Therapeutic potential of chemically induced liver progenitor cells for liver fibrosis

Background and Aims: We have recently reported a novel method to generate liver progenitor-like cells, named chemically induced liver progenitors (CLiPs), from adult mature hepatocytes by just adding small molecules in the medium (A-83-01 and CHIR-99021) (Cell Stem Cell 20:41, 2017; Elife 8:e47313, 2019). When we transplanted human hepatocyte-derived CLiPs (hCLiPs) in severe acute liver failure model mice, a significant repopulation capacity was observed. Here, we examined whether hCLiPs could also be useful for the treatment of liver fibrosis.
Methods: Liver fibrosis was induced by intraperitoneal administration of carbon tetrachloride (0.5 mL/kg) twice a week for 8 weeks to NOD-SCID mice. hCLiPs or vehicles were intrasplenically transplanted into the liver fibrosis model mice. A co-culture experiment of hCLiPs and hepatic stellate cells was also conducted.
Results: Pathological liver fibrosis level and hydroxyproline level were improved by the transplantation of hCLiPs. The mRNA expression levels of MMP2 were increased, while those of COL1A, αSMA, and TIMP1 were decreased in the transplantation groups. In vitro, protein and mRNA levels of αSMA in the activated hepatic stellate cells were downregulated by the co-culture of hCLiPs and by the exposure to hCLiP-derived extracellular vesicles.
Conclusion: hCLiPs and their secretory contents could have therapeutic potential for liver fibrosis.