Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.
Stem Cells Transl Med. 2017 Jan;6(1):209-222. doi: 10.5966/sctm.2015-0386. Epub 2016 Aug 29.
Our group recently reported positive therapeutic benefit of human endometrium-derived mesenchymal stem cells (EnMSCs) delivered to infarcted rat myocardium, an effect that correlated with enhanced secretion of protective cytokines and growth factors compared with parallel cultures of human bone marrow MSCs (BMMSCs). To define more precisely the molecular mechanisms of EnMSC therapy, in the present study, we assessed in parallel the paracrine and therapeutic properties of MSCs derived from endometrium, bone marrow, and adipose tissues in a rat model of myocardial infarction (MI). EnMSCs, BMMSCs, and adipose-derived MSCs (AdMSCs) were characterized by fluorescence-activated cell sorting (FACS). Paracrine and cytoprotective actions were assessed in vitro by coculture with neonatal cardiomyocytes and human umbilical vein endothelial cells. A rat MI model was used to compare cell therapy by intramyocardial injection of BMMSCs, AdMSCs, and EnMSCs. We found that EnMSCs conferred superior cardioprotection relative to BMMSCs or AdMSCs and supported enhanced microvessel density. Inhibitor studies indicated that the enhanced paracrine actions of EnMSCs were mediated by secreted exosomes. Analyses of exosomal microRNAs (miRs) by miR array and quantitative polymerase chain reaction revealed that miR-21 expression was selectively enhanced in exosomes derived from EnMSCs. Selective antagonism of miR-21 by anti-miR treatment abolished the antiapoptotic and angiogenic effects of EnMSCs with parallel effects on phosphatase and tensin homolog (PTEN), a miR-21 target and downstream Akt. The results of the present study confirm the superior cardioprotection by EnMSCs relative to BMMSCs or AdMSCs and implicates miR-21 as a potential mediator of EnMSC therapy by enhancing cell survival through the PTEN/Akt pathway. The endometrium might be a preferential source of MSCs for cardiovascular cell therapy. Stem Cells Translational Medicine 2017;6:209-222.
我们的研究小组最近报道了将人子宫内膜间充质干细胞（EnMSCs）移植到梗死大鼠心肌中可产生积极的治疗效果，与平行培养的人骨髓间充质干细胞（BMMSCs）相比，这种效果与增强保护性细胞因子和生长因子的分泌有关。为了更准确地定义 EnMSC 治疗的分子机制，在本研究中，我们在大鼠心肌梗死（MI）模型中平行评估了源自子宫内膜、骨髓和脂肪组织的 MSC 的旁分泌和治疗特性。通过荧光激活细胞分选（FACS）对 EnMSCs、BMMSCs 和脂肪衍生的 MSCs 进行了特征描述。通过与新生心肌细胞和人脐静脉内皮细胞共培养评估旁分泌和细胞保护作用。使用大鼠 MI 模型比较了将 BMMSCs、AdMSCs 和 EnMSCs 心肌内注射的细胞治疗。我们发现，与 BMMSCs 或 AdMSCs 相比，EnMSCs 赋予了更好的心脏保护作用，并支持增强的微血管密度。抑制剂研究表明，EnMSCs 增强的旁分泌作用是由分泌的外泌体介导的。通过 miR 阵列和定量聚合酶链反应分析外泌体中的 microRNAs（miRs）发现，miR-21 的表达在 EnMSCs 衍生的外泌体中被选择性增强。通过抗 miR 处理选择性拮抗 miR-21 可消除 EnMSCs 的抗凋亡和血管生成作用，对磷酸酶和张力蛋白同源物（PTEN）产生平行作用，PTEN 是 miR-21 的靶标和下游 Akt。本研究的结果证实了 EnMSCs 相对于 BMMSCs 或 AdMSCs 的优越的心脏保护作用，并暗示 miR-21 可能通过增强细胞存活通过 PTEN/Akt 途径成为 EnMSC 治疗的潜在介质。子宫内膜可能是心血管细胞治疗中 MSC 的首选来源。干细胞转化医学 2017；6:209-222。
