Hepatocyte buds derived from progenitor cells repopulate regions of parenchymal extinction in human cirrhosis

Repair of cirrhotic livers occurs, in part, by repopulation with hepatocytes through the stem/progenitor pathway. There remain many uncertainties regarding this pathway. Hepatocyte “buds” occurring in broad septa are hypothesized to be the anatomic manifestation of this pathway. Our purpose was to define a morphologic sequence of bud maturation to allow a quantitative measure of the importance of the stem/progenitor pathway in humans. Histologic sections from 37 liver resection specimens were stained with trichrome, epithelial cell adhesion molecule (EpCAM), K19, CD34, glutamine synthetase (GS), and Ki‐67. Specimens were stratified by etiology (10 biliary, 22 nonbiliary, five controls) and stage. Buds were defined as clusters of hepatocytes within septa. Five levels of bud maturation (0‐4) were defined by the progressive increase in hepatocyte progeny relative to cholangiocytes. Level 0 single‐cell buds are K19 + /GS + /EpCAM + /Heppar1 − . In level 1, the progeny are morphologically hepatocytes (K19 − /GS + /EpCAM + /Heppar1 + ). In level 2‐4 buds, hepatocytes increase and become progressively GS − and EpCAM − . Associated endothelium is CD34 + in level 1‐2 buds and becomes CD34 − near hepatic veins in level 3‐4 buds. Progeny of the bud sequence may represent up to 70% of hepatocytes (immaturity index of 70%). In biliary disease, bud number is reduced in association with duct loss and cholestatic destruction of nascent buds. Conclusions : The stem/progenitor pathway, manifested anatomically by the bud sequence, is a major mechanism for repopulation of cirrhotic livers. The bud sequence reveals some critical features of hepatic morphogenesis, including that 1) the majority of distal cholangiocytes have stem‐like properties, and 2) availability of bile ducts and/or venous drainage are limiting factors for regeneration. (H epatology 2015;61:1696–1707)