Chemically Derived Hepatic Progenitors Are Reprogrammed through Autophagy Suppression by A83-01

Area of Science:

• Hepatology
• Cell Biology
• Regenerative Medicine

Background:

• Chemically derived hepatic progenitors (hCdHs) show therapeutic potential for liver disease.
• The underlying mechanism of hCdH generation, particularly the role of autophagy, remains unclear.

Purpose of the Study:

• To investigate the role of autophagy in the generation mechanism of chemically derived hepatic progenitors (CdHs).
• To determine if modulating autophagy affects CdH proliferation and generation.

Main Methods:

• Utilized hepatocytes from C57BL/6 mice and human hepatocytes.
• Investigated autophagy flux during CdH generation using chemical inducers (HGF, A83-01, CHIR99021).
• Assessed the impact of autophagy suppression (bafilomycin A1) on CdH proliferation.

Main Results:

• Autophagy flux was inhibited during mouse CdH (mCdH) generation, with partial compensation by CHIR99021.
• Suppression of autophagy using bafilomycin A1 enhanced mCdH proliferation.
• Human CdHs (hCdHs) exhibited a similar autophagy inhibition pattern during generation.

Conclusions:

• Autophagy downregulation is a key mechanism promoting CdH proliferation during their generation.
• This study provides insights into the stable production of hCdHs for potential therapeutic applications in severe liver diseases.