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FNDC5/irisin improves the therapeutic efficacy of bone marrow-derived mesenchymal stem cells for myocardial infarction.
Stem Cell Research & Therapy ( IF 7.5 ) Pub Date : 2020-06-10 , DOI: 10.1186/s13287-020-01746-z
Jingyu Deng 1 , Ning Zhang 2 , Yong Wang 3 , Chao Yang 4 , Yabin Wang 5 , Chao Xin 4 , Jinming Zhao 6 , Zhitao Jin 4 , Feng Cao 5 , Zheng Zhang 4
Affiliation  

The beneficial functions of bone marrow mesenchymal stem cells (BM-MSCs) decline with decreased cell survival, limiting their therapeutic efficacy for myocardial infarction (MI). Irisin, a novel myokine which is cleaved from its precursor fibronectin type III domain-containing protein 5 (FNDC5), is believed to be involved in a cardioprotective effect, but little was known on injured BM-MSCs and MI repair yet. Here, we investigated whether FNDC5 or irisin could improve the low viability of transplanted BM-MSCs and increase their therapeutic efficacy after MI. BM-MSCs, isolated from dual-reporter firefly luciferase and enhanced green fluorescent protein positive (Fluc+–eGFP+) transgenic mice, were exposed to normoxic condition and hypoxic stress for 12 h, 24 h, and 48 h, respectively. In addition, BM-MSCs were treated with irisin (20 nmol/L) and overexpression of FNDC5 (FNDC5-OV) in serum deprivation (H/SD) injury. Furthermore, BM-MSCs were engrafted into infarcted hearts with or without FNDC5-OV. Hypoxic stress contributed to increased apoptosis, decreased cell viability, and paracrine effects of BM-MSCs while irisin or FNDC5-OV alleviated these injuries. Longitudinal in vivo bioluminescence imaging and immunofluorescence results illustrated that BM-MSCs with overexpression of FNDC5 treatment (FNDC5-MSCs) improved the survival of transplanted BM-MSCs, which ameliorated the increased apoptosis and decreased angiogenesis of BM-MSCs in vivo. Interestingly, FNDC5-OV elevated the secretion of exosomes in BM-MSCs. Furthermore, FNDC5-MSC therapy significantly reduced fibrosis and alleviated injured heart function. The present study indicated that irisin or FNDC5 improved BM-MSC engraftment and paracrine effects in infarcted hearts, which might provide a potential therapeutic target for MI.

中文翻译:

FNDC5/irisin 提高骨髓间充质干细胞对心肌梗死的治疗效果。

骨髓间充质干细胞 (BM-MSCs) 的有益功能随着细胞存活率的降低而下降,从而限制了它们对心肌梗死 (MI) 的治疗效果。鸢尾素是一种从其前体纤连蛋白 III 型结构域蛋白 5 (FNDC5) 中切割下来的新型肌动蛋白,据信它具有心脏保护作用,但对受损的 BM-MSCs 和 MI 修复知之甚少。在这里,我们研究了 FNDC5 或鸢尾素是否可以改善移植的 BM-MSCs 的低活力并提高其在 MI 后的治疗效果。从双报告萤火虫萤光素酶和增强型绿色荧光蛋白阳性 (Fluc+–eGFP+) 转基因小鼠中分离的 BM-MSCs 分别暴露于常氧条件和缺氧应激 12 小时、24 小时和 48 小时。此外,在血清剥夺 (H/SD) 损伤中用鸢尾素 (20 nmol/L) 和过表达 FNDC5 (FNDC5-OV) 处理 BM-MSC。此外,BM-MSCs 被移植到有或没有 FNDC5-OV 的梗塞心脏中。缺氧应激导致 BM-MSCs 的细胞凋亡增加、细胞活力降低和旁分泌作用,而鸢尾素或 FNDC5-OV 减轻了这些损伤。纵向体内生物发光成像和免疫荧光结果表明,过表达 FNDC5 处理的 BM-MSCs (FNDC5-MSCs) 提高了移植的 BM-MSCs 的存活率,从而改善了体内 BM-MSCs 的细胞凋亡增加和血管生成减少。有趣的是,FNDC5-OV 提高了 BM-MSCs 中外泌体的分泌。此外,FNDC5-MSC 疗法显着减少了纤维化并减轻了受损的心脏功能。
更新日期:2020-06-10
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