Hepatic cell therapy could provide a valuable strategy to generate new functional tissue in the diseased liver. We therefore investigated the repopulation capacity of undifferentiated epithelial stem/progenitor cells and mature hepatocytes transplanted into livers with advanced fibrosis/cirrhosis.

 

The livers had ongoing fibrogenesis and massive hepatocellular damage, indicated by increased levels of fibrogenic markers (e.g., α-SMA, procollagen, TIMP-1, MMP-2) and decreased levels of hepatocyte-specific mRNA transcripts (e.g., ASGPR, CYP3A1, G6Pase mRNA), induced by thioacetamide (TAA) administration in the DPPIV–  F344 rats. Prolonged TAA administration caused extensive stellate and stem/progenitor cell activation and bile duct proliferation in the fibrotic septa. At 3 months after starting TAA administration, fetal liver stem/progenitor cells derived from DPPIV+ F344 rats were transplanted in conjunction with partial hepatectomy (PH). During continued TAA administration, transplanted stem/progenitor cells differentiated into hepatocytic and biliary cells, formed large DPPIV+ cell clusters, and replaced whole fibrotic nodules. At 4 months after cell transplantation, ~40% repopulation was achieved by DPPIV+ cell clusters that encompassed entire fibrotic lobules. Importantly, after cell transplantation of stem/progenitor cells without PH, undifferentiated cells engrafted and formed small clusters within days after cell transplantation, leading to 24% liver replacement after 4 months. Stem/progenitor cells are 2-3 times smaller than hepatocytes, which allowed us to infuse much higher numbers of cells, and comparative studies with hepatocytes showed a clear advantage of stem/progenitor cells over mature hepatocytes. However, transplanted hepatocytes were also capable of engrafting and replaced up to ~10% fibrotic liver tissue at 4 months after cell infusion.

 

To investigate whether transplantation of stem/progenitor cells can reverse fibrosis, advanced fibrosis/cirrhosis was induced in DPPIV–  rats. At 3 months, cells were transplanted into TAA-treated rats, followed by continued TAA administration for 2 months, which was then discontinued for 1 month. Stem/progenitor cell-transplanted rats showed down-regulated expression of fibrosis-related genes (α-SMA, Col1a1, TIMP-1), indicating reduced fribrogenesis after cell transplantation.