N1,N11-diethylnorspermine triggers dedifferentiation of HepaRG cells via modulation of spermidine levels

Human hepatic progenitor HepaRG cells were differentiated into mature hepatocyte-like cells, and their transcriptome was compared to transcriptome of genes in human hepatoma Huh7.5 cells. Analysis revealed that HepaRG cells display high levels of expression of hepatocyte-specific genes. Using transcriptome analysis it was shown that treatment of differentiated HepaRG cells caused with 5 uM N1,N11-diethylnorspermine (DENSpm), an inducer of spermidine/spermine-N1-acetylt transferase (SSAT) for 72 h, caused dedifferentiation of the cells resembling epithelial-mesenchymal transition. This dedifferentiation was abolished by addition of (R)-3-methylspermidine, a metabolically-stable functionally-active analogue of biogenic polyamine spermidine. These results demonstrate that polyamine metabolism and levels of spermidine are tightly linked to differentiation of hepatocytes.