Nakano Toshiaki, Chen I-Hsuan, Goto Shigeru, Lai Chia-Yun, Tseng Hui-Peng, Hsu Li-Wen, Chiu King-Wah, Lin Chih-Che, Wang Chih-Chi, Cheng Yu-Fan, Chen Chao-Long
1 Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine , Kaohsiung, Taiwan .
2 Division of Transplant immunology, Liver Transplantation Center, Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine , Kaohsiung, Taiwan .
OMICS. 2017 Jan;21(1):55-66. doi: 10.1089/omi.2016.0164.
Acute rejection (AR) of liver transplantation remains a formidable challenge for diagnostic medicine and biomarker discovery. We characterized AR-related microRNAs (miRNAs) and the underlying AR mechanisms in liver transplantation. Using a rat model of orthotopic liver transplantation (OLT) as well as microarrays, we compared the miRNA expression profiles between naive and AR livers on day 7 after OLT with short- (<14 days, donor Dark Agouti [DA] liver into Lewis [LEW] recipient) and long-term (>60 days, donor DA liver into Piebald Virol Glaxo [PVG] recipient) survival fates. The microarray analysis revealed that the levels of miR-301a in the lethal AR livers were significantly higher than in naive and tolerogenic AR livers. The reduced expression of miR-301a in inflamed livers suggested a difference between AR and inflammation in terms of miR-301a-mediated molecular events. Overexpression of hepatic miR-301a induced IL-6 production in rat primary hepatocytes. Hepatocytes overexpressing miR-301a were capable of transferring miR-301a to cocultured splenocytes through exosomes. These splenocytes then showed overexpression of miR-301a and downregulation of protein inhibitor of activated STAT3 (PIAS3) expression, resulting in the induction of T helper 17 cell differentiation. In conclusion, this report raises the possibility that hepatic miR-301a might potentially prove value as a biomarker of liver transplant rejection. We call for future research on this molecular target and the attendant pathways as liver transplant rejection and its early diagnosis continue to be veritable healthcare challenges.
肝移植急性排斥反应（AR）对于诊断医学和生物标志物发现而言仍然是一项艰巨的挑战。我们对肝移植中与AR相关的微小RNA（miRNA）及其潜在的AR机制进行了表征。利用原位肝移植（OLT）大鼠模型以及微阵列，我们比较了OLT术后第7天初次肝和AR肝之间的miRNA表达谱，这些肝移植具有短期（<14天，供体黑褐大鼠[DA]肝移植到刘易斯[LEW]受体）和长期（>60天，供体DA肝移植到花斑维尔罗格拉克索[PVG]受体）存活结局。微阵列分析显示，致死性AR肝中miR-301a的水平显著高于初次肝和耐受性AR肝。炎症肝中miR-301a表达的降低表明在miR-301a介导的分子事件方面AR和炎症之间存在差异。肝miR-301a的过表达诱导大鼠原代肝细胞中白细胞介素-6（IL-6）的产生。过表达miR-301a的肝细胞能够通过外泌体将miR-301a转移至共培养的脾细胞。这些脾细胞随后显示miR-301a过表达以及信号转导子和转录激活子3（STAT3）的蛋白抑制剂（PIAS3）表达下调，从而导致辅助性T细胞17（Th17）细胞分化的诱导。总之，本报告提出了肝miR-301a可能作为肝移植排斥反应生物标志物具有潜在价值的可能性。鉴于肝移植排斥反应及其早期诊断仍然是切实的医疗挑战，我们呼吁针对这一分子靶点及其相关途径开展未来研究。
