PPARβ/δ Is Required for Mesenchymal Stem Cell Cardioprotective Effects Independently of Their Anti-inflammatory Properties in Myocardial Ischemia-Reperfusion Injury.
PPARβ/δ Is Required for Mesenchymal Stem Cell Cardioprotective Effects Independently of Their Anti-inflammatory Properties in Myocardial Ischemia-Reperfusion Injury.
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DOI：
10.3389/fcvm.2021.681002
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发表时间：
2021
影响因子：
3.6
通讯作者：
Djouad F
中科院分区：
文献类型：
--
作者：
Nernpermpisooth N;Sarre C;Barrere C;Contreras R;Luz-Crawford P;Tejedor G;Vincent A;Piot C;Kumphune S;Nargeot J;Jorgensen C;Barrère-Lemaire S;Djouad F
心肌梗死是世界上死亡率最高的疾病。由于成人心脏不能再生，纤维化的发展是为了弥补梗塞后收缩组织的损失，导致心脏重塑和心力衰竭。成体间充质干细胞（MSC）的再生特性及其安全性和有效性已在临床前模型中得到证实。然而，在临床试验中，它们的有益效果是有争议的。在关节炎的实验模型中，我们之前已经证明PPARβ/δ缺乏增强了MSC的治疗效果。本研究的目的是比较野生型MSC （MSC）和缺乏型MSC （KO MSC）灌注在离体小鼠缺血再灌注（IR）损伤模型中的治疗效果。为此，C57BL/6J小鼠的心脏在体外缺血30分钟后再灌注1小时。再灌注时将MSC和KO MSC注入Langendorff系统。再灌注1 h后，采用TTC法评估梗死面积。在基础条件下（缺血前）和缺血后1 h再灌注时收集冠状动脉流出物，分析其细胞因子谱。在体外建立不同剂量MSC（3.105、6.105和24.105细胞/心脏）对心脏保护作用的剂量-反应曲线，发现6.105剂量的MSC为最佳浓度。我们发现MSC的心脏保护作用是PPARβ/δ依赖的，因为它在使用KO MSC时丢失了。此外，再灌注60分钟后洗脱液中收集的冠状动脉流出物的细胞因子谱显示，与未治疗的心脏相比，MSC治疗减少了CXCL1趋化因子和白细胞介素-6的释放。当用PPARβ/δ缺乏的MSC处理心脏时，也观察到MSC的这种抗炎作用。总之，我们的研究表明，在体外IR损伤模型中，MSC的急性心脏保护特性是PPARβ/δ依赖的，但与它们的抗炎作用无关，通过再灌注1小时梗死面积的减少来评估。
Myocardial infarction ranks first for the mortality worldwide. Because the adult heart is unable to regenerate, fibrosis develops to compensate for the loss of contractile tissue after infarction, leading to cardiac remodeling and heart failure. Adult mesenchymal stem cells (MSC) regenerative properties, as well as their safety and efficacy, have been demonstrated in preclinical models. However, in clinical trials, their beneficial effects are controversial. In an experimental model of arthritis, we have previously shown that PPARβ/δ deficiency enhanced the therapeutic effect of MSC. The aim of the present study was to compare the therapeutic effects of wild-type MSC (MSC) and MSC deficient for PPARβ/δ (KO MSC) perfused in an ex vivo mouse model of ischemia-reperfusion (IR) injury. For this purpose, hearts from C57BL/6J mice were subjected ex vivo to 30 min ischemia followed by 1-h reperfusion. MSC and KO MSC were injected into the Langendorff system during reperfusion. After 1 h of reperfusion, the TTC method was used to assess infarct size. Coronary effluents collected in basal condition (before ischemia) and after ischemia at 1 h of reperfusion were analyzed for their cytokine profiles. The dose-response curve for the cardioprotection was established ex vivo using different doses of MSC (3.105, 6.105, and 24.105 cells/heart) and the dose of 6.105 MSC was found to be the optimal concentration. We showed that the cardioprotective effect of MSC was PPARβ/δ-dependent since it was lost using KO MSC. Moreover, cytokine profiling of the coronary effluents collected in the eluates after 60 min of reperfusion revealed that MSC treatment decreases CXCL1 chemokine and interleukin-6 release compared with untreated hearts. This anti-inflammatory effect of MSC was also observed when hearts were treated with PPARβ/δ-deficient MSC. In conclusion, our study revealed that the acute cardioprotective properties of MSC in an ex vivo model of IR injury, assessed by a decreased infarct size at 1 h of reperfusion, are PPARβ/δ-dependent but not related to their anti-inflammatory effects.
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影响因子：
4.8
作者：
Henon, Philippe
通讯作者：
Henon, Philippe
影响因子：
4.5
作者：
Lee JW;Lee SH;Youn YJ;Ahn MS;Kim JY;Yoo BS;Yoon J;Kwon W;Hong IS;Lee K;Kwan J;Park KS;Choi D;Jang YS;Hong MK
通讯作者：
Hong MK
影响因子：
14.9
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Adhikary T;Wortmann A;Schumann T;Finkernagel F;Lieber S;Roth K;Toth PM;Diederich WE;Nist A;Stiewe T;Kleinesudeik L;Reinartz S;Müller-Brüsselbach S;Müller R
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Müller R
影响因子：
5.4
作者：
Dong, Li-Ya;Qiu, Xiao-Xiao;Xue, Song
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Xue, Song
影响因子：
3.5
作者：
Gao, Lian R.;Pei, Xue T.;Yang, Ye
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Yang, Ye