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经血来源间充质干细胞通过与 A2AR 激动剂联用减轻炎症并提高急性肝衰竭小鼠的存活率。

Menstrual blood-derived mesenchymal stem cells attenuate inflammation and improve the mortality of acute liver failure combining with A2AR agonist in mice.

机构信息

Department of Gastroenterology, Peking University First Hospital, Beijing, China.

Department of Oncological Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

出版信息

J Gastroenterol Hepatol. 2021 Sep;36(9):2619-2627. doi: 10.1111/jgh.15493. Epub 2021 Apr 5.

DOI:10.1111/jgh.15493
PMID:33729623
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8518829/
Abstract

BACKGROUND AND AIM

Acute liver failure (ALF) poses a serious public health issue. The menstrual blood-derived mesenchymal stem cells (MenSCs) have been applied to cure various liver-related diseases. However, the efficacy and mechanism are far from clear. This study aims to explore the efficacy and potential mechanism of MenSCs to cure ALF.

METHODS

We investigate the potential mechanism of MenSCs on the ALF in vitro and in vivo. A2A adenosine receptor (A2AR) activation was investigated as the potential reinforcer for MenSCs treatment. Lipid polysaccharide/d-galactosamine (d-GalN) was employed to induce ALF. Diverse techniques were used to measure the inflammatory cytokines and key signaling molecules. Hematoxylin-eosin stain and aminotransaminases were applied to evaluate the liver injury. Flow cytometry was employed to assess the T cells.

RESULTS

The MenSCs can decrease the lipid polysaccharide-induced inflammatory cytokine elevation and related signaling molecules in ALF, including TLR4, phosphorylated-NF-kBp65 (p-NF-kBp65), PI3K, and p-AKT, p-mTOR and p-IKK in vitro. Moreover, MenSCs also can significantly reverse the liver injury, inflammatory cytokines elevation and related signaling molecules increase, and Treg/Th17 ratio decrease in vivo. In addition, MenSCs plus A2AR agonist can enhance the above changes.

CONCLUSIONS

The MenSCs can attenuate the ALF-induced liver injury via inhibition of TLR4-mediated PI3K/Akt/mTOR/IKK signaling. Then, this inhibits the p-NF-κBp65 translocate into nuclear, which causes a decrease of inflammatory cytokines release. Moreover, A2AR agonist can play a synergic role with MenSCs and enhance the above-mentioned effects.

摘要

背景与目的

急性肝衰竭（ALF）是一个严重的公共卫生问题。月经血源性间充质干细胞（MenSCs）已被应用于治疗各种肝脏相关疾病。然而，其疗效和机制尚不清楚。本研究旨在探讨 MenSCs 治疗 ALF 的疗效及潜在机制。

方法

我们在体外和体内研究了 MenSCs 治疗 ALF 的潜在机制。研究了 A2A 腺苷受体（A2AR）的激活作为 MenSCs 治疗的潜在增强剂。脂多糖/半乳糖胺（d-GalN）用于诱导 ALF。采用多种技术检测炎症细胞因子和关键信号分子。苏木精-伊红染色和氨基转移酶用于评估肝损伤。流式细胞术用于评估 T 细胞。

结果

MenSCs 可降低脂多糖诱导的 ALF 中炎症细胞因子的升高和相关信号分子，包括 TLR4、磷酸化-NF-κBp65（p-NF-κBp65）、PI3K 和 p-AKT、p-mTOR 和 p-IKK。此外，MenSCs 还能显著逆转肝损伤、炎症细胞因子升高和相关信号分子增加以及 Treg/Th17 比值降低。此外，MenSCs 加 A2AR 激动剂可增强上述变化。

结论

MenSCs 通过抑制 TLR4 介导的 PI3K/Akt/mTOR/IKK 信号通路减轻 ALF 诱导的肝损伤。随后，这抑制了 p-NF-κBp65 向核内易位，导致炎症细胞因子释放减少。此外，A2AR 激动剂可与 MenSCs 发挥协同作用，增强上述作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04bd/8518829/3e199350f8ac/JGH-36-2619-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04bd/8518829/4e84d061750d/JGH-36-2619-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04bd/8518829/83a5f14aed2f/JGH-36-2619-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04bd/8518829/dcf30dcb1fd5/JGH-36-2619-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04bd/8518829/608526e2beae/JGH-36-2619-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04bd/8518829/d53458c925f0/JGH-36-2619-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04bd/8518829/3e199350f8ac/JGH-36-2619-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04bd/8518829/4e84d061750d/JGH-36-2619-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04bd/8518829/83a5f14aed2f/JGH-36-2619-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04bd/8518829/dcf30dcb1fd5/JGH-36-2619-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04bd/8518829/608526e2beae/JGH-36-2619-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04bd/8518829/d53458c925f0/JGH-36-2619-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04bd/8518829/3e199350f8ac/JGH-36-2619-g003.jpg

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