Regeneration of hepatocyte 'buds' in cirrhosis from intrabiliary stem cells.
OBJECTIVE
In massive hepatic necrosis, hepatic stem cells constitute a canal of Hering derived, cytokeratin 19 (CK19) positive 'ductular reaction' (DR). Whether DRs in cirrhosis are activated stem cells (so called 'buds') or biliary metaplasia of cholestatic, injured hepatocytes is still debated. We investigate derivation of intraseptal hepatocytes (ISHs) from DRs and from the biliary tree in cirrhosis.


METHODS
Explants of hepatitis B and C, alcohol, primary biliary cirrhosis and primary sclerosing cholangitis-related cirrhosis were examined. ISHs were quantified and their associations with DRs and cholestasis recorded. 3D-reconstruction of ISHs and nearby bile ducts was performed in blocks from hepatitis C and primary sclerosing cholangitis cirrhosis.


RESULTS
Seven hundred seventy five/830 (94%) ISHs were associated with CK19 positive DRs. ISHs without ductular reactions were more likely to show cholestatic features (P<0.0001). In 3D, ISHs were seen to bud directly from the biliary tree. In summary: ISHs: (1) are usually associated with stem cell-like DRs; (2) are rarely cholestatic, leaving the associated DRs unexplained; and (3) are linked to the biliary tree in 3D. Dynamic proliferation rates in hepatitis C over time suggest that hepatocyte replication diminishes in late stages, with an associated activation of the biliary stem cell compartment.


CONCLUSIONS
We therefore suggest that the biliary tree, from at least its smaller branches up to the canals of Hering, are composed of or at least harbor facultative hepatic stem cells, and that ISH largely represent 'buds' of newly formed hepatocytes.
Falkowski
Olga
O
Department of Pathology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA.
An
Hee Jung
HJ
Ianus
I Andreea
IA
Chiriboga
Luis
L
Yee
Herman
H
West
A Brian
AB
Theise
Neil D
ND
D001659:Biliary Tract / Q000473:pathology / Q000503:physiopathology*; D002455:Cell Division; D022781:Hepatocytes; D006801:Humans; D007091:Image Processing, Computer-Assisted; D021621:Imaging, Three-Dimensional; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000473:pathology / Q000503:physiopathology*; D008115:Liver Regeneration; D013234:Stem Cells