Role of miRNA-mRNA Interaction in Neural Stem Cell Differentiation of Induced Pluripotent Stem Cells

Abstract

miRNA regulates the expression of protein coding genes and plays a regulatory role in human development and disease. The human iPSCs and their differentiated progenies provide a unique opportunity to identify these miRNA-mediated regulatory mechanisms. To identify miRNA–mRNA regulatory interactions in human nervous system development, well characterized NSCs were differentiated from six validated iPSC lines and analyzed for differentially expressed (DE) miRNome and transcriptome by RNA sequencing. Following the criteria, moderated t statistics, FDR-corrected p-value ≤ 0.05 and fold change—absolute (FC-abs) ≥2.0, 51 miRNAs and 4033 mRNAs were found to be significantly DE between iPSCs and NSCs. The miRNA target prediction analysis identified 513 interactions between 30 miRNA families (mapped to 51 DE miRNAs) and 456 DE mRNAs that were paradoxically oppositely expressed. These 513 interactions were highly enriched in nervous system development functions (154 mRNAs; FDR-adjusted p-value range: 8.06 × 10−15–1.44 × 10−4). Furthermore, we have shown that the upregulated miR-10a-5p, miR-30c-5p, miR23-3p, miR130a-3p and miR-17-5p miRNA families were predicted to down-regulate several genes associated with the differentiation of neurons, neurite outgrowth and synapse formation, suggesting their role in promoting the self-renewal of undifferentiated NSCs. This study also provides a comprehensive characterization of iPSC-generated NSCs as dorsal neuroepithelium, important for their potential use in in vitro modeling of human brain development and disease.

MiR-539-3p inhibited chondrogenic differentiation in human adipose stem cells by targeting Sox9

“…MiRNAs regulate gene expression at the posttranscriptional level in many developmental and metabolic processes. Emerging evidence demonstrates that miRNAs also play an essential role in stem cell self-renewal and differentiation [ 20 , 21 ]. Some miRNAs are abnormally expressed in stem cells, control stem cell self-renewal, and differentiation through negatively regulating the expression of certain key genes in stem cells [ 22 ].…”

MicroRNA-Based Diagnosis and Therapeutics for Vascular Cognitive Impairment and Dementia

“…However, miR-485-3p has the complete opposite effect; miR-485-3p can reduce proliferation but can promote the differentiation of NSCs by decreasing TRIP-6 activity ( 70 ). Following the criteria and moderated t -statistics, miR-10a-5p was shown to attenuate the self-renewal of undifferentiated NSCs; however, similar to miR-574, miR-30c-5p, miR23-3p, miR130a-3p, and miR-17-5p miRNA families were predicted to decrease the expression of several genes associated with the differentiation of neurons, synapse formation, and neurite outgrowth ( 71 ). The miR-214 not only affects the differentiation of NSCs but also plays a key role that helps maintain the balance between proliferation and differentiation by binding the 3′-UTR of Qki mRNA, affecting downstream its signal transmission ( 72 ).…”

Human Adult Astrocyte Extracellular Vesicle Transcriptomics Study Identifies Specific RNAs Which Are Preferentially Secreted as EV Luminal Cargo

“…EVs released in response to stimulation of astrocytes by IL-1β or TNF-α carry miRNAs which influence neuronal survival and differentiation in a rodent model [ 14 ]. Several secreted miRNAs have been shown to have functions such as the modulation of dendritic size and dendritic density [ 15 ], regulation of long-term potentiation and neuronal differentiation [ 16 , 17 , 18 , 19 , 20 ], and myelination [ 21 ].…”