MiRNA-137-mediated modulation of mitochondrial dynamics regulates human neural stem cell fate

Abstract

The role of miRNAs in determining human neural stem cell (NSC) fate remains elusive despite their high expression in the developing nervous system. In this study, we investigate the role of miR-137, a brain-enriched miRNA, in determining the fate of human induced pluripotent stem cells-derived NSCs (hiNSCs). We show that ectopic expression of miR-137 in hiNSCs reduces proliferation and accelerates neuronal differentiation and migration. TargetScan and MicroT-CDS predict myocyte enhancer factor-2A (MEF2A), a transcription factor that regulates peroxisome proliferator-activated receptor-gamma coactivator (PGC1α) transcription, as a target of miR-137. Using a reporter assay, we validate MEF2A as a downstream target of miR-137. Our results indicate that reduced levels of MEF2A reduce the transcription of PGC1α, which in turn impacts mitochondrial dynamics. Notably, miR-137 accelerates mitochondrial biogenesis in a PGC1α independent manner by upregulating nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2) and transcription factor A of mitochondria (TFAM). In addition, miR-137 modulates mitochondrial dynamics by inducing mitochondrial fusion and fission events, resulting in increased mitochondrial content and activation of oxidative phosphorylation (OXPHOS) and oxygen consumption rate. Pluripotency transcription factors OCT4 and SOX2 are known to have binding sites in the promoter region of miR-137 gene. Ectopic expression of miR-137 elevates the expression levels of OCT4 and SOX2 in hiNSCs which establishes a feed-forward self-regulatory loop between miR-137 and OCT4/SOX2. Our study provides novel molecular insights into NSC fate determination by miR-137.

Keywords: fission; human induced pluripotent stem cells; miRNA; mitochondria dynamics; mitochondria fusion; mitochondrial biogenesis; neural stem cells; neurodevelopment.