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Cardiac Nestin+ Mesenchymal Stromal Cells Enhance Healing of Ischemic Heart through Periostin-Mediated M2 Macrophage Polarization.
Molecular Therapy ( IF 12.1 ) Pub Date : 2020-01-15 , DOI: 10.1016/j.ymthe.2020.01.011
Yan Liao 1 , Guilan Li 2 , Xiaoran Zhang 1 , Weijun Huang 1 , Dongmei Xie 3 , Gang Dai 4 , Shuanghua Zhu 5 , Dihan Lu 6 , Zhongyuan Zhang 1 , Junyi Lin 7 , Bingyuan Wu 5 , Wanwen Lin 5 , Yang Chen 5 , Zhihong Chen 7 , Chaoquan Peng 5 , Maosheng Wang 8 , Xinxin Chen 9 , Mei Hua Jiang 10 , Andy Peng Xiang 11
Affiliation  

Mesenchymal stromal cells (MSCs) show potential for treating cardiovascular diseases, but their therapeutic efficacy exhibits significant heterogeneity depending on the tissue of origin. This study sought to identify an optimal source of MSCs for cardiovascular disease therapy. We demonstrated that Nestin was a suitable marker for cardiac MSCs (Nes+cMSCs), which were identified by their self-renewal ability, tri-lineage differentiation potential, and expression of MSC markers. Furthermore, compared with bone marrow-derived MSCs (Nes+bmMSCs) or saline-treated myocardial infarction (MI) controls, intramyocardial injection of Nes+cMSCs significantly improved cardiac function and decreased infarct size after acute MI (AMI) through paracrine actions, rather than transdifferentiation into cardiac cells in infarcted heart. We further revealed that Nes+cMSC treatment notably reduced pan-macrophage infiltration while inducing macrophages toward an anti-inflammatory M2 phenotype in ischemic myocardium. Interestingly, Periostin, which was highly expressed in Nes+cMSCs, could promote the polarization of M2-subtype macrophages, and knockdown or neutralization of Periostin remarkably reduced the therapeutic effects of Nes+cMSCs by decreasing M2 macrophages at lesion sites. Thus, the present work systemically shows that Nes+cMSCs have greater efficacy than do Nes+bmMSCs for cardiac healing after AMI, and that this occurs at least partly through Periostin-mediated M2 macrophage polarization.

中文翻译:

心肌巢蛋白+间质间质细胞通过骨膜素介导的M2巨噬细胞极化增强缺血性心脏的愈合。

间充质基质细胞(MSCs)具有治疗心血管疾病的潜力,但其治疗功效依来源组织而异。这项研究试图确定用于心血管疾病治疗的MSC的最佳来源。我们证明了巢蛋白是适合于心脏MSC(Nes + cMSCs)的标记,可通过其自我更新能力,三谱系分化潜能和MSC标记的表达来鉴定。此外,与骨髓来源的MSC(Nes + bmMSCs)或生理盐水治疗的心肌梗塞(MI)对照相比,通过旁分泌作用,心肌内注射Nes + cMSCs可以显着改善急性MI(AMI)后的心脏功能并减少梗死面积,而比梗死心脏中的心肌细胞转分化更重要。我们进一步揭示,Nes + cMSC处理可显着减少泛巨噬细胞浸润,同时诱导巨噬细胞趋向于缺血心肌中的抗炎M2表型。有趣的是,在Nes + cMSCs中高表达的Periostin可以促进M2亚型巨噬细胞的极化,并且Periostin的敲除或中和通过减少病变部位的M2巨噬细胞而显着降低了Nes + cMSCs的治疗效果。因此,本工作系统地表明,对于AMI后的心脏愈合,Nes + cMSC比Nes + bmMSC具有更大的功效,并且这至少部分是通过Periostin介导的M2巨噬细胞极化发生的。在Nes + cMSCs中高表达的蛋白可以促进M2亚型巨噬细胞的极化,而Periostin的敲除或中和通过减少病变部位的M2巨噬细胞而明显降低了Nes + cMSCs的治疗效果。因此,本工作系统地显示,对于AMI后的心脏愈合,Nes + cMSC比Nes + bmMSC具有更大的功效,并且这至少部分是通过Periostin介导的M2巨噬细胞极化发生的。在Nes + cMSCs中高表达的蛋白可以促进M2亚型巨噬细胞的极化,而Periostin的敲除或中和通过减少病变部位的M2巨噬细胞而明显降低了Nes + cMSCs的治疗效果。因此,本工作系统地表明,对于AMI后的心脏愈合,Nes + cMSC比Nes + bmMSC具有更大的功效,并且这至少部分是通过Periostin介导的M2巨噬细胞极化发生的。
更新日期:2020-01-15
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