Modeling psychiatric disorders: from genomic findings to cellular phenotypes

Major programs in psychiatric genetics have identified >150 risk loci for psychiatric disorders. These loci converge on a small number of functional pathways, which span conventional diagnostic criteria, suggesting a partly common biology underlying schizophrenia, autism and other psychiatric disorders. Nevertheless, the cellular phenotypes that capture the fundamental features of psychiatric disorders have not yet been determined. Recent advances in genetics and stem cell biology offer new prospects for cell-based modeling of psychiatric disorders. The advent of cell reprogramming and induced pluripotent stem cells (iPSC) provides an opportunity to translate genetic findings into patient-specific in vitro models. iPSC technology is less than a decade old but holds great promise for bridging the gaps between patients, genetics and biology. Despite many obvious advantages, iPSC studies still present multiple challenges. In this expert review, we critically review the challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes.

[1]  F. Gage,et al.  Modeling psychiatric disorders through reprogramming , 2011, Disease Models & Mechanisms.

[2]  Yi Zhang,et al.  Genetic and epigenetic variations in iPSCs: potential causes and implications for application. , 2013, Cell stem cell.

[3]  D. Geschwind,et al.  Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture , 2015, Nature Methods.

[4]  E. Banks,et al.  De novo mutations in schizophrenia implicate synaptic networks , 2014, Nature.

[5]  Zhihai Ma,et al.  Identification of Human Neuronal Protein Complexes Reveals Biochemical Activities and Convergent Mechanisms of Action in Autism Spectrum Disorders. , 2015, Cell systems.

[6]  Marcelo P. Coba,et al.  Knockdown of mental disorder susceptibility genes disrupts neuronal network physiology in vitro , 2011, Molecular and Cellular Neuroscience.

[7]  S. Buka.  Psychiatric Epidemiology: Reducing the Global Burden of Mental Illness , 2008, American Journal of Epidemiology.

[8]  S. Bonner-Weir,et al.  Concise Review: Pancreas Regeneration: Recent Advances and Perspectives , 2012, Stem cells translational medicine.

[9]  R Kucherlapati,et al.  Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia , 2007, Molecular Psychiatry.

[10]  Mari Pekkanen-Mattila,et al.  A 3D Alzheimer's disease culture model and the induction of P21-activated kinase mediated sensing in iPSC derived neurons. , 2014, Biomaterials.

[11]  Lisle W. Blackbourn,et al.  A Simple and Efficient System for Regulating Gene Expression in Human Pluripotent Stem Cells and Derivatives , 2014, Stem cells.

[12]  V. Sandler,et al.  Development of Patient-Specific Neurons in Schizophrenia Using Induced Pluripotent Stem Cells , 2011, Journal of neurogenetics.

[13]  G. Kirov,et al.  Common alleles contribute to schizophrenia in CNV carriers , 2015, Molecular Psychiatry.

[14]  Toshiro K. Ohsumi,et al.  Sequencing Chromosomal Abnormalities Reveals Neurodevelopmental Loci that Confer Risk across Diagnostic Boundaries , 2012, Cell.

[15]  N. Uranova,et al.  Ultrastructural Alterations of Myelinated Fibers and Oligodendrocytes in the Prefrontal Cortex in Schizophrenia: A Postmortem Morphometric Study , 2011, Schizophrenia research and treatment.

[16]  K. Brennand,et al.  Modeling Heterogeneous Patients With a Clinical Diagnosis of Schizophrenia With Induced Pluripotent Stem Cells , 2014, Biological Psychiatry.

[17]  Christopher S. Poultney,et al.  Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci , 2015, Neuron.

[18]  Eric S. Lander,et al.  A polygenic burden of rare disruptive mutations in schizophrenia , 2014, Nature.

[19]  D. Krainc,et al.  Human iPSC-based modeling of late-onset disease via progerin-induced aging. , 2013, Cell stem cell.

[20]  M. Gerstein,et al.  FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders , 2015, Cell.

[21]  Patrick F. Sullivan,et al.  Genetic architectures of psychiatric disorders: the emerging picture and its implications , 2012, Nature Reviews Genetics.

[22]  R. Dolmetsch,et al.  SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients , 2013, Nature.

[23]  V. Haroutunian,et al.  Cortical expression of glial fibrillary acidic protein and glutamine synthetase is decreased in schizophrenia , 2008, Schizophrenia Research.

[24]  Jun S. Song,et al.  Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells , 2011, Nature Cell Biology.

[25]  David W. Nauen,et al.  Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity. , 2014, Cell stem cell.

