A Novel Human Long Noncoding RNA SCDAL Promotes Angiogenesis through SNF5-Mediated GDF6 Expression

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Stem Cell Biology

Background:

• Angiogenesis is crucial for vascular development, but the role of long noncoding RNAs (lncRNAs) is not fully understood.
• Human embryonic stem cell-derived mesenchymal stem cells (hES-MSCs) show superior cardioprotective effects and neovascularization compared to human bone marrow-derived MSCs (hBM-MSCs).

Purpose of the Study:

• To identify angiogenic lncRNAs enriched in hES-MSCs.
• To investigate the function and molecular mechanisms of these lncRNAs in angiogenesis and cardiac repair.

Main Methods:

• Comparative analysis of lncRNA expression in hES-MSCs and hBM-MSCs.
• Functional studies involving knockdown and overexpression of the identified lncRNA (SCDAL).
• Mechanistic investigations using promoter interaction assays and assessment of downstream signaling pathways (GDF6, VEGFR2).

Main Results:

• AC103746.1, named SCDAL (stem cell-derived angiogenic lncRNA), was highly expressed in hES-MSCs.
• SCDAL knockdown impaired hES-MSC angiogenic potential and cardiac repair, while SCDAL overexpression enhanced angiogenesis and cardiac function recovery.
• SCDAL upregulates GDF6 expression by interacting with SNF5 at the GDF6 promoter, leading to enhanced endothelial angiogenesis via non-canonical VEGFR2 activation.

Conclusions:

• A novel lncRNA-dependent regulatory pathway, SCDAL-GDF6, governing angiogenesis has been uncovered.
• This pathway enhances endothelial cell angiogenesis in vitro and in vivo.
• Targeting the SCDAL-GDF6 pathway presents a potential therapeutic strategy for ischemic heart diseases.