Pharmacological priming of adipose-derived stem cells promotes myocardial repair.
Pharmacological priming of adipose-derived stem cells promotes myocardial repair.
复制标题
脂肪干细胞的药理学启动可促进心肌修复。
DOI：
10.1136/jim-2015-000018
复制
发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Hill,JosephA
中科院分区：
文献类型：
--
作者：
Burchfield,JanaS;Paul,AshleyL;Lanka,Vishy;Tan,Wei;Kong,Yongli;McCallister,Camille;Rothermel,BeverlyA;Schneider,JayW;Gillette,ThomasG;Hill,JosephA
脂肪干细胞（ADSC）具有心肌再生潜力，在动物模型中心肌梗塞（MI）后移植这些细胞可适度改善心脏功能。我们假设移植前 ADSC 的药物启动将进一步改善 MI 后左心室功能恢复。我们之前从 3,5-二取代异恶唑家族中鉴定出一种化合物 ISX1，能够激活 Nkx2-5 驱动的启动子构建体。在这里，使用 ADSC，我们发现 ISX1（20 mM，4 天）引发 Nkx2-5 表达的强劲、剂量依赖性四倍增加，Nkx2-5 表达是心肌细胞分化的早期标志，并增加了 ADSC 的体外活力。新生儿心肌细胞与 ISX1 处理的 ADSC 共培养可增加早期和晚期心脏基因表达。虽然ISX1促进ADSC向心源性谱系分化，但它并没有引起它们完全分化或分化成成熟脂肪细胞、成骨细胞或软骨细胞，这表明重新编程是心肌细胞特异性的。 ADSC 的心脏移植改善了 MI 后的左心室功能恢复，移植 ISX1 预处理的细胞可显着增强这种反应。此外，MIX1 处理和移植的 ADSC 在 MI 后 3 周植入并在心肌中可检测到，尽管数量相对较少。 ISX1 处理增加了 ADSC 中的组蛋白乙酰转移酶 (HAT) 活性，这与组蛋白 3 和组蛋白 4 乙酰化有关。最后，用ISX1处理的ADSC移植的心脏显示新血管形成显着增加，这可能是心脏功能改善的原因。这些发现表明，药物促进启动肌细胞分化的策略可增强外源移植的 ADSC 在体内的持久性，以及随后的组织新血管形成，从而改善心脏功能。
Adipose-derived stem cells (ADSCs) have myocardial regeneration potential, and transplantation of these cells following myocardial infarction (MI) in animal models leads to modest improvements in cardiac function. We hypothesized that pharmacological priming of pre-transplanted ADSCs would further improve left ventricular functional recovery after MI. We previously identified a compound from a family of 3,5-disubstituted isoxazoles, ISX1, capable of activating an Nkx2-5-driven promoter construct. Here, using ADSCs, we found that ISX1 (20 mM, 4 days) triggered a robust, dose-dependent, fourfold increase in Nkx2-5 expression, an early marker of cardiac myocyte differentiation and increased ADSC viability in vitro. Co-culturing neonatal cardiomyocytes with ISX1-treated ADSCs increased early and late cardiac gene expression. Whereas ISX1 promoted ADSC differentiation toward a cardiogenic lineage, it did not elicit their complete differentiation or their differentiation into mature adipocytes, osteoblasts, or chondrocytes, suggesting that re-programming is cardiomyocyte specific. Cardiac transplantation of ADSCs improved left ventricular functional recovery following MI, a response which was significantly augmented by transplantation of ISX1- pretreated cells. Moreover, ISX1-treated and transplanted ADSCs engrafted and were detectable in the myocardium 3 weeks following MI, albeit at relatively small numbers. ISX1 treatment increased histone acetyltransferase (HAT) activity in ADSCs, which was associated with histone 3 and histone 4 acetylation. Finally, hearts transplanted with ISX1-treated ADSCs manifested significant increases in neovascularization, which may account for the improved cardiac function. These findings suggest that a strategy of drug-facilitated initiation of myocyte differentiation enhances exogenously transplanted ADSC persistence in vivo, and consequent tissue neovascularization, to improve cardiac function.