[26]  F. Vaccarino,et al.  Neurobiology meets genomic science: The promise of human-induced pluripotent stem cells , 2012, Development and Psychopathology.

[27]  P. Visscher,et al.  Nature Genetics Advance Online Publication , 2022 .

[28]  M. Ohkura,et al.  A high signal-to-noise Ca2+ probe composed of a single green fluorescent protein , 2001, Nature Biotechnology.

[29]  R. Ophoff,et al.  Genome-wide burden of deleterious coding variants increased in schizophrenia , 2015, Nature Communications.

[30]  Stormy J. Chamberlain,et al.  Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1 , 2014, Molecular Autism.

[31]  C A Jones,et al.  Animal models of schizophrenia , 2011, British journal of pharmacology.

[32]  Xin Li,et al.  A comparison of non-integrating reprogramming methods , 2014, Nature Biotechnology.

[33]  P. Sullivan,et al.  Specific glial functions contribute to schizophrenia susceptibility. , 2014, Schizophrenia bulletin.

[34]  D. Selkoe,et al.  Genomic DISC1 Disruption in hiPSCs Alters Wnt Signaling and Neural Cell Fate. , 2015, Cell reports.

[35]  A. Nairn,et al.  Assessment of cognitive function in the heterozygous reeler mouse , 2006, Psychopharmacology.

[36]  Daniel J. Gaffney,et al.  Genetic Background Drives Transcriptional Variation in Human Induced Pluripotent Stem Cells , 2014, PLoS genetics.

[37]  F. Gage,et al.  Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro , 2015, Proceedings of the National Academy of Sciences.

[38]  R. Dolmetsch,et al.  Timothy Syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons , 2012, Nature Neuroscience.

[39]  S. Tsang,et al.  Personalized therapeutic strategies for patients with retinitis pigmentosa , 2015, Expert opinion on biological therapy.

[40]  F. Benes.  Building models for postmortem abnormalities in hippocampus of schizophrenics , 2015, Schizophrenia Research.

[41]  David W. Nauen,et al.  Synaptic dysregulation in a human iPS cell model of mental disorders , 2014, Nature.

[42]  Katsushige Sato,et al.  Using voltage‐sensitive dye recording to image the functional development of neuronal circuits in vertebrate embryos , 2008, Developmental neurobiology.

[43]  K. Eggan,et al.  Modeling human disease with pluripotent stem cells: from genome association to function. , 2013, Cell stem cell.

[44]  Kun-Yong Kim,et al.  Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome , 2011, Proceedings of the National Academy of Sciences.

[45]  Yun Liu,et al.  Risk variants in the S100B gene, associated with elevated S100B levels, are also associated with visuospatial disability of schizophrenia , 2011, Behavioural Brain Research.

[46]  Simon C. Potter,et al.  Genome-wide Association Analysis Identifies 14 New Risk Loci for Schizophrenia , 2013, Nature Genetics.

[47]  K. Brennand,et al.  EMBRYONIC STEM CELLS / INDUCED PLURIPOTENT STEM CELLS Concise Review : The Promise of Human Induced Pluripotent Stem Cell-Based Studies of Schizophrenia , 2011 .

[48]  Deyou Zheng,et al.  MicroRNA Profiling of Neurons Generated Using Induced Pluripotent Stem Cells Derived from Patients with Schizophrenia and Schizoaffective Disorder, and 22q11.2 Del , 2015, PloS one.

[49]  R. Weksberg,et al.  Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation , 2011, Human molecular genetics.

[50]  Y. Bozzi,et al.  Mutant Mouse Models of Autism Spectrum Disorders , 2012, Disease markers.

[51]  M. Gerstein,et al.  Annual Research Review: The promise of stem cell research for neuropsychiatric disorders. , 2011, Journal of Child Psychology and Psychiatry and Allied Disciplines.

[52]  P. Froguel,et al.  Pluripotent Stem Cells as a Potential Tool for Disease Modelling and Cell Therapy in Diabetes , 2014, Stem Cell Reviews and Reports.

[53]  J. Nurnberger,et al.  Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder , 2015, Nature.

[54]  S. Rehen,et al.  Altered Oxygen Metabolism Associated to Neurogenesis of Induced Pluripotent Stem Cells Derived from a Schizophrenic Patient , 2012, Cell transplantation.

[55]  J. Stockman,et al.  Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study , 2010 .

[56]  Robert Langer,et al.  Three-dimensional biomaterials for the study of human pluripotent stem cells , 2011, Nature Methods.

[57]  Madeline A. Lancaster,et al.  Cerebral organoids model human brain development and microcephaly , 2013, Nature.

