From the Department of Cardiology (Y.Y., Shingo Minatoguchi, A.M., K.H., S.B., H.K., M.K., K.N., Shinya Minatoguchi) and Intelligent Image Information (C.M.), Gifu University Graduate School of Medicine, Japan; Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan (S.W., Y. Kushida, T.S., Y. Kuroda, M.A., M.D.); Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Egypt (M.A.); and Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Japan (M.T., T.I.).
Circ Res. 2018 Apr 13;122(8):1069-1083. doi: 10.1161/CIRCRESAHA.117.311648. Epub 2018 Feb 23.
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.
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.
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 ≈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 α-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 ≈52%, and the ejection fraction was increased by ≈38% compared with vehicle injection at 2 months, ≈2.5 and ≈2.1 times higher, respectively, than that induced by mesenchymal stem cells. These effects were partially attenuated by the administration of -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.
Muse cells may provide reparative effects and robust functional recovery and may, thus, provide a novel strategy for the treatment of acute myocardial infarction.
多谱系分化应激耐受（Muse）细胞是多能性标志物阶段特异性胚胎抗原-3 细胞，是一种非肿瘤性的内源性多能样干细胞，可从包括骨髓在内的各种组织中获得。它们的治疗效果尚未在急性心肌梗死中得到验证。
本研究的主要目的是阐明静脉输注兔自体移植物、同种异体移植物和异种（人）骨髓-Muse 细胞在兔急性心肌梗死模型中的疗效及其组织修复机制。
体内纳米灯笼标记的 Muse 细胞动力学研究显示，细胞在 3 天和 2 周时优先归巢到梗死心肌，约 14.5%的注射 GFP（绿色荧光蛋白）-Muse 细胞在 3 天内被移植到心脏。Muse 细胞的迁移和归巢通过药理学（S1PR2 [鞘氨醇单磷酸盐受体 2]特异性拮抗剂 JTE-013 共注射）和遗传学（S1PR2-siRNA [小干扰核糖核酸]导入的 Muse 细胞）证实是通过 S1P（鞘氨醇单磷酸盐）-S1PR2 轴介导的。它们自发分化为心肌标志物阳性的细胞，如心肌肌钙蛋白 I、肌节α-肌动蛋白和连接蛋白-43，以及血管标志物。移植到缺血区的 GCaMP3（基于 GFP 的钙钙调蛋白探针）标记的 Muse 细胞在收缩期显示出增强的 GCaMP3 荧光，在舒张期显示出降低的荧光。与载体注射相比，在 2 个月时，梗死面积减少约 52%，射血分数增加约 38%，分别比间充质干细胞诱导的增加约 2.5 倍和 2.1 倍。给予基因沉默的 Muse 细胞可部分减弱这些作用。Muse 细胞同种异体移植物和异种移植物有效地移植并恢复功能，同种异体移植物在组织中停留并持续功能恢复长达 6 个月，无需免疫抑制。
Muse 细胞可能提供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策略。
