Periplakin Attenuates Liver Fibrosis via Reprogramming CD44(Low) Cells into CD44(High) Liver Progenitor Cells.

BACKGROUND & AIMS: Liver progenitor cells (LPCs) contribute significantly to the restoration of injured liver parenchyma and promote liver regeneration, thereby ameliorating liver fibrosis. However, the mechanism of the derivation of LPCs remains poorly understood. METHODS: We first examined the expression of periplakin (PPL) in patients and mouse models with liver fibrosis. Adenovirus overexpressing PPL was injected into the tail vein of mouse models to detect the regulatory effect of PPL on liver fibrosis. Single-cell sequencing explored how PPL influences liver fibrosis progression. Additionally, PPL(+)CD44(Low) cells and PPL(+)CD44(High) LPCs were transplanted into 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced mouse models to assess their therapeutic efficacy in treating liver fibrosis. RESULTS: The expression of PPL is upregulated in fibrotic livers in human and mouse models of liver fibrosis. Functionally, we found that PPL overexpression significantly attenuated liver fibrosis. Mechanistically, PPL was specifically expressed in LPCs and promoted LPC expansion. Moreover, we observed that PPL(+) cells could be categorized into PPL(+)CD44(Low) and PPL(+)CD44(High) subsets, and PPL(+)CD44(Low) cells were found to redifferentiate into PPL(+)CD44(High) LPCs during liver fibrosis. Furthermore, transplantation of PPL(+)CD44(High) LPCs notably suppressed liver fibrosis. CONCLUSIONS: These findings demonstrate that PPL(+)CD44(Low) cells can be reprogrammed into PPL(+)CD44(High) LPCs, which ameliorate liver fibrosis, suggesting a potential application of PPL for the treatment of liver fibrosis.