S1P-S1PR2 Axis Mediates Homing of Muse Cells into Damaged Heart for Long Lasting Tissue Repair and Functional Recovery After Acute Myocardial Infarction
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.
- infarct size
- LV remodeling
- acute myocardial infarction
- adult stem cells
- cell transplantation
- bone marrow
- Received July 3, 2017.
- Revision received February 8, 2018.
- Accepted February 22, 2018.