[58]  K. Baldwin,et al.  Advances in reprogramming-based study of neurologic disorders. , 2015, Stem cells and development.

[59]  K. Iwamoto,et al.  Gene Expression Profiling in Schizophrenia and Related Mental Disorders , 2006, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[60]  V. Kalscheuer,et al.  CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons , 2012, Nature Cell Biology.

[61]  E. Costa,et al.  Down-regulation of dendritic spine and glutamic acid decarboxylase 67 expressions in the reelin haploinsufficient heterozygous reeler mouse , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[62]  J. Rubenstein,et al.  Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. , 2013, Cell stem cell.

[63]  P. Sullivan,et al.  Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. , 2003, Archives of general psychiatry.

[64]  J. Pritchard,et al.  Reprogramming LCLs to iPSCs Results in Recovery of Donor-Specific Gene Expression Signature , 2015, bioRxiv.

[65]  L. Mei,et al.  Neuregulin 1 in neural development, synaptic plasticity and schizophrenia , 2008, Nature Reviews Neuroscience.

[66]  Fred H. Gage,et al.  Modeling Hippocampal Neurogenesis Using Human Pluripotent Stem Cells , 2014, Stem cell reports.

[67]  Hao Wang,et al.  Dysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia , 2008, Schizophrenia Research.

[68]  J. Al-Aama,et al.  Concise Review: Cardiac Disease Modeling Using Induced Pluripotent Stem Cells , 2015, Stem cells.

[69]  G. Wallace,et al.  The potential of induced pluripotent stem cells in models of neurological disorders: implications on future therapy , 2015, Expert review of neurotherapeutics.

[70]  Paul J. Harrison,et al.  Neuregulin 1 and Schizophrenia: Genetics, Gene Expression, and Neurobiology , 2006, Biological Psychiatry.

[71]  P. Hagerman,et al.  Signaling defects in iPSC-derived fragile X premutation neurons. , 2012, Human molecular genetics.

[72]  G. Feng,et al.  Micro-electrode array recordings reveal reductions in both excitation and inhibition in cultured cortical neuron networks lacking Shank3 , 2016, Molecular Psychiatry.

[73]  M. Didriksen,et al.  The heterozygous reeler mouse: behavioural phenotype , 2004, Behavioural Brain Research.

[74]  P. Pasceri,et al.  Rett syndrome induced pluripotent stem cell-derived neurons reveal novel neurophysiological alterations , 2012, Molecular Psychiatry.

[75]  George M. Church,et al.  Elevated Coding Mutation Rate During the Reprogramming of Human Somatic Cells into Induced Pluripotent Stem Cells , 2012, Stem cells.

[76]  Y. Sasai.  Next-generation regenerative medicine: organogenesis from stem cells in 3D culture. , 2013, Cell stem cell.

[77]  C. Robson,et al.  Using induced pluripotent stem cells as a tool for modelling carcinogenesis. , 2015, World journal of stem cells.

[78]  W. Singer,et al.  Abnormal neural oscillations and synchrony in schizophrenia , 2010, Nature Reviews Neuroscience.

[79]  T. Ichisaka,et al.  Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 2007, Cell.

[80]  H. Jaaro-Peled.  Gene models of schizophrenia: DISC1 mouse models. , 2009, Progress in brain research.

[81]  Giulio Genovese,et al.  Schizophrenia risk from complex variation of complement component 4 , 2016, Nature.

[82]  S. Horvath,et al.  Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome , 2014, Genome Medicine.

[83]  O. Brüstle,et al.  Disease-specific iPS cell models in neuroscience. , 2013, Current molecular medicine.

[84]  E. Grigorenko,et al.  Induced pluripotent stem cells: A new tool to confront the challenge of neuropsychiatric disorders , 2011, Neuropharmacology.

[85]  F. Gage,et al.  Induced pluripotent stem cells (iPSCs) and neurological disease modeling: progress and promises. , 2011, Human molecular genetics.

[86]  A. Terzic,et al.  Nuclear Reprogramming Strategy Modulates Differentiation Potential of Induced Pluripotent Stem Cells , 2011, Journal of cardiovascular translational research.

[87]  Paul J. Harrison.  Postmortem studies in schizophrenia , 2000, Dialogues in clinical neuroscience.

[88]  S. Rehen,et al.  Valproate reverts zinc and potassium imbalance in schizophrenia-derived reprogrammed cells , 2014, Schizophrenia Research.

