Hepatic progenitor cells (HPCs) are potential seed cells for hepatocyte transplantation treatment of liver diseases. ATRA can induce the differentiation and mature function of hepatic progenitor cells, but the mechanism is still poorly understood. Here, by using microRNA array to analyze the expression profiles of microRNA (miR), we found that miR-200 family molecules in HPCs were upregulated after ATRA treatment, especially miR-200a-3p, 200c-3p, and 141-3p. ATRA induction could downregulate the expression of hepatic stem markers Oct4 and AFP, and improve the expression of hepatic markers ALB, CK18, and TAT, and the activity of ALB-GLuc, as well as indocyanine green uptake and glycogen storage function of HPCs. These above effects of ATRA on HPC differentiation were almost inhibited by blocking of miR-200a-3p, but not miR-200c-3p and 141-3p using antagomir. Cell autophagy is associated with ATRA regulation in HPCs, compared with control group, the expression of LC3 and Beclin1 increased in ATRA-treated HPCs, and orange and red fluorescent spot, which represents autophagy flow, also enhanced after ATRA treatment. However, ATRA-induced cell autophagy level was inhibited in antagomir-200a-3p+ATRA-treated cells. Therefore, the present study indicates that antagomir-200a-3p is related to ATRA-induced hepatic differentiation of HPCs through regulating cell autophagy, supporting the possible use of ATRA as a key inducer in HPC-based therapy of liver diseases.

中文翻译：

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ATRA通过上调microRNA-200a诱导肝祖细胞分化。

肝祖细胞（HPC）是用于肝细胞肝移植治疗肝脏疾病的潜在种子细胞。ATRA可以诱导肝祖细胞的分化和成熟功能，但其机制仍知之甚少。在这里，通过使用microRNA阵列分析microRNA（miR）的表达谱，我们发现HPC中的miR-200家族分子在ATRA处理后被上调，尤其是miR-200a-3p，200c-3p和141-3p。ATRA诱导可下调肝干标志物Oct4和AFP的表达，并改善肝标志物ALB，CK18和TAT的表达，改善ALB-GLuc的活性，以及​​HPCs的吲哚菁绿吸收和糖原存储功能。ATRA对HPC分化的上述作用几乎被miR-200a-3p的阻断所抑制，但不是使用antagomir的miR-200c-3p和141-3p。细胞自噬与HPC中的ATRA调节有关，与对照组相比，ATRA处理的HPC中LC3和Beclin1的表达增加，橙色和红色荧光点代表自噬，在ATRA处理后也增强。但是，在antagomir-200a-3p + ATRA处理的细胞中，ATRA诱导的细胞自噬水平受到抑制。因此，本研究表明，antagomir-200a-3p通过调节细胞自噬与ATRA诱导的HPC肝分化有关，支持将ATRA用作基于HPC的肝脏疾病治疗的关键诱导剂。它代表自噬流，在ATRA治疗后也增强了。但是，在antagomir-200a-3p + ATRA处理的细胞中，ATRA诱导的细胞自噬水平受到抑制。因此，本研究表明，antagomir-200a-3p通过调节细胞自噬与ATRA诱导的HPC肝分化有关，支持将ATRA用作基于HPC的肝脏疾病治疗的关键诱导剂。它代表自噬流，在ATRA治疗后也增强了。但是，在antagomir-200a-3p + ATRA处理的细胞中，ATRA诱导的细胞自噬水平受到抑制。因此，本研究表明，antagomir-200a-3p通过调节细胞自噬与ATRA诱导的HPC肝分化有关，支持将ATRA用作基于HPC的肝脏疾病治疗的关键诱导剂。