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

Vardine Sahakyan, Robin Duelen, Wai Long Tam, Scott J Roberts, Hanne Grosemans, Pieter Berckmans, Gabriele Ceccarelli, Gloria Pelizzo, Vania Broccoli, Jan Deprest, Frank P Luyten, Catherine M Verfaillie, Maurilio Sampaolesi

Journal: Scientific reports 2019;8(1):2942

PMID: 29440666

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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.

Address: Translational Cardiomyology Laboratory, Stem Cell Biology and Embryology Unit, Stem Cell Institute, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.; Tissue Engineering Laboratory, Skeletal Biology and Engineering Research Center, and Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium.; Institute of Orthopaedics and Musculoskeletal Science, Division of Surgery and Interventional Science, University College London, The Royal National Orthopaedic Hospital, London, UK.; Stem Cell Institute and Stem Cell Biology and Embryology Unit, Department Development and Regeneration, KU Leuven, Leuven, Belgium.; Human Anatomy Unit, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy.; Pediatric Surgery Department, Istituto Mediterraneo di Eccellenza Pediatrica (ISMEP), Children's Hospital "G di Cristina", Palermo, Italy.; Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.; CNR-Institute of Neuroscience, Milan, Italy.; Department of Obstetrics and Gynecology, Division Woman and Child, Fetal Medicine Unit, University Hospitals KU Leuven, Leuven, Belgium.; Institute for Women's Health (IWH), University College London, London, United Kingdom.; Translational Cardiomyology Laboratory, Stem Cell Biology and Embryology Unit, Stem Cell Institute, Department of Development and Regeneration, KU Leuven, Leuven, Belgium. [email protected].; Human Anatomy Unit, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy. [email protected].

DOI: 10.1038/s41598-018-21103-8

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MeSH Terms: Cell Differentiation, Down-Regulation, Folic Acid, Humans, Induced Pluripotent Stem Cells, Muscle Development, Neurons, PAX3 Transcription Factor, PAX7 Transcription Factor, Phenotype, Spheroids, Cellular, Spina Bifida Cystica, Up-Regulation