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Exp Cell Res. 2019 Oct 15;383(2):111511. doi: 10.1016/j.yexcr.2019.111511. Epub 2019 Jul 27.

MSC-triggered metabolomic alterations in liver-resident immune cells isolated from CCl4-induced mouse ALI model.

Author information

1
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. Electronic address: xiaoweishi@zju.edu.cn.
2
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. Electronic address: jqliu97@zju.edu.cn.
3
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou, 310003, China; 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. Electronic address: deyingchen@zju.edu.cn.
4
Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada. Electronic address: minglei@ualberta.ca.
5
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou, 310003, China; 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. Electronic address: yujiong@zju.edu.cn.
6
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. Electronic address: xiehy@zju.edu.cn.
7
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; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou, 310003, China. Electronic address: zhoulin99@zju.edu.cn.
8
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou, 310003, China; Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada. Electronic address: liang.li@ualberta.ca.
9
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; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou, 310003, China. Electronic address: shusenzheng@zju.edu.cn.

Abstract

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.

KEYWORDS:

Acute liver injury; Chemical isotope labeling; Liquid chromatography−mass spectrometry; Liver-resident immune cells; Mesenchymal stem cell; Metabolomics; Pathway analysis

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