Mature hepatocytes are the source of small hepatocyte-like progenitor cells in the retrorsine model of liver injury.
OBJECTIVE
Mature hepatocytes divide to restore liver mass after injury. However, when hepatocyte division is impaired by retrorsine poisoning, regeneration proceeds from another cell type: the small hepatocyte-like progenitor cells (SHPCs). Our aim was to test whether SHPCs could originate from mature hepatocytes.


METHODS
Mature hepatocytes were genetically labeled using retroviral vectors harboring the beta-galactosidase gene. After labeling, retrorsine was administered to rats followed by a partial hepatectomy to trigger regeneration. A liver biopsy was performed one month after surgery and rats were sacrificed one month later.


RESULTS
We observed the proliferation of small hepatocytes arranged in clusters in liver biopsies. These cells expressed Ki67 antigen and displayed a high mitotic index. At sacrifice, regeneration was completed and clusters had merged. A significant proportion of clusters also expressed beta-galactosidase demonstrating their origin from labeled mature hepatocytes. Finally, the overall proportion of beta-galactosidase positive cells was identical at the time of hepatectomy as well as in liver biopsy and at sacrifice.


CONCLUSIONS
The constant proportion of beta-galactosidase positive cells during the regeneration process demonstrates that mature hepatocytes are randomly recruited to proliferate and compensate parenchyma loss in this model. Furthermore, mature hepatocytes are the source of SHPC after retrorsine injury.
Avril
Audrey
A
Biothérapies Hépatiques, CIC-INSERM 00-04, CHU Hôtel-Dieu, 44093 Nantes Cedex 01, France.
Pichard
Virginie
V
Bralet
Marie-Pierre
MP
Ferry
Nicolas
N
D000818:Animals; D030801:Animals, Genetically Modified; D000972:Antineoplastic Agents, Phytogenic / Q000506:poisoning; D056486:Chemical and Drug Induced Liver Injury; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000166:cytology*; D007763:Lac Operon; D008107:Liver Diseases / Q000473:pathology*; D008115:Liver Regeneration / Q000502:physiology; D008297:Male; D011763:Pyrrolizidine Alkaloids / Q000506:poisoning; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology*; D001616:beta-Galactosidase / Q000235:genetics
D000972:Antineoplastic Agents, Phytogenic; D011763:Pyrrolizidine Alkaloids; D001616:beta-Galactosidase; C003300:retrorsine