Pyrogallol enhances therapeutic effect of human umbilical cord mesenchymal stem cells against LPS-mediated inflammation and lung injury via activation of Nrf2/HO-1 signaling.
Pyrogallol enhances therapeutic effect of human umbilical cord mesenchymal stem cells against LPS-mediated inflammation and lung injury via activation of Nrf2/HO-1 signaling.
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DOI：
10.1016/j.freeradbiomed.2022.08.030
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发表时间：
2022-08
影响因子：
7.4
通讯作者：
Yue Zhang;Sushan Yang;Zhenhua Qiu;Li Huang;Linyan Huang;Yue-Dong Liang;Xuanyu Liu;Maosheng Wang-Maosheng-Wa
中科院分区：
文献类型：
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作者：
Yue Zhang;Sushan Yang;Zhenhua Qiu;Li Huang;Linyan Huang;Yue-Dong Liang;Xuanyu Liu;Maosheng Wang-Maosheng-Wa
间充质干细胞（MSCs）的异质性是其临床应用的主要挑战。认为用活性化合物预处理MSC可以增强潜在治疗分子的表达，从而实现稳定和有效的治疗结果。在本研究中，我们研究了连苯三酚增加人脐带间充质干细胞（hUCMSCs）对LPS诱导的急性肺损伤（ALI）的治疗效果的机制。用连苯三酚处理的hUCMSCs在mRNA和蛋白水平上增加HO-1的表达，伴随着Kelch样ECH相关蛋白1（Keap 1）降解，Nrf 2蛋白水平上调以及Nrf 2的核转位。此外，用N-乙酰半胱氨酸（NAC）和P38激酶抑制剂（SB 203580）预处理可逆转焦性没食子酸对Keap 1和Nrf 2的调节以及HO-1的上调。而NAC预处理消除了焦性没食子酚介导的P38激酶激活，表明焦性没食子酚衍生的ROS导致P38激酶激活，从而促进Nrf 2/HO-1信号传导。此外，我们发现，由邻苯三酚介导的ROS/P38/Nrf 2轴诱导的p62与Keap 1相互作用，导致Keap 1的自噬降解，这产生了一个正反馈回路，以进一步释放Nrf 2。此外，邻苯三酚预处理的hUCMSCs中HO-1的表达增加导致对BEAS-2B细胞中LPS介导的TLR 4/P-P65信号转导的抑制作用增强，从而导致对LPS诱导的一系列促炎介质表达的抑制增加。与未处理的hUCMSCs相比，经邻苯三酚预处理的hUCMSCs移植的Sprague-Dawley（SD）大鼠在LPS介导的肺病理改变、肺指数（肺/体比）增加、上皮细胞凋亡、TLR 4/NF-κB信号传导激活以及促炎介质释放方面表现出增强的改善。总之，这些结果表明，用邻苯三酚预处理的hUCMSC增强了hUCMSC的治疗功效，这可以提供一种有前景的治疗策略，以最大化基于hUCMSC的疗法用于治疗LPS相关的ALI的治疗功效。
The main challenges in clinical applications of mesenchymal stem cells (MSCs) are attributed to their heterogeneity. It is believed that preconditioning of MSCs with active compounds may enhance the expression of potentially therapeutic molecules and thus achieve stable and effective therapeutic outcomes. In the present study, we investigated the mechanism by which pyrogallol increased the therapeutic efficacy of human umbilical cord mesenchymal stem cells (hUCMSCs) against LPS-induced acute lung injury (ALI). hUCMSCs with pyrogallol treatment increased expression of HO-1 at both mRNA and protein levels, accompanied by Kelch-Like ECH-Associated Protein 1 (Keap1) degradation, and upregulation of the Nrf2 protein levels as well as nuclear translocation of Nrf2. Moreover, the modulation of Keap1 and Nrf2 as well as HO-1 upregulation by pyrogallol was reversed by pretreatment with N-acetylcysteine (NAC) and a P38 kinase inhibitor (SB203580). Whereas, NAC pretreatment abrogated pyrogallol-mediated activation of P38 kinase, indicating that pyrogallol-derived ROS led to P38 kinase activation, thus promoting Nrf2/HO-1 signaling. Additionally, we found that the induction of p62 by the pyrogallol-mediated ROS/P38/Nrf2 axis interacted with Keap1 and resulted in autophagic degradation of Keap1, which created a positive feedback loop to further release of Nrf2. Furthermore, the increased expression of HO-1 in pyrogallol-pretreated hUCMSCs led to enhanced inhibitory effects on LPS-mediated TLR4/P–P65 signaling in BEAS-2B cells, resulting in increasing suppression of LPS-indued expression of a series of pro-inflammatory mediators. Compared to untreated hUCMSCs, Sprague-Dawley (SD) rats with pyrogallol-primed hUCMSCs transplantation showed enhanced improvements in LPS-mediated lung pathological alterations, the increased lung index (lung/body ratio), apoptosis of epithelial cells, the activation of TLR4/NF-κB signaling as well as the release of pro-inflammatory mediators. Together, these results suggested that hUCMSCs with pyrogallol pretreatment enhanced the therapeutic efficacy of hUCMSCs, which may provide a promising therapeutic strategy to maximize the therapeutic efficacy of hUCMSC-based therapy for treating LPS-associated ALI.