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

• Published in: Circulation research Vol. 122; no. 8; pp. 1069 - 1083
• Main Authors: Yamada, Yoshihisa, Wakao, Shohei, Kushida, Yoshihiro, Minatoguchi, Shingo, Mikami, Atsushi, Higashi, Kenshi, Baba, Shinya, Shigemoto, Taeko, Kuroda, Yasumasa, Kanamori, Hiromitsu, Amin, Mohamad, Kawasaki, Masanori, Nishigaki, Kazuhiko, Taoka, Masato, Isobe, Toshiaki, Muramatsu, Chisako, Dezawa, Mari, Minatoguchi, Shinya
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 13-04-2018; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Allografts; Bone marrow; Bone marrow transplantation; Calcium-binding protein; Calmodulin; Connexin 43; Green fluorescent protein; Heart; Heart attacks; Heart diseases; Immunosuppression; Ischemia; Mesenchyme; Myocardial infarction; Pluripotency; Recovery of function; siRNA; Stem cells; Troponin; Xenografts; α-Actinin; cell transplantation; stem cells; bone marrow; heart; myocardial infarction
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.117.311648

RATIONALE:Muse cells, pluripotent marker SSEA-3 cells, are non-tumorigenic endogenous pluripotent-like stem cells obtainable from various tissues including the bone marrow (BM). Their therapeutic efficiency has not been validated in the acute myocardial infarction (AMI).
OBJECTIVE:To clarify the efficiency of intravenously infused rabbit autograft, allograft, and xenograft (human) BM-Muse cells in a rabbit AMI 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 post-infarct heart at 3 days and 2 weeks, with ~14.5% of injected GFP-Muse cells estimated to be engrafted into the heart at 3 days. The migration and homing of the Muse cells was confirmed pharmacologically (S1P receptor 2 [S1PR2]-specific antagonist JTE-013 co-injection) and genetically (S1PR2-siRNA-introcuded Muse cells) to be mediated through the S1P-S1PR2 axis. They spontaneously differentiated into cells positive for cardiac markers, such as cardiac troponin-I, sarcomeric α-actinin, and connexin43, as well as vascular markers. GCaMP3-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 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 AMI.