Feng Lei, Wang Yi, Fu Yu, Yimamu Adilijiang, Guo Zeyi, Zhou Chenjie, Li Shao, Zhang Linya, Qin Jiasheng, Liu Shusong, Xu Xiaoping, Jiang Zesheng, Cai Shaoru, Zhang Jianmin, Li Yang, Peng Qing, Yi Xiao, He Guolin, Li Ting, Gao Yi
Department of Hepatobiliary Surgery II, Zhujiang Hospital Southern Medical University Guangzhou Guangdong China.
Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital Southern Medical University Guangzhou Guangdong China.
Bioeng Transl Med. 2023 Jun 2;8(5):e10552. doi: 10.1002/btm2.10552. eCollection 2023 Sep.
Acute liver failure (ALF) is a life-threatening condition. Cell-based and cell-free-based therapies have proven to be effective in treating ALF; however, their clinical application is limited by cell tumorigenicity and extracellular vesicle (EV) isolation in large doses. Here, we explored the effectiveness and mechanism of umbilical cord mesenchymal stem cells (hUCMSCs)-based bioartificial liver (hUCMSC-BAL), which is a simple and efficient strategy for ALF. D-galactosamine-based pig and mouse ALF models were used to explore the effectiveness of hUCMSC-BAL and hUCMSC-sEV therapies. Furthermore, high-throughput sequencing, miRNA transcriptome analysis, and western blot were performed to clarify whether the miR-139-5p/PDE4D axis plays a critical role in the ALF model in vivo and in vitro. hUCMSC-BAL significantly reduced inflammatory responses and cell apoptosis. hUCMSC-sEV significantly improved liver function in ALF mice and enhanced the regeneration of liver cells. Furthermore, hUCMSC-sEV miRNA transcriptome analysis showed that miR-139-5p had the highest expression and that PDE4D was one of its main target genes. The sEV miR-139-5p/PDE4D axis played a role in the treatment of ALF by inhibiting cell apoptosis. Our data indicate that hUCMSC-BAL can inhibit cytokine storms and cell apoptosis through the sEV miR-139-5p/PDE4D axis. Therefore, we propose hUCMSC-BAL as a therapeutic strategy for patients with early ALF.
急性肝衰竭（ALF）是一种危及生命的病症。基于细胞和基于无细胞的疗法已被证明在治疗ALF方面有效；然而，它们的临床应用受到细胞致瘤性和大剂量细胞外囊泡（EV）分离的限制。在此，我们探索了基于脐带间充质干细胞（hUCMSCs）的生物人工肝（hUCMSC - BAL）的有效性和机制，这是一种针对ALF的简单而有效的策略。基于D - 半乳糖胺的猪和小鼠ALF模型用于探索hUCMSC - BAL和hUCMSC - sEV疗法的有效性。此外，进行了高通量测序、miRNA转录组分析和蛋白质印迹，以阐明miR - 139 - 5p/PDE4D轴在体内和体外的ALF模型中是否起关键作用。hUCMSC - BAL显著降低了炎症反应和细胞凋亡。hUCMSC - sEV显著改善了ALF小鼠的肝功能并增强了肝细胞的再生。此外，hUCMSC - sEV miRNA转录组分析表明miR - 139 - 5p表达最高，且PDE4D是其主要靶基因之一。sEV miR - 139 - 5p/PDE4D轴通过抑制细胞凋亡在ALF治疗中发挥作用。我们的数据表明，hUCMSC - BAL可通过sEV miR - 139 - 5p/PDE4D轴抑制细胞因子风暴和细胞凋亡。因此，我们提出hUCMSC - BAL作为早期ALF患者的一种治疗策略。
