Background

Mesenchymal stem cell (MSC) found in bone marrow (BM-MSCs) and the Wharton's jelly matrix of human umbilical cord (WJ-MSCs) are able to transdifferentiate into neuronal lineage cells both in vitro and in vivo and therefore hold the potential to treat neural disorders such as stroke or Parkinson's disease. In bone marrow MSCs, miR-130a and miR-206 have been show to regulate the synthesis of neurotransmitter substance P in human mesenchymal stem cell-derived neuronal cells. However, how neuronal differentiation is controlled in WJ-MSC remains unclear.

Methods

WJ-MSCs were isolated from human umbilical cords. We subjected WJ-MSCs into neurogenesis by a published protocol, and the miRNome patterns of WJ-MSCs and their neuronal progenitors (day 9 after differentiation) were analyzed by the Agilent microRNA microarray.

Results

Five miRNAs were enriched in WJ-MSCs, including miR-345, miR-106a, miR-17-5p, miR-20a and miR-20b. Another 11 miRNAs (miR-206, miR-34a, miR-374, miR-424, miR-100, miR-101, miR-323, miR-368, miR-137, miR-138 and miR-377) were abundantly expressed in transdifferentiated neuronal progenitors. Among these miRNAs, miR-34a and miR-206 were the only 2 miRNAs been linked to BM-MSC neurogenesis. Overexpressing miR-34a in cells suppressed the expression of 136 neuronal progenitor genes, which all possess putative miR-34a binding sites. Gene enrichment analysis according to the Gene Ontology database showed that those 136 genes were associated with cell motility, energy production (including those with oxidative phosphorylation, electron transport and ATP synthesis) and actin cytoskeleton organization, indicating that miR-34a plays a critical role in precursor cell migration. Knocking down endogenous miR-34a expression in WJ-MSCs resulted in the augment of WJ-MSC motility.

Conclusions

Our data suggest a critical role of miRNAs in MSC neuronal differentiation, and miR-34a contributes in neuronal precursor motility, which may be crucial for stem cells to home to the target sites they should be.

Background

Intracranial pediatric germ cell tumors (GCTs) are rare and heterogeneous neoplasms and vary in histological differentiation, prognosis and clinical behavior. Germinoma and mature teratoma are GCTs that have a good prognosis, while other types of GCTs, termed nongerminomatous malignant germ cell tumors (NGMGCTs), are tumors with an intermediate or poor prognosis. The second group of tumors requires more extensive drug and irradiation treatment regimens. The mechanisms underlying the differences in incidence and prognosis of the various GCT subgroups are unclear.

Results

We identified a distinct mRNA profile correlating with GCT histological differentiation and prognosis, and also present in this study the first miRNA profile of pediatric primary intracranial GCTs. Most of the differentially expressed miRNAs were downregulated in germinomas, but miR-142-5p and miR-146a were upregulated. Genes responsible for self-renewal (such as POU5F1 (OCT4), NANOG and KLF4) and the immune response were abundant in germinomas, while genes associated with neuron differentiation, Wnt/β-catenin pathway, invasiveness and epithelial-mesenchymal transition (including SNAI2 (SLUG) and TWIST2) were abundant in NGMGCTs. Clear transcriptome segregation based on patient survival was observed, with malignant NGMGCTs being closest to embryonic stem cells. Chromosome copy number variations (CNVs) at cytobands 4q13.3-4q28.3 and 9p11.2-9q13 correlated with GCT malignancy and clinical risk. Six genes (BANK1, CXCL9, CXCL11, DDIT4L, ELOVL6 and HERC5) within 4q13.3-4q28.3 were more abundant in germinomas.

Conclusions

Our results integrate molecular profiles with clinical observations and provide insights into the underlying mechanisms causing GCT malignancy. The genes, pathways and microRNAs identified have the potential to be novel therapeutic targets.