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Circ Res. 2018 Apr 13;122(8):1069-1083. doi: 10.1161/CIRCRESAHA.117.311648. Epub 2018 Feb 23.

S1P-S1PR2 Axis Mediates Homing of Muse Cells Into Damaged Heart for Long-Lasting Tissue Repair and Functional Recovery After Acute Myocardial Infarction.

Author information

1
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.).
2
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.). minatos@gifu-u.ac.jp mdezawa@med.tohoku.ac.jp.

Abstract

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 ≈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 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.

KEYWORDS:

bone marrow; cell transplantation; heart; myocardial infarction; stem cells

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