul J
PJ
Wright
Nicholas A
NA
Thomas
Howard C
HC
Alison
Malcolm R
MR
Forbes
Stuart J
SJ
D000818:Animals; D016026:Bone Marrow Transplantation; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006514:Hepatitis B Surface Antigens; D008099:Liver / Q000166:cytology* / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011763:Pyrrolizidine Alkaloids / Q000494:pharmacology; D013234:Stem Cells / Q000502:physiology
D006514:Hepatitis B Surface Antigens; D011763:Pyrrolizidine Alkaloids; C003300:retrorsine