Angiogenesis is essential for vascular development. The roles of regulatory long noncoding RNAs (lncRNAs) in mediating angiogenesis remain under-explored. Human embryonic stem cell-derived mesenchymal stem cells (hES-MSCs) are shown to exert more potent cardioprotective effects against cardiac ischemia than human bone marrow-derived MSCs (hBM-MSCs), associated with enhanced neovascularization. The purpose of this study is to search for angiogenic lncRNAs enriched in hES-MSCs, and investigate their roles and mechanisms. AC103746.1 is one of the most highly expressed intergenic lncRNAs detected in hES-MSCs versus hBM-MSCs, and named as SCDAL (stem cell-derived angiogenic lncRNA). SCDAL knockdown significantly reduce the angiogenic potential and reparative effects of hES-MSCs in the infarcted hearts, while overexpression of SCDAL in either hES-MSCs or hBM-MSCs exhibits augmented angiogenesis and cardiac function recovery. Mechanistically, SCDAL induces growth differentiation factor 6 (GDF6) expression via direct interaction with SNF5 at GDF6 promoter. Secreted GDF6 promotes endothelial angiogenesis via non-canonical vascular endothelial growth factor receptor 2 activation. Furthermore, SCDAL-GDF6 is expressed in human endothelial cells, and directly enhances endothelial angiogenesis in vitro and in vivo. Thus, these findings uncover a previously unknown lncRNA-dependent regulatory circuit for angiogenesis. Targeted intervention of the SCDAL-GDF6 pathway has potential as a therapy for ischemic heart diseases.

中文翻译：

---

一种新型人类长链非编码 RNA SCDAL 通过 SNF5 介导的 GDF6 表达促进血管生成

血管生成对于血管发育至关重要。调节性长非编码 RNA (lncRNA) 在介导血管生成中的作用仍未得到充分探索。人胚胎干细胞来源的间充质干细胞 (hES-MSCs) 显示出比人骨髓来源的间充质干细胞 (hBM-MSCs) 对心脏缺血发挥更有效的心脏保护作用，与增强的新血管形成相关。本研究的目的是寻找富含hES-MSCs的血管生成lncRNA，并研究它们的作用和机制。AC103746.1 是在 hES-MSC 与 hBM-MSC 中检测到的最高表达的基因间 lncRNA 之一，并命名为SCDAL （干细胞衍生的血管生成l ncRNA ）。SCDAL敲低显着降低了梗塞心脏中 hES-MSCs 的血管生成潜力和修复作用，而SCDAL在 hES-MSCs 或 hBM-MSCs 中的过表达表现出增强的血管生成和心脏功能恢复。从机制上讲，SCDAL通过在 GDF6 启动子处与 SNF5 直接相互作用来诱导生长分化因子 6 (GDF6) 的表达。分泌的 GDF6 通过非经典血管内皮生长因子受体 2 的激活促进内皮血管生成。此外，SCDAL-GDF6 在人内皮细胞中表达，并在体外和体内直接增强内皮血管生成。因此，这些发现揭示了一个以前未知的依赖 lncRNA 的血管生成调节回路。SCDAL- GDF6 通路的靶向干预具有治疗缺血性心脏病的潜力。