title: Detailed analysis of the genetic and epigenetic signatures of iPSC-derived mesodiencephalic dopaminergic neurons.
abstract: Induced pluripotent stem cells (iPSCs) hold great promise for in vitro generation of disease-relevant cell types, such as mesodiencephalic dopaminergic (mdDA) neurons involved in Parkinson's disease. Although iPSC-derived midbrain DA neurons have been generated, detailed genetic and epigenetic characterizations of such neurons are lacking. The goal of this study was to examine the authenticity of iPSC-derived DA neurons obtained by established protocols. We FACS purified mdDA (Pitx3 (Gfp/+) ) neurons derived from mouse iPSCs and primary mdDA (Pitx3 (Gfp/+) ) neurons to analyze and compare their genetic and epigenetic features. Although iPSC-derived DA neurons largely adopted characteristics of their in vivo counterparts, relevant deviations in global gene expression and DNA methylation were found. Hypermethylated genes, mainly involved in neurodevelopment and basic neuronal functions, consequently showed reduced expression levels. Such abnormalities should be addressed because they might affect unambiguous long-term functionality and hamper the potential of iPSC-derived DA neurons for in vitro disease modeling or cell-based therapy.
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, 9713AV Groningen, the Netherlands.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Roessler
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Sebastien A
authors.initials: SA
authors.lastname: Smallwood
authors.affiliation: Center for Neuroscience, Swammerdam Institute for Life Science, Science Park Amsterdam, 1098XH Amsterdam, the Netherlands.
authors.forename: Jesse V
authors.initials: JV
authors.lastname: Veenvliet
authors.affiliation: Unit of Pharmacoepidemiology and Pharmacoeconomics, Department of Pharmacy, University of Groningen, 9713AV Groningen, the Netherlands.
authors.forename: Petros
authors.initials: P
authors.lastname: Pechlivanoglou
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, 9713AV Groningen, the Netherlands.
authors.forename: Su-Ping
authors.initials: SP
authors.lastname: Peng
authors.affiliation: Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Koushik
authors.initials: K
authors.lastname: Chakrabarty
authors.affiliation: Molecular Cancer Research, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Marian J A
authors.initials: MJ
authors.lastname: Groot-Koerkamp
authors.affiliation: Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: R Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, 9713AV Groningen, the Netherlands.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Wesseling
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Kelsey
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, 9713AV Groningen, the Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Boddeke
authors.affiliation: Center for Neuroscience, Swammerdam Institute for Life Science, Science Park Amsterdam, 1098XH Amsterdam, the Netherlands.
authors.forename: Marten P
authors.initials: MP
authors.lastname: Smidt
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, 9713AV Groningen, the Netherlands.
authors.forename: Sjef
authors.initials: S
authors.lastname: Copray
mesh_terms: D000818:Animals; D015415:Biomarkers; D019175:DNA Methylation; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000378:metabolism*; D044127:Epigenesis, Genetic; D015870:Gene Expression; D020869:Gene Expression Profiling; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics; D059467:Transcriptome
chemical_list: D015415:Biomarkers
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