Dynamic expression characteristics of Notch signal in bone marrow-derived mesenchymal stem cells during the process of differentiation into hepatocytes.

Notch signaling is often involved in early development which helps to determine the differentiation state and fate of stem cells destined to form different tissues in the body. Its role in the differentiation of BM-MSCs (bone marrow-derived mesenchymal stem cells) is much less clear. As there is great interest in the potential of BM-MSCs as a source of cells for treating liver damage, it is important to understand if Notch signaling promotes or suppresses BM-MSCs differentiation into hepatocytes. In the present study, RT-PCR, Western blot results and morphologic changes demonstrated that BM-MSCs could successfully differentiate into hepatocytes in our special induction system including the tissue extract of damaged liver. On the 21st day when the differentiation direction was determined in BM-MSCs, the mRNA level of Jagged2, Delta1, Delta3, Notch1, Notch2, Notch3 and Presenilin1, was significantly lower than that on days 0, 7, and 11. In the further experiments, down-regulation of Notch signaling was shown to be critical for BM-MSCs to differentiate into hepatocytes, as increased Jagged1 resulted in up-regulated Notch activation leading to higher levels of expression of Hes1 and Hey1, which completely blocked Albumin expresion in BM-MSCs. These results in our study showed that Notch signaling in BM-MSCs was necessary to initiate differentiation into hepatocytes, but must be down-regulated for the differentiation to proceed continuously.