S1P-S1PR2 Axis Mediates Homing of Muse Cells Into Damaged Heart for Long-Lasting Tissue Repair and Functional Recovery After Acute Myocardial Infarction
S1P-S1PR2 Axis Mediates Homing of Muse Cells Into Damaged Heart for Long-Lasting Tissue Repair and Functional Recovery After Acute Myocardial Infarction
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DOI：
10.1161/circresaha.117.311648
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发表时间：
2018-04-13
影响因子：
20.1
通讯作者：
Minatoguchi, Shinya
中科院分区：
文献类型：
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作者：
Yamada, Yoshihisa;Wakao, Shohei;Minatoguchi, Shinya
原理：多系分化应激耐受（Muse）细胞，多能标记阶段特异性胚胎抗原-3+细胞，是一种非致瘤性内源性多能干细胞，可从包括骨髓在内的各种组织中获得。其治疗急性心肌梗死的效果尚未得到证实。目的：本研究的主要目的是阐明静脉输注兔自体、异体和异种（人）骨髓-缪斯细胞在兔急性心肌梗死模型中的修复效果及其组织修复机制。方法和结果：纳米灯笼标记的Muse细胞的体内动力学显示，细胞在梗死后3天和2周优先归家到心脏，大约14.5%的注射的GFP（绿色荧光蛋白）-Muse细胞在3天植入心脏。通过药理学（S1PR2[单磷酸鞘氨醇受体2]特异性拮抗剂JTE-013联合注射）和遗传学（S1PR2- sirna[小干扰核糖核酸]引入Muse细胞）证实Muse细胞的迁移和归巢是通过S1P（单磷酸鞘氨醇）-S1PR2轴介导的。它们自发分化为心肌标记物（如心肌肌钙蛋白- 1、肌动蛋白和连接蛋白-43）和血管标记物阳性的细胞。GCaMP3（基于gfp的Ca calmodulin探针）标记的Muse细胞移植到缺血区域后，在收缩期GCaMP3荧光增加，舒张期荧光降低。2个月时，与载体注射相比，梗死面积减少了约52%，射血分数增加了约38%，分别是间充质干细胞诱导的约2.5倍和约2.1倍。这些作用被gata4基因沉默的Muse细胞部分减弱。同种异体和异种缪斯细胞移植物有效地植入并恢复了功能，同种异体移植物在组织中保留并维持了长达6个月的功能恢复，没有免疫抑制。结论：Muse细胞可能具有修复作用和强大的功能恢复，因此可能为急性心肌梗死的治疗提供一种新的策略。
Rationale: Multilineage-differentiating stress enduring (Muse) cells, pluripotent marker stage-specific embryonic antigen-3+ cells, are nontumorigenic endogenous pluripotent-like stem cells obtainable from various tissues including the bone marrow. Their therapeutic efficiency has not been validated in acute myocardial infarction.Objective: The main objective of this study is to clarify the efficiency of intravenously infused rabbit autograft, allograft, and xenograft (human) bone marrow-Muse cells in a rabbit acute myocardial infarction model and their mechanisms of tissue repair.Methods and Results: In vivo dynamics of Nano-lantern-labeled Muse cells showed preferential homing of the cells to the postinfarct heart at 3 days and 2 weeks, with approximate to 14.5% of injected GFP (green fluorescent protein)-Muse cells estimated to be engrafted into the heart at 3 days. The migration and homing of the Muse cells was confirmed pharmacologically (S1PR2 [sphingosine monophosphate receptor 2]-specific antagonist JTE-013 coinjection) and genetically (S1PR2-siRNA [small interfering ribonucleic acid]-introduced Muse cells) to be mediated through the S1P (sphingosine monophosphate)-S1PR2 axis. They spontaneously differentiated into cells positive for cardiac markers, such as cardiac troponin-I, sarcomeric a-actinin, and connexin-43, and vascular markers. GCaMP3 (GFP-based Ca calmodulin probe)-labeled Muse cells that engrafted into the ischemic region exhibited increased GCaMP3 fluorescence during systole and decreased fluorescence during diastole. Infarct size was reduced by approximate to 52%, and the ejection fraction was increased by approximate to 38% compared with vehicle injection at 2 months, approximate to 2.5 and approximate to 2.1 times higher, respectively, than that induced by mesenchymal stem cells. These effects were partially attenuated by the administration of GATA4-gene-silenced Muse cells. Muse cell allografts and xenografts efficiently engrafted and recovered functions, and allografts remained in the tissue and sustained functional recovery for up to 6 months without immunosuppression.Conclusions: Muse cells may provide reparative effects and robust functional recovery and may, thus, provide a novel strategy for the treatment of acute myocardial infarction.