A Novel Human Long Noncoding RNA SCDAL Promotes Angiogenesis through SNF5-Mediated GDF6 Expression.
Rongrong WuWangxing HuHuan ChenYingchao WangQingju LiChangchen XiaoLin FanZhiwei ZhongXiaoying ChenKaiqi LvShuhan ZhongYanna ShiJinghai ChenWei ZhuJianyi ZhangXinyang HuWangxing HuPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2021)
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.
Keyphrases
- endothelial cells
- vascular endothelial growth factor
- mesenchymal stem cells
- umbilical cord
- high glucose
- long noncoding rna
- stem cells
- poor prognosis
- transcription factor
- randomized controlled trial
- bone marrow
- dna methylation
- left ventricular
- gene expression
- cell proliferation
- long non coding rna
- heart failure
- atrial fibrillation
- ischemia reperfusion injury
- oxidative stress
- blood brain barrier
- cancer therapy
- climate change
- genome wide identification