Periplakin Attenuates Liver Fibrosis via Reprogramming CD44Cells into CD44Liver Progenitor Cells.

Abstract

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, PPLCD44cells and PPLCD44LPCs 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 PPLcells could be categorized into PPLCD44and PPLCD44subsets, and PPLCD44cells were found to redifferentiate into PPLCD44LPCs during liver fibrosis. Furthermore, transplantation of PPLCD44LPCs notably suppressed liver fibrosis. CONCLUSIONS: These findings demonstrate that PPLCD44cells can be reprogrammed into PPLCD44LPCs, which ameliorate liver fibrosis, suggesting a potential application of PPL for the treatment of liver fibrosis.