BACKGROUND Bone 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. METHODS We 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. RESULTS BMSCs-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 or SFRP2 knockdown 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. CONCLUSIONS These 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.

中文翻译：

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IGF-1通过分泌的卷曲相关蛋白2途径增强心肌梗死中BMSC的活力，迁移和抗凋亡。

背景技术骨髓间充质干细胞（BMSC）移植代表缺血性心脏病的一种有前途的治疗策略。但是，移植细胞的生存能力差和缺血区域的不利微环境阻碍了它的作用。胰岛素样生长因子-1（IGF-1）是BMSC的重要旁分泌生长因子，在BMSC的性质中起重要作用。在这里，我们调查了过表达的IGF-1是否可以增强BMSC的活力，迁移，抗凋亡以及对心肌细胞的保护作用，并探讨了潜在的机制侧重于AKT /分泌的卷曲相关蛋白2（SFRP2）的作用。 /β-catenin途径。方法我们使用慢病毒构建了过表达胰岛素样生长因子-1（BMSCs-IGF-1）或空载体（BMSCs-NC）的BMSC，并评估了在常氧和低氧条件下的细胞存活，增殖和迁移。进行大鼠心肌成纤维细胞与BMSC的共培养，以探索BMSCs-IGF-1在缺氧条件下抢救心肌成纤维细胞的旁分泌作用。BMSCs在急性心肌梗死大鼠中的移植用于探讨BMSCs-IGF-1治疗的效果。结果BMSCs-IGF-1在低氧条件下具有较高的细胞增殖速率，迁移能力和干性，并且对细胞凋亡具有更高的抵抗力。IGF-1的过表达通过AKT分泌的卷曲相关蛋白2（SFRP2）途径上调了总β-连环蛋白和核β-连环蛋白的表达，从而增强了细胞存活率。siRNA抑制AKT或SFRP2敲低可显着拮抗IGF-1的作用并降低β-catenin的表达。因此，β-catenin靶基因（包括细胞周期蛋白D1和c-Myc）的表达降低。此外，BMSCs-IGF-1可以挽救心肌细胞免受缺氧诱导的细胞凋亡，并在缺氧条件下保持细胞活力。将BMSCs-IGF-1移植到心肌梗死大鼠中比BMSCs-NC大大减少了梗塞体积，并且SFRP2和β-catenin的表达明显增加。结论这些结果表明，在过表达IGF-1的BMSC中，SFRP2是通过激活而不是拮抗Wnt /β-catenin途径来增强干细胞活力的重要介质。将BMSCs-IGF-1移植到心肌梗死大鼠中比BMSCs-NC大大减少了梗塞体积，并且SFRP2和β-catenin的表达明显增加。结论这些结果表明，在过表达IGF-1的BMSC中，SFRP2是通过激活而不是拮抗Wnt /β-catenin途径来增强干细胞活力的重要介质。将BMSCs-IGF-1移植到心肌梗死大鼠中比BMSCs-NC大大减少了梗塞体积，并且SFRP2和β-catenin的表达明显增加。结论这些结果表明，在过表达IGF-1的BMSC中，SFRP2是通过激活而不是拮抗Wnt /β-catenin途径来增强干细胞活力的重要介质。