Periplakin attenuates liver fibrosis via reprogramming CD44Low cells into CD44High liver progenitor cells.

Abstract

Background & aims: Liver progenitor cells (LPCs) contribute significantly to the restoration of injured liver parenchyma and promoting liver regeneration, thereby ameliorating liver fibrosis. However, the mechanism of the derivation of LPCs remains poorly understood.

Methods: We first examined the expression of 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 DDC-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 re-differentiate into PPL⁺CD44^High LPCs during liver fibrosis. Furthermore, transplantation of PPL⁺CD44^High LPCs notably suppressed liver fibrosis.

Conclusion: 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.