MiRNA influences in mesenchymal stem cell commitment to neuroblast lineage development.

Mesenchymal Stem Cells (MSCs) are widely used in therapeutic applications. Their plasticity and predisposition to differentiate into a variety of cell types, including those of the neuronal lineage, makes them ideal to study whether a selection of miRNAs may direct the differentiation of MSCs into neuroblasts or neuroblastoma to mature neurons. Following a short-listing, miR-107, 124 and 381 were selected as the most promising candidates for this differentiation. MSCs differentiated into cells of the neural lineage (Conditioned Cells) upon addition of conditioned medium (rich in microvesicles containing miRNAs) obtained from cultured SH-SY5Y neuroblastoma cells. Characterisation of stemness (including SOX2, OCT4, Nanog and HCG) and neural markers (including Nestin, MASH1, TUBB3 and NeuN1) provided insight regarding the neuronal state of each cell type. This was followed by transfection of the three miRNA antagonists and mimics, and quantification of their respective target genes. MiRNA target gene expression following transfection of MSCs with miRNA inhibitors and mimics demonstrated that these three miRNAs were not sufficient to induce differentiation. In conditioned cells the marginal changes in the miRNA target expression levels reflected potential for the modulation of intermediate neural progenitors and immature neuron cell types. Transfection of various combinations of miRNA inhibitors and/or mimics revealed more promise. Undoubtedly, a mix of biomolecules is being released by the SH-SY5Y in culture that induce MSCs to differentiate. Screening for those biomolecules acting synergistically with specific miRNAs will allow further combinatorial testing to elucidate the role of miRNA modulation.

Positioning Europe for the EPITRANSCRIPTOMICS challenge.

The genetic alphabet consists of the four letters: C, A, G, and T in DNA and C,A,G, and U in RNA. Triplets of these four letters jointly encode 20 different amino acids out of which proteins of all organisms are built. This system is universal and is found in all kingdoms of life. However, bases in DNA and RNA can be chemically modified. In DNA, around 10 different modifications are known, and those have been studied intensively over the past 20 years. Scientific studies on DNA modifications and proteins that recognize them gave rise to the large field of epigenetic and epigenomic research. The outcome of this intense research field is the discovery that development, ageing, and stem-cell dependent regeneration but also several diseases including cancer are largely controlled by the epigenetic state of cells. Consequently, this research has already led to the first FDA approved drugs that exploit the gained knowledge to combat disease. In recent years, the ~150 modifications found in RNA have come to the focus of intense research. Here we provide a perspective on necessary and expected developments in the fast expanding area of RNA modifications, termed epitranscriptomics.

MiRNA Influences in Neuroblast Modulation: An Introspective Analysis.

Neuroblastoma (NB) is the most common occurring solid paediatric cancer in children under the age of five years. Whether of familial or sporadic origin, chromosome abnormalities contribute to the development of NB and cause dysregulation of microRNAs (miRNAs). MiRNAs are small non-coding, single stranded RNAs that target messenger RNAs at the post-transcriptional levels by repressing translation within all facets of human physiology. Such gene 'silencing' activities by miRNAs allows the development of regulatory feedback loops affecting multiple functions within the cell, including the possible differentiation of neural stem cell (NSC) lineage selection. Neurogenesis includes stages of self-renewal and fate specification of NSCs, migration and maturation of young neurones, and functional integration of new neurones into the neural circuitry, all of which are regulated by miRNAs. The role of miRNAs and their interaction in cellular processes are recognised aspects of cancer genetics, and miRNAs are currently employed as biomarkers for prognosis and tumour characterisation in multiple cancer models. Consequently, thorough understanding of the mechanisms of how these miRNAs interplay at the transcriptomic level will definitely lead to the development of novel, bespoke and efficient therapeutic measures, with this review focusing on the influences of miRNAs on neuroblast modulations leading to neuroblastoma.