[89]  Jason A Hendry,et al.  Human induced pluripotent stem cell derived neurons as a model for Williams-Beuren syndrome , 2015, Molecular Brain.

[90]  F. Gage,et al.  Modeling psychiatric disorders at the cellular and network levels , 2012, Molecular Psychiatry.

[91]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[92]  Pall I. Olason,et al.  Common variants conferring risk of schizophrenia , 2009, Nature.

[93]  Elena Papaleo,et al.  Molecular dynamics investigation of cyclic natriuretic peptides: dynamic properties reflect peptide activity. , 2010, Journal of molecular graphics & modelling.

[94]  Peilin Zhang,et al.  Functional Impacts of NRXN1 Knockdown on Neurodevelopment in Stem Cell Models , 2013, PloS one.

[95]  S. Kasper,et al.  Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients , 2013, Molecular Psychiatry.

[96]  D. Martins‐de‐Souza.  Proteome and transcriptome analysis suggests oligodendrocyte dysfunction in schizophrenia. , 2010, Journal of psychiatric research.

[97]  Tamas L. Horvath,et al.  Modeling human cortical development in vitro using induced pluripotent stem cells , 2012, Proceedings of the National Academy of Sciences.

[98]  I. Kohane,et al.  iPSC-derived neurons as a higher-throughput readout for autism: promises and pitfalls. , 2014, Trends in molecular medicine.

[99]  Jianping Fu,et al.  On human pluripotent stem cell control: The rise of 3D bioengineering and mechanobiology. , 2015, Biomaterials.

[100]  Laura J. Scott,et al.  Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways , 2015, Nature Neuroscience.

[101]  Marius Wernig,et al.  Human Neuropsychiatric Disease Modeling using Conditional Deletion Reveals Synaptic Transmission Defects Caused by Heterozygous Mutations in NRXN1. , 2015, Cell stem cell.

[102]  M. Maier,et al.  Astrocyte decrease in the subgenual cingulate and callosal genu in schizophrenia , 2013, European Archives of Psychiatry and Clinical Neuroscience.

[103]  Fred H. Gage,et al.  A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem Cells , 2010, Cell.

[104]  A. Guidotti,et al.  Reelin down-regulation in mice and psychosis endophenotypes , 2006, Neuroscience & Biobehavioral Reviews.

[105]  L. Fang,et al.  Roles of heat shock factor 1 in isoproterenol‑induced myocardial fibrosis in mice. , 2015, Molecular medicine reports.

[106]  G. Nestadt,et al.  The burden of mental disorders. , 2008, Epidemiologic reviews.

[107]  L. Siever,et al.  Spatial and Temporal Mapping of De Novo Mutations in Schizophrenia to a Fetal Prefrontal Cortical Network , 2013, Cell.

[108]  G. Daley,et al.  The promise of induced pluripotent stem cells in research and therapy , 2012, Nature.

[109]  F. Gage,et al.  Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia , 2014, Molecular Psychiatry.

[110]  S. Haggarty,et al.  Epigenetic Characterization of the FMR1 Gene and Aberrant Neurodevelopment in Human Induced Pluripotent Stem Cell Models of Fragile X Syndrome , 2011, PloS one.

[111]  P. Fairchild.  The challenge of immunogenicity in the quest for induced pluripotency , 2010, Nature Reviews Immunology.

[112]  P. Mortensen,et al.  Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. , 2011, The American journal of psychiatry.

[113]  Michael E. Greenberg,et al.  Activity-dependent neuronal signalling and autism spectrum disorder , 2013, Nature.

[114]  S. Cichon,et al.  Evaluating Historical Candidate Genes for Schizophrenia , 2015, Molecular Psychiatry.

[115]  J. Kleinman,et al.  Glial fibrillary acidic protein mRNA levels in the cingulate cortex of individuals with depression, bipolar disorder and schizophrenia , 2005, Neuroscience.

[116]  G. Daley,et al.  Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. , 2010, Cell stem cell.

[117]  Rudolf Jaenisch,et al.  One-Step Generation of Mice Carrying Mutations in Multiple Genes by CRISPR/Cas-Mediated Genome Engineering , 2013, Cell.

[118]  Jianxin Shi,et al.  Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs , 2013, Nature Genetics.

[119]  J. Sebat,et al.  CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics , 2012, Cell.

[120]  F. Gage,et al.  Human iPSC Neurons Display Activity-Dependent Neurotransmitter Secretion: Aberrant Catecholamine Levels in Schizophrenia Neurons , 2014, Stem cell reports.

[121]  Concepcion R. Nierras,et al.  The promise of human induced pluripotent stem cells for research and therapy , 2008, Nature Reviews Molecular Cell Biology.

