ISX-9 通过 NGFR-ERK-TAU-β-Catenin 信号轴促进间充质干细胞分泌 KGF 以缓解 ALI。

IF 5.4 2区 医学 Q1 CELL & TISSUE ENGINEERING
Yi Tian, Qinyi Deng, Xiaotong Yang, Chen Wang, Van Minh Le, Ri Ji, Xin Liang, Yun Feng
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引用次数: 0

摘要

背景:间充质干细胞(MSCs)因其旁分泌功能而被广泛用于缓解急性肺损伤(ALI)。然而,炎症爆发的微环境极大地限制了间充质干细胞分泌的因子,如角质形成细胞生长因子(KGF)。KGF是一种具有组织修复能力的生长因子。间充质干细胞与促进其旁分泌功能的化合物结合是否有更好的治疗前景?通过化合物筛选,我们筛选出异噁唑-9(ISX-9)可促进间充质干细胞分泌KGF,并对其作用机制进行了研究:方法:通过双荧光素酶报告基因试验筛选出促进KGF分泌的化合物。方法:通过双荧光素酶报告基因检测法筛选出促进KGF分泌的化合物,并采用TMT同位素标记定量技术检测ISX-9在间充质干细胞中的差异蛋白。通过 Western 印迹检测了 NGFR、ERK、TAU 和 β-catenin 的表达。在 ALI 模型中,我们通过 HE 染色、SOD 含量检测、RT-qPCR、免疫荧光等方法测定了炎症变化。通过光学活体成像探讨了 ISX-9 对间叶干细胞移植停留时间的影响:结果:我们发现 ISX-9 能促进间充质干细胞中 KGF 的表达。ISX-9作用于膜受体蛋白NGFR,上调下游信号蛋白ERK和TAU的磷酸化,下调β-catenin的磷酸化,并加速β-catenin进入细胞核,进一步提高KGF的表达。在ALI模型中,ISX-9与间充质干细胞联合治疗可提高KGF在肺部的表达,与间充质干细胞单独治疗相比,可增强间充质干细胞在减轻炎症和修复肺损伤方面的作用:结论:ISX-9能促进间充质干细胞在体内和体外分泌KGF。结论:ISX-9可促进间充质干细胞在体内和体外分泌KGF,与单独应用间充质干细胞治疗ALI相比,ISX-9与间充质干细胞联合应用可增强间充质干细胞的旁分泌功能和抗炎作用。ISX-9在间充质干细胞移植治疗ALI中起到了促进作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ISX-9 Promotes KGF Secretion From MSCs to Alleviate ALI Through NGFR-ERK-TAU-β-Catenin Signaling Axis.

Background: Mesenchymal stem cells (MSCs) have been widely studied to alleviate acute lung injury (ALI) due to their paracrine function. However, the microenvironment of inflammatory outbreaks significantly restricted the factors secreted from MSCs like keratinocyte growth factor (KGF). KGF is a growth factor with tissue-repaired ability. Is there a better therapeutic prospect for MSCs in combination with compounds that promote their paracrine function? Through compound screening, we screened out isoxazole-9 (ISX-9) to promote MSCs derived KGF secretion and investigated the underlying mechanisms of action.

Methods: Compounds that promote KGF secretion were screened by a dual-luciferase reporter gene assay. The TMT isotope labeling quantitative technique was used to detect the differential proteins upon ISX-9 administrated to MSCs. The expressions of NGFR, ERK, TAU, and β-catenin were detected by Western blot. In the ALI model, we measured the inflammatory changes by HE staining, SOD content detection, RT-qPCR, immunofluorescence, etc. The influence of ISX-9 on the residence time of MSCs transplantation was explored by optical in vivo imaging.

Results: We found out that ISX-9 can promote the expression of KGF in MSCs. ISX-9 acted on the membrane receptor protein NGFR, upregulated phosphorylation of downstream signaling proteins ERK and TAU, downregulated phosphorylation of β-catenin, and accelerated β-catenin into the nucleus to further increase the expression of KGF. In the ALI model, combined ISX-9 with MSCs treatments upgraded the expression of KGF in the lung, and enhanced the effect of MSCs in reducing inflammation and repairing lung damage compared with MSCs alone.

Conclusions: ISX-9 facilitated the secretion of KGF from MSCs both in vivo and in vitro. The combination of ISX-9 with MSCs enhanced the paracrine function and anti-inflammatory effect of MSCs compared with MSCs applied alone in ALI. ISX-9 played a contributive role in the transplantation of MSCs for the treatment of ALI.

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来源期刊
Stem Cells Translational Medicine
Stem Cells Translational Medicine CELL & TISSUE ENGINEERING-
CiteScore
12.90
自引率
3.30%
发文量
140
审稿时长
6-12 weeks
期刊介绍: STEM CELLS Translational Medicine is a monthly, peer-reviewed, largely online, open access journal. STEM CELLS Translational Medicine works to advance the utilization of cells for clinical therapy. By bridging stem cell molecular and biological research and helping speed translations of emerging lab discoveries into clinical trials, STEM CELLS Translational Medicine will help move applications of these critical investigations closer to accepted best patient practices and ultimately improve outcomes. The journal encourages original research articles and concise reviews describing laboratory investigations of stem cells, including their characterization and manipulation, and the translation of their clinical aspects of from the bench to patient care. STEM CELLS Translational Medicine covers all aspects of translational cell studies, including bench research, first-in-human case studies, and relevant clinical trials.
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