Cardiac Nestin+ Mesenchymal Stromal Cells Enhance Healing of Ischemic Heart through Periostin-Mediated M2 Macrophage Polarization
Cardiac Nestin+ Mesenchymal Stromal Cells Enhance Healing of Ischemic Heart through Periostin-Mediated M2 Macrophage Polarization
复制标题
心脏 Nestin( ) 间充质基质细胞通过骨膜素介导的 M2 巨噬细胞极化增强缺血心脏的愈合
DOI：
10.1016/j.ymthe.2020.01.011
复制
发表时间：
2020-03-04
影响因子：
12.4
通讯作者：
Xiang, Andy Peng
中科院分区：
文献类型：
--
作者：
Liao, Yan;Li, Guilan;Xiang, Andy Peng
间充质基质细胞（MSC）显示出治疗心血管疾病的潜力，但其治疗效果表现出显着的异质性，这取决于组织的起源。本研究旨在确定用于心血管疾病治疗的MSC的最佳来源。我们证明Nestin是心肌间充质干细胞（内斯（+）cMSCs）的合适标记物，其通过其自我更新能力、三系分化潜能和MSC标记物的表达来鉴定。此外，与骨髓来源的MSCs（内斯（+）bmMSCs）或盐水处理的心肌梗死（MI）对照相比，心肌内注射内斯（+）cMSCs通过旁分泌作用而不是在梗死心脏内转分化为心肌细胞，显著改善急性MI（AMI）后的心功能，缩小梗死面积。我们进一步发现，内斯（+）cMSC治疗显著减少泛巨噬细胞浸润，同时诱导巨噬细胞向缺血心肌中的抗炎M2表型。有趣的是，在内斯（+）cMSCs中高表达的Periostin可促进M2亚型巨噬细胞的极化，并且Periostin的敲低或中和通过减少损伤部位的M2巨噬细胞而显著降低内斯（+）cMSCs的治疗效果。因此，本工作系统性地表明，对于AMI后的心脏愈合，内斯（+）cMSC比内斯（+）bmMSC具有更大的功效，并且这至少部分地通过骨膜蛋白介导的M2巨噬细胞极化发生。
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-treatedmyocardial 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 inducingmacrophages toward an anti-inflammatory M2 phenotype in ischemic myocardium. Interestingly, Periostin, which was highly expressed in Nes(+)cMSCs, could promote the polarization of M2-subtypemacrophages, 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.