Transl Res. 2017 Apr;182:61-74.e8.
Stem Cell Reports. 2017 Jul 11;9(1):247-263
The irreversibility of developmental processes in mammalian cells has been challenged by rising evidence that de-differentiation of hepatocytes occurs in adult liver. However, the underlying mechanism is still unclear. Here we found that the hepatic lineage reversibility is modulated by DNA methyltransferases (DNMTs) through studying within a useful model, hepatogenic differentiation of MSCs. Respectively, DNMT1 repressed and DNMT3a promoted hepatogenic differentiation. Besides, DNMT1 knockdown shortened hepatogenic differentiation time from 28 to 14 days. DNMTs are regulated by TGFb1, which in turn controls hepatogenic differentiation and de-differentiation. Also, a stepwise reduction in TGFb1 concentrations in culture alters the expression of DNMTs in primary hepatocytes (Heps) and confers Heps with multi-differentiation potentials similarly to MSCs. This previously unrecognized TGFb1-DNMTs-MSC-HD axis may further increase the understanding the normal and pathological processes in the liver, as well as functions of MSCs after transplantation to treat liver diseases. (Lee CW, et al. Stem cell reports. 2017 Jun.)