Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Rd., Hangzhou, 310003, China; NHFPC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China.
Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada; State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Rd., Hangzhou, 310003, China.
Exp Cell Res. 2019 Oct 15;383(2):111511. doi: 10.1016/j.yexcr.2019.111511. Epub 2019 Jul 27.
Clinical trials testing mesenchymal stem cell (MSC) as a cellular remedy for acute liver injury (ALI) are underway, but its underlying mechanism has not been thoroughly scrutinized. We highlight that the metabolomic profile of the liver-resident immune cells is significantly altered after MSC administration; its potential correlation with ALI remission is discussed in this study. C57BL/6 mice are randomly divided into three groups: the sham group, MSC-treated ALI group and PBS-treated ALI group; acute liver injury is induced by intraperitoneal injection of carbon tetrachloride. A high-performance chemical isotope labeling liquid chromatography-mass spectrometry (CIL LC-MS) is exploited to profile amine, phenol and carbonyl submetabolome of the liver-resident immune cells in different treatments. 4295 peak pairs are quantified and 2461 peak pairs are further identified in zero-reaction and one-reaction libraries. Clear separation of the three groups is observed in the global PCA and OPLS-DA analyses. We identified 256 metabolites to be candidate biomarkers for ALI-activated immunity and 114 metabolites to be candidate biomarkers for MSC-modulated immunity. Ariginine, aspartate and glutamate metabolism are most affected in both cases, with eight significantly regulated metabolites as joints (glutamic-gamma-semialdehyde, aspartate acid, glutamate acid, gamma-Aminobutyric acidorinithine, 2-keto-glutaramic acid, N-acetylornithine, citrulline and ornithine). These findings shed new light on the therapeutic benefit of immune modulation during ALI rescue. It needs to be further investigated whether exogenous supply of certain metabolites will exert a profound impact on the metabolic network, crosstalking with immune responses and modulating ALI prognosis.
正在进行临床试验以测试间充质干细胞（MSC）作为急性肝损伤（ALI）的细胞治疗方法，但尚未对其潜在机制进行深入研究。我们强调，MSC 给药后肝驻留免疫细胞的代谢组学特征发生了明显改变；本研究讨论了其与 ALI 缓解的潜在相关性。C57BL/6 小鼠随机分为三组：假手术组、MSC 治疗 ALI 组和 PBS 治疗 ALI 组；通过腹腔注射四氯化碳诱导急性肝损伤。利用高性能化学同位素标记液相色谱-质谱（CIL LC-MS）对不同治疗组肝驻留免疫细胞的胺、酚和羰基亚代谢组进行分析。定量了 4295 个峰对，在零反应和一反应文库中进一步鉴定了 2461 个峰对。在全局 PCA 和 OPLS-DA 分析中观察到三组的明显分离。我们确定了 256 种代谢物作为 ALI 激活免疫的候选生物标志物，114 种代谢物作为 MSC 调节免疫的候选生物标志物。精氨酸、天冬氨酸和谷氨酸代谢在两种情况下都受到影响最大，有八个显著调节的代谢物作为关键代谢物（谷氨酸-γ-亚氨基戊醛、天冬氨酸酸、谷氨酸酸、γ-氨基丁酸、鸟氨酸、2-酮-谷氨酸、N-乙酰鸟氨酸、瓜氨酸和鸟氨酸）。这些发现为 ALI 抢救过程中的免疫调节治疗益处提供了新的见解。需要进一步研究外源性供应某些代谢物是否会对代谢网络产生深远影响，与免疫反应相互作用并调节 ALI 预后。
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