[122]  Allison E. Songstad,et al.  Patient-specific induced pluripotent stem cells (iPSCs) for the study and treatment of retinal degenerative diseases , 2015, Progress in Retinal and Eye Research.

[123]  B. Bogerts,et al.  Glial cells as key players in schizophrenia pathology: recent insights and concepts of therapy , 2015, Schizophrenia Research.

[124]  Zhiping P. Pang,et al.  Integrative genomic and functional analyses reveal neuronal subtype differentiation bias in human embryonic stem cell lines , 2007, Proceedings of the National Academy of Sciences.

[125]  Sam W. Lee,et al.  Induced cancer stem-like cells as a model for biological screening and discovery of agents targeting phenotypic traits of cancer stem cell , 2014, Oncotarget.

[126]  Molly J. Harding,et al.  The roles and regulation of multicellular rosette structures during morphogenesis , 2014, Development.

[127]  J. Rinn,et al.  A comparison of genetically matched cell lines reveals the equivalence of human iPSCs and ESCs , 2015, Nature Biotechnology.

[128]  박찬영.  Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome , 2012 .

[129]  Fred H. Gage,et al.  Modelling schizophrenia using human induced pluripotent stem cells , 2011, Nature.

[130]  Patrick F Sullivan,et al.  Recurrence risks for schizophrenia in a Swedish National Cohort , 2006, Psychological Medicine.

[131]  R. Yolken,et al.  Association study of IL10, IL1β, and IL1RN and schizophrenia using tag SNPs from a comprehensive database: Suggestive association with rs16944 at IL1β , 2006, Schizophrenia Research.

[132]  A. Odawara,et al.  Long-term electrophysiological activity and pharmacological response of a human induced pluripotent stem cell-derived neuron and astrocyte co-culture. , 2014, Biochemical and biophysical research communications.

[133]  H. Nasrallah,et al.  Corpus Callosum Thickness in Chronic Schizophrenia , 1983, British Journal of Psychiatry.

[134]  N. Benvenisty,et al.  Molecular analysis of FMR1 reactivation in fragile-X induced pluripotent stem cells and their neuronal derivatives. , 2012, Journal of molecular cell biology.

[135]  David A. Orlando,et al.  Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons. , 2013, Cell stem cell.

[136]  Jianxin Shi,et al.  Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. , 2011, The American journal of psychiatry.

[137]  V. Haroutunian,et al.  Gene expression abnormalities and oligodendrocyte deficits in the internal capsule in schizophrenia , 2010, Schizophrenia Research.

[138]  G. Ananiev,et al.  Isogenic Pairs of Wild Type and Mutant Induced Pluripotent Stem Cell (iPSC) Lines from Rett Syndrome Patients as In Vitro Disease Model , 2011, PloS one.

[139]  Bin Zhou,et al.  Molecular Substrates of Schizophrenia: Homeostatic Signaling to Connectivity , 2015, Molecular Psychiatry.

[140]  K. Brennand,et al.  Altered WNT Signaling in Human Induced Pluripotent Stem Cell Neural Progenitor Cells Derived from Four Schizophrenia Patients , 2015, Biological Psychiatry.

[141]  Jeffrey A. Porter,et al.  CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency , 2016, Science.

[142]  P. Holmans,et al.  Pathway Analyses Implicate Glial Cells in Schizophrenia , 2014, PloS one.

[143]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[144]  Chanjuan Hao,et al.  DTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release , 2008, The Journal of cell biology.

[145]  J. Lupski,et al.  Passage Number is a Major Contributor to Genomic Structural Variations in Mouse iPSCs , 2014, Stem cells.

[146]  R. Harvey,et al.  Schizophrenia‐related endophenotypes in heterozygous neuregulin‐1 ‘knockout’ mice , 2010, The European journal of neuroscience.

[147]  Jie Du,et al.  Human induced pluripotent stem cell for modeling cardiovascular diseases , 2014, Regenerative Medicine Research.

[148]  Marton.,et al.  Copy Number Variants , 2018, Methods in Molecular Biology.

[149]  Alexander Meissner,et al.  Automated, high-throughput derivation, characterization and differentiation of induced pluripotent stem cells , 2015, Nature Methods.

[150]  P. Crino,et al.  Focal malformations of cortical development: New vistas for molecular pathogenesis , 2013, Neuroscience.

[151]  Jarno M. A. Tanskanen,et al.  Human embryonic stem cell-derived neuronal cells form spontaneously active neuronal networks in vitro , 2009, Experimental Neurology.