IGF-1 enhances BMSC viability, migration, and anti-apoptosis in myocardial infarction via secreted frizzled-related protein 2 pathway
IGF-1 enhances BMSC viability, migration, and anti-apoptosis in myocardial infarction via secreted frizzled-related protein 2 pathway
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IGF-1 通过分泌卷曲相关蛋白 2 途径增强心肌梗死中 BMSC 的活力、迁移和抗凋亡作用
DOI：
10.1186/s13287-019-1544-y
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发表时间：
2020-01-09
影响因子：
7.5
通讯作者：
Huang, Yuli
中科院分区：
文献类型：
--
作者：
Lin, Mingzhuo;Liu, Xinyue;Huang, Yuli
背景骨髓间充质干细胞（BMSC）移植是治疗缺血性心脏病的一种有希望的策略。然而，其效果受到移植细胞存活力差和缺血区域微环境恶劣的阻碍。胰岛素样生长因子-1（IGF-1）是一种重要的BMSC旁分泌生长因子，对BMSC的生物学特性起重要作用。本研究旨在探讨过表达IGF-1是否能增强BMSC的存活、迁移、抗凋亡和心肌细胞保护作用，并探讨AKT/分泌型卷曲相关蛋白2（SFRP 2）/β-catenin通路在其中的作用机制使用慢病毒将BMSCs-IGF-1或空载体（BMSCs-NC）接种于小鼠骨髓基质细胞（BMSCs-IGF-1）中，并评估在常氧和低氧条件下的细胞存活、增殖和迁移。将大鼠心肌细胞与骨髓间充质干细胞共培养，探讨BMSCs-IGF-1在缺氧条件下对心肌细胞的旁分泌作用。结果BMSCs-IGF-1具有较高的细胞增殖率、迁移能力和干细胞性，在缺氧条件下更耐凋亡。IGF-1的过表达通过AKT分泌的卷曲相关蛋白2（SFRP 2）途径上调总β-连环蛋白和核β-连环蛋白的表达，从而增强细胞存活。通过SiRNA抑制AKT或SFRP 2的敲低可显着拮抗IGF-1的作用并降低β-catenin的表达。β-catenin靶基因cyclin D1和c-Myc的表达相应降低。此外，BMSCs-IGF-1可以挽救缺氧诱导的心肌细胞凋亡，并保持细胞在缺氧条件下的活力。BMSCs-IGF-1移植到心肌梗死大鼠大大减少梗死体积比BMSCs-NC，与显著更高的表达SFRP 2和β-catenin.ConclusionsThese结果表明，在过表达IGF-1的BMSCs，SFRP 2是一个重要的介质，通过激活，而不是拮抗，Wnt/β-catenin通路的干细胞活力的增强。
BackgroundBone marrow mesenchymal stem cell (BMSC) transplantation represents a promising therapeutic strategy for ischemic heart disease. However, its effects are hampered by the poor viability of transplanted cells and the hostile microenvironment of the ischemic region. Insulin-like growth factor-1 (IGF-1) is an important paracrine growth factor of BMSC and plays an important role in the properties of BMSC. Here, we investigated whether overexpressing IGF-1 could enhance the BMSC viability, migration, anti-apoptosis, and protective effects of cardiomyocytes, and explore the underlying mechanisms’ focus on the role of the AKT/secreted frizzled-related protein 2 (SFRP2)/β-catenin pathway.MethodsWe constructed BMSCs overexpressing insulin-like growth factor-1 (BMSCs-IGF-1) or empty vector (BMSCs-NC) using lentivirus, and evaluated cell survival, proliferation, and migration under normoxic and hypoxic conditions. Co-culture of rat cardiomyoblasts with BMSCs was performed to explore the paracrine effect of BMSCs-IGF-1 for rescuing cardiomyoblasts under hypoxia. Transplantation of BMSCs in acute myocardial infarction rats was used to explore the effect of BMSCs-IGF-1 therapy.ResultsBMSCs-IGF-1 exhibited a higher cell proliferation rate, migration capacity, and stemness, and were more resistant to apoptosis under hypoxia. Overexpression of IGF-1 upregulated the expression of total and nuclear β-catenin via the AKT-secreted frizzled-related protein 2 (SFRP2) pathway, which enhanced cell survival. Inhibition of AKT orSFRP2knockdown by siRNA significantly antagonized the effect of IGF-1 and decreased the expression of β-catenin. The expression of β-catenin target genes, including cyclin D1 and c-Myc, were accordingly decreased. Moreover, BMSCs-IGF-1 could rescue cardiomyoblasts from hypoxia-induced apoptosis and preserve cell viability under hypoxia. Transplantation of BMSCs-IGF-1 into myocardial infarction rats greatly reduced infarct volume than BMSCs-NC, with significantly greater expression of SFRP2 and β-catenin.ConclusionsThese results suggest that in BMSCs overexpressing IGF-1, SFRP2 is an important mediator for the enhancement of stem cell viability via activating, rather than antagonizing, the Wnt/β-catenin pathway.