Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 11221, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
Institute of Bioinformatics and Systems Biology, National Chiao Tung University, HsinChu 30010, Taiwan.
Stem Cell Reports. 2017 Jul 11;9(1):247-263. doi: 10.1016/j.stemcr.2017.05.008. Epub 2017 Jun 8.
The irreversibility of developmental processes in mammalian cells has been challenged by rising evidence that de-differentiation of hepatocytes occurs in adult liver. However, whether reversibility exists in mesenchymal stromal cell (MSC)-derived hepatocytes (dHeps) remains elusive. In this study, we find that hepatogenic differentiation (HD) of MSCs is a reversible process and is modulated by DNA methyltransferases (DNMTs). DNMTs are regulated by transforming growth factor β1 (TGFβ1), which in turn controls hepatogenic differentiation and de-differentiation. In addition, a stepwise reduction in TGFβ1 concentrations in culture media increases DNMT1 and decreases DNMT3 in primary hepatocytes (Heps) and confers Heps with multi-differentiation potentials similarly to MSCs. Hepatic lineage reversibility of MSCs and lineage conversion of Heps are regulated by DNMTs in response to TGFβ1. This previously unrecognized TGFβ1-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.
哺乳动物细胞发育过程的不可逆性一直受到质疑，因为越来越多的证据表明，肝细胞在成年肝脏中会去分化。然而，间充质基质细胞（MSC）衍生的肝细胞（dHeps）是否具有可逆性仍不清楚。在这项研究中，我们发现 MSC 的肝向分化（HD）是一个可逆的过程，受 DNA 甲基转移酶（DNMTs）的调控。DNMTs 受转化生长因子 β1（TGFβ1）的调节，而 TGFβ1 又反过来控制肝向分化和去分化。此外，培养物中 TGFβ1 浓度的逐步降低增加了原代肝细胞（Heps）中的 DNMT1，降低了 DNMT3，并使 Heps 具有与 MSC 相似的多向分化潜能。MSC 的肝系可逆性和 Heps 的谱系转化受 TGFβ1 调节的 DNMTs 调控。这条以前未被识别的 TGFβ1-DNMTs-MSC-HD 轴可能会进一步增加对肝脏正常和病理过程以及移植治疗肝脏疾病后 MSC 功能的理解。
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