Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities

Autor: Frank H. Lau, Pamela Sklar, Stephen J. Haggarty, Samuel A. Rose, Roy H. Perlis, Steven D. Sheridan, Steven A. McCarroll, James Nemesh, Philip A. Wolf, Colm O'Dushlaine, A Hussain, Ralda Nehme, A Nigam, E H Rueckert, Douglas Barker, Daniel M. Fass, M Fleishman, Joey Hsu, Jon M. Madison, Fen Zhou, K van der Ven, Kimberly Chambert, Thomas E. Mullen, Tim Ahfeldt, Laurence Daheron
Rok vydání: 2015
Předmět:
Male
Bipolar Disorder
Cellular differentiation
Gene Expression
GSK3
Membrane Potentials
Glycogen Synthase Kinase 3
0302 clinical medicine
GSK-3
calcium channels
Gene expression
Induced pluripotent stem cell
Wnt Signaling Pathway
Cells
Cultured
Neurons
0303 health sciences
iPSC
neurodevelopment
Wnt signaling pathway
ion channels
Cell Differentiation
3. Good health
Psychiatry and Mental health
lithium
Schizophrenia
Cytokines
Intercellular Signaling Peptides and Proteins
Female
Stem cell
Receptors
CXCR4
DNA Copy Number Variations
neuroplasticity
Induced Pluripotent Stem Cells
Biology
Polymorphism
Single Nucleotide
Article
03 medical and health sciences
Cellular and Molecular Neuroscience
mental disorders
medicine
Humans
RNA
Messenger
Bipolar disorder
Molecular Biology
030304 developmental biology
Family Health
medicine.disease
stem cell
Cancer research
Neuroscience
030217 neurology & neurosurgery
corticogenesis
Transcription Factors
Zdroj: Molecular psychiatry
ISSN: 1476-5578
1359-4184
DOI: 10.1038/mp.2015.7
Popis: Bipolar disorder (BD) is a common neuropsychiatric disorder characterized by chronic recurrent episodes of depression and mania. Despite evidence for high heritability of BD, little is known about its underlying pathophysiology. To develop new tools for investigating the molecular and cellular basis of BD we applied a family-based paradigm to derive and characterize a set of 12 induced pluripotent stem cell (iPSC) lines from a quartet consisting of two BD-affected brothers and their two unaffected parents. Initially, no significant phenotypic differences were observed between iPSCs derived from the different family members. However, upon directed neural differentiation we observed that CXCR4 (CXC chemokine receptor-4) expressing central nervous system (CNS) neural progenitor cells (NPCs) from both BD patients compared to their unaffected parents exhibited multiple phenotypic differences at the level of neurogenesis and expression of genes critical for neuroplasticity, including WNT pathway components and ion channel subunits. Treatment of the CXCR4+ NPCs with a pharmacological inhibitor of glycogen synthase kinase 3 (GSK3), a known regulator of WNT signaling, was found to rescue a progenitor proliferation deficit in the BD-patient NPCs. Taken together, these studies provide new cellular tools for dissecting the pathophysiology of BD and evidence for dysregulation of key pathways involved in neurodevelopment and neuroplasticity. Future generation of additional iPSCs following a family-based paradigm for modeling complex neuropsychiatric disorders in conjunction with in-depth phenotyping holds promise for providing insights into the pathophysiological substrates of BD and is likely to inform the development of targeted therapeutics for its treatment and ideally prevention.
Databáze: OpenAIRE
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