Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities.
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 with 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, 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.
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [3] Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
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JM
Madison
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA.
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Zhou
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
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Nigam
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA.
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A
Hussain
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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DD
Barker
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
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Nehme
Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA.
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K
van der Ven
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA.
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J
Hsu
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [3] Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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Wolf
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA.
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M
Fleishman
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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C
O'Dushlaine
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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S
Rose
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Chambert
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
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FH
Lau
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
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T
Ahfeldt
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [3] Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
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EH
Rueckert
Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
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SD
Sheridan
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA [3] Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
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DM
Fass
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Department of Genetics, Harvard Medical School, Boston, MA, USA.
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J
Nemesh
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Department of Genetics, Harvard Medical School, Boston, MA, USA.
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TE
Mullen
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
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L
Daheron
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Department of Genetics, Harvard Medical School, Boston, MA, USA.
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McCarroll
1] Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Sklar
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [3] Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA [4] Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
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RH
Perlis
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [3] Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA [4] Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA [5] Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
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Haggarty
D001714:Bipolar Disorder / Q000473:pathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D056915:DNA Copy Number Variations / Q000235:genetics; D005192:Family Health; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology
C527276:CXCR4 protein, human; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D014157:Transcription Factors; D038362:Glycogen Synthase Kinase 3