Dataset Information

Folic Acid Exposure Rescues Spina Bifida Aperta Phenotypes in Human Induced Pluripotent Stem Cell Model.

ABSTRACT: Neural tube defects (NTDs) are severe congenital abnormalities, caused by failed closure of neural tube during early embryonic development. Periconceptional folic acid (FA) supplementation greatly reduces the risk of NTDs. However, the molecular mechanisms behind NTDs and the preventive role of FA remain unclear. Here, we use human induced pluripotent stem cells (iPSCs) derived from fetuses with spina bifida aperta (SBA) to study the pathophysiology of NTDs and explore the effects of FA exposure. We report that FA exposure in SBA model is necessary for the proper formation and maturation of neural tube structures and robust differentiation of mesodermal derivatives. Additionally, we show that the folate antagonist methotrexate dramatically affects the formation of neural tube structures and FA partially reverts this aberrant phenotype. In conclusion, we present a novel model for human NTDs and provide evidence that it is a powerful tool to investigate the molecular mechanisms underlying NTDs, test drugs for therapeutic approaches.

SUBMITTER: Sahakyan V

PROVIDER: S-EPMC5811493 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Folic Acid Exposure Rescues Spina Bifida Aperta Phenotypes in Human Induced Pluripotent Stem Cell Model.

Sahakyan Vardine V Duelen Robin R Tam Wai Long WL Roberts Scott J SJ Grosemans Hanne H Berckmans Pieter P Ceccarelli Gabriele G Pelizzo Gloria G Broccoli Vania V Deprest Jan J Luyten Frank P FP Verfaillie Catherine M CM Sampaolesi Maurilio M

Scientific reports 20180213 1

Neural tube defects (NTDs) are severe congenital abnormalities, caused by failed closure of neural tube during early embryonic development. Periconceptional folic acid (FA) supplementation greatly reduces the risk of NTDs. However, the molecular mechanisms behind NTDs and the preventive role of FA remain unclear. Here, we use human induced pluripotent stem cells (iPSCs) derived from fetuses with spina bifida aperta (SBA) to study the pathophysiology of NTDs and explore the effects of FA exposure ...[more]

PMID: 29440666

Similar Datasets

Project description:Background: Spina bifida aperta (SBA) is a birth defect associated with severe anatomical changes in the developing fetal brain. Brain magnetic resonance imaging (MRI) atlases are popular tools for studying neuropathology in the brain anatomy, but previous fetal brain MRI atlases have focused on the normal fetal brain. We aimed to develop a spatio-temporal fetal brain MRI atlas for SBA. Methods: We developed a semi-automatic computational method to compute the first spatio-temporal fetal brain MRI atlas for SBA. We used 90 MRIs of fetuses with SBA with gestational ages ranging from 21 to 35 weeks. Isotropic and motion-free 3D reconstructed MRIs were obtained for all the examinations. We propose a protocol for the annotation of anatomical landmarks in brain 3D MRI of fetuses with SBA with the aim of making spatial alignment of abnormal fetal brain MRIs more robust. In addition, we propose a weighted generalized Procrustes method based on the anatomical landmarks for the initialization of the atlas. The proposed weighted generalized Procrustes can handle temporal regularization and missing annotations. After initialization, the atlas is refined iteratively using non-linear image registration based on the image intensity and the anatomical land-marks. A semi-automatic method is used to obtain a parcellation of our fetal brain atlas into eight tissue types: white matter, ventricular system, cerebellum, extra-axial cerebrospinal fluid, cortical gray matter, deep gray matter, brainstem, and corpus callosum. Results: An intra-rater variability analysis suggests that the seven anatomical land-marks are sufficiently reliable. We find that the proposed atlas outperforms a normal fetal brain atlas for the automatic segmentation of brain 3D MRI of fetuses with SBA. Conclusions: We make publicly available a spatio-temporal fetal brain MRI atlas for SBA, available here: https://doi.org/10.7303/syn25887675. This atlas can support future research on automatic segmentation methods for brain 3D MRI of fetuses with SBA.

Project description:BackgroundSpina bifida aperta (SBA) is a relatively common clinical type of neural tube defect. Although prenatal fetal surgery has been proven to be an effective treatment for SBA, the recovery of neurological function remains unsatisfactory due to neuron deficiencies. Our previous results demonstrated that intra-amniotic transplanted bone marrow mesenchymal stem cells (BMSCs) could preserve neural function through lesion-specific engraftment and regeneration. To further optimize the role of BMSCs and improve the environment of defective spinal cords so as to make it more conducive to nerve repair, the intra-amniotic transplanted BMSCs were modified with brain-derived neurotrophic factor (BDNF-BMSCs), and the therapeutic potential of BDNF-BMSCs was verified in this study.MethodsBMSCs were modified by adenovirus encoding a green fluorescent protein and brain-derived neurotrophic factor (Ad-GFP-BDNF) in vitro and then transplanted into the amniotic cavity of rat fetuses with spina bifida aperta which were induced by all-trans-retinoic acid on embryonic day 15. Immunofluorescence, western blot and real-time quantitative PCR were used to detect the expression of different neuron markers and apoptosis-related genes in the defective spinal cords. Lesion areas of the rat fetuses with spina bifida aperta were measured on embryonic day 20. The microenvironment changes after intra-amniotic BDNF-BMSCs transplantation were investigated by a protein array with 90 cytokines.ResultsWe found that BDNF-BMSCs sustained the characteristic of directional migration, engrafted at the SBA lesion area, increased the expression of BDNF in the defective spinal cords, alleviated the apoptosis of spinal cord cells, differentiated into neurons and skin-like cells, reduced the area of skin lesions, and improved the amniotic fluid microenvironment. Moreover, the BDNF-modified BMSCs showed a better effect than pure BMSCs on the inhibition of apoptosis and promotion of neural differentiation.ConclusionThese findings collectively indicate that intra-amniotic transplanted BDNF-BMSCs have an advantage of promoting the recovery of defective neural tissue of SBA fetuses.

Dataset Information

Folic Acid Exposure Rescues Spina Bifida Aperta Phenotypes in Human Induced Pluripotent Stem Cell Model.

Publications

Folic Acid Exposure Rescues Spina Bifida Aperta Phenotypes in Human Induced Pluripotent Stem Cell Model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets