Dataset Information

Methotrexate and Valproic Acid Affect Early Neurogenesis of Human Amniotic Fluid Stem Cells from Myelomeningocele.

ABSTRACT: Myelomeningocele (MMC) is a severe type of neural tube defect (NTD), in which the backbone and spinal canal do not close completely during early embryonic development. This condition results in serious morbidity and increased mortality after birth. Folic acid significantly reduces, and conversely, folate antagonist methotrexate (MTX) and valproic acid (VPA) increase the occurrence of NTDs, including MMC. How these pharmacological agents exactly influence the early neurulation process is still largely unclear. Here, we characterized human amniotic fluid-derived stem cells (AFSCs) from prenatally diagnosed MMC and observed an effect of MTX and VPA administration on the early neural differentiation process. We found that MMC-derived AFSCs highly expressed early neural and radial glial genes that were negatively affected by MTX and VPA exposure. In conclusion, we setup a human cell model of MMC to study early neurogenesis and for drug screening purposes. We also proposed the detection of early neural gene expression in AFSCs as an additional MMC diagnostic tool.

SUBMITTER: Sahakyan V

PROVIDER: S-EPMC5615990 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Methotrexate and Valproic Acid Affect Early Neurogenesis of Human Amniotic Fluid Stem Cells from Myelomeningocele.

Sahakyan Vardine V Pozzo Enrico E Duelen Robin R Deprest Jan J Sampaolesi Maurilio M

Stem cells international 20170913

Myelomeningocele (MMC) is a severe type of neural tube defect (NTD), in which the backbone and spinal canal do not close completely during early embryonic development. This condition results in serious morbidity and increased mortality after birth. Folic acid significantly reduces, and conversely, folate antagonist methotrexate (MTX) and valproic acid (VPA) increase the occurrence of NTDs, including MMC. How these pharmacological agents exactly influence the early neurulation process is still la ...[more]

PMID: 29056972

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Project description:BackgroundCell-free RNA in amniotic fluid supernatant reflects developmental changes in gene expression in the living fetus, which includes genes that are specific to the central nervous system. Although it has been previously shown that central nervous system-specific transcripts are present in amniotic fluid supernatant, it is not known whether changes in the amniotic fluid supernatant transcriptome reflect the specific pathophysiologic condition of fetal central nervous system disorders. In myelomeningocele, there is open communication between the central nervous system and amniotic fluid.ObjectivesThe purpose of this study was to identify molecular pathophysiologic changes and novel disease mechanisms that are specific to myelomeningocele by the analysis of amniotic fluid supernatant cell-free RNA in fetuses with open myelomeningocele.Study designAmniotic fluid supernatant was collected from 10 pregnant women at the time of the open myelomeningocele repair in the second trimester (24.5±1.0 weeks); 10 archived amniotic fluid supernatant from sex and gestational age-matched euploid fetuses without myelomeningocele were used as controls (20.9±0.9 weeks). Differentially regulated gene expression patterns were analyzed with the use of human genome expression arrays.ResultsFetuses with myelomeningocele had 284 differentially regulated genes (176 up- and 108 down-regulated) in amniotic fluid supernatant. Known genes that were associated with myelomeningocele (PRICKLE2, GLI3, RAB23, HES1, FOLR1) and novel dysregulated genes were identified in association with neurodevelopment and neuronal regeneration (up-regulated, GAP43 and ZEB1) or axonal growth and guidance (down-regulated, ACAP1). Pathway analysis demonstrated a significant contribution of inflammation to disease and a broad influence of Wnt signaling pathways (Wnt1, Wnt5A, ITPR1).ConclusionTranscriptomic analyses of living fetuses with myelomeningocele with the use of amniotic fluid supernatant cell-free RNA demonstrated differential regulation of specific genes and molecular pathways relevant to this central nervous system disorder, which resulted in a new understanding of pathophysiologic changes. The data also suggested the importance of pathways that involve secondary disease, such as inflammation, in myelomeningocele. These newly identified pathways may lead to hypotheses that can test novel therapeutic targets as adjuncts to fetal surgical repair.

Dataset Information

Methotrexate and Valproic Acid Affect Early Neurogenesis of Human Amniotic Fluid Stem Cells from Myelomeningocele.

Publications

Methotrexate and Valproic Acid Affect Early Neurogenesis of Human Amniotic Fluid Stem Cells from Myelomeningocele.

Similar Datasets

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