Department of Cardiology, Second Affiliated Hospital, Military Medical University of the Air Force, Xi'an 710038, China.
Department of Cardiology, Second Affiliated Hospital, Military Medical University of the Air Force, Xi'an 710038, China.
Life Sci. 2018 Dec 15;215:31-42. doi: 10.1016/j.lfs.2018.10.047. Epub 2018 Oct 24.
The sphingolipid metabolite sphingosine 1‑phosphate (S1P) has emerged as a potential cardioprotective molecule against ischemic heart disease. Moreover, S1P triggers mobilization and homing of bone marrow-derived stem/progenitor cells into the damaged heart. However, it remains elusive whether S1P promotes mesenchymal stem cells (MSCs)-mediated cardioprotection against ischemic heart diseases.
Adipose tissue-derived MSCs (AT-MSCs) were obtained from GFP transgenic mice or C57BL/6J. Myocardial infarction (MI) was induced in C57BL/6J mice by ligation of the left anterior descending coronary artery (LAD). Subsequently, S1P-treated AT-MSCs or vehicle-treated AT-MSCs were intravenously administered for 24 h after induction of MI or sham procedure.
Pre-conditioning with S1P significantly enhanced the migratory and anti-apoptotic efficacies of AT-MSCs. In MI-induced mice, intravenous administration of S1P-treated AT-MSCs significantly augmented their homing and engraftment in ischemic area. Besides, AT-MSCs with S1P pre-treatment exhibited enhanced potencies to inhibit cardiomyocyte apoptosis and fibrosis, and stimulate angiogenesis and preserve cardiac function. Mechanistic studies revealed that S1P promoted AT-MSCs migration through activation of ERK1/2-MMP-9, and protected AT-MSCs against apoptosis via Akt activation. Further, S1P activated the ERK1/2 and Akt via S1P receptor 2 (S1PR2), but not through S1PR1. S1PR2 knockdown by siRNA, however, significantly attenuated S1P-mediated AT-MSCs migration and anti-apoptosis.
The findings of the present study revealed the protective efficacies of S1P pretreatment on the survival/retention and cardioprotection of engrafted MSCs. Pre-conditioning of donor MSCs with S1P is an effective strategy to promote the therapeutic potential of MSCs for ischemic heart diseases.
鞘氨醇 1-磷酸（S1P）作为一种潜在的抗缺血性心脏病的心脏保护分子而出现。此外，S1P 触发骨髓源性干细胞/祖细胞向受损心脏的动员和归巢。然而，S1P 是否促进间充质干细胞（MSCs）介导的对缺血性心脏病的保护作用仍不清楚。
从 GFP 转基因小鼠或 C57BL/6J 小鼠中获得脂肪组织源性 MSCs（AT-MSCs）。通过结扎左前降支冠状动脉（LAD）在 C57BL/6J 小鼠中诱导心肌梗死（MI）。随后，在 MI 诱导或假手术之后 24 小时，静脉内给予 S1P 处理的 AT-MSCs 或载体处理的 AT-MSCs。
S1P 预处理显著增强了 AT-MSCs 的迁移和抗凋亡作用。在 MI 诱导的小鼠中，静脉内给予 S1P 处理的 AT-MSCs 显著增加了它们在缺血区的归巢和植入。此外，经 S1P 预处理的 AT-MSCs 表现出增强的抑制心肌细胞凋亡和纤维化、刺激血管生成和保护心脏功能的能力。机制研究表明，S1P 通过激活 ERK1/2-MMP-9 促进 AT-MSCs 的迁移，并通过激活 Akt 来保护 AT-MSCs 免受凋亡。此外，S1P 通过 S1P 受体 2（S1PR2）而不是 S1PR1 激活 ERK1/2 和 Akt。然而，通过 siRNA 敲低 S1PR2 显著减弱了 S1P 介导的 AT-MSCs 迁移和抗凋亡作用。
本研究的结果揭示了 S1P 预处理对植入的 MSCs 的存活/保留和心脏保护作用的保护作用。用 S1P 预处理供体 MSCs 是一种促进 MSCs 治疗缺血性心脏病潜力的有效策略。
