From the Psychiatrist’s Couch to Induced Pluripotent Stem Cells: Bipolar Disease in a Dish

Hoffmann, Anke; Sportelli, Vincenza; Ziller, Michael J.; Spengler, Dietmar

doi:10.3390/ijms19030770

Cited by 17 publications

(9 citation statements)

References 109 publications

(143 reference statements)

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“…As iPSC technology developed and became more accessible, researchers began to focus on less well-defined psychiatric diseases, such as bipolar disorder (Hoffmann et al 2018;Miller and Kelsoe 2017;O'Shea and McInnis 2015;Viswanath et al 2015;Watmuff et al 2016), alcohol use disorder (Prytkova et al 2018) and anorexia nervosa (Maussion et al 2019). There has also been a great interest in the use of 3D brain organoids instead of 2D neuronal cells, and the use of CRISPR/cas9 to genetically edit iPSC-derived models, which have been extensively reviewed elsewhere (Korhonen et al 2018;Lee et al 2017;Rehbach et al 2020;Tian et al 2020).…”

Section: Introductionmentioning

confidence: 99%

Mental health dished up—the use of iPSC models in neuropsychiatric research

et al. 2020

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Genetic and molecular mechanisms that play a causal role in mental illnesses are challenging to elucidate, particularly as there is a lack of relevant in vitro and in vivo models. However, the advent of induced pluripotent stem cell (iPSC) technology has provided researchers with a novel toolbox. We conducted a systematic review using the PRISMA statement. A PubMed and Web of Science online search was performed (studies published between 2006–2020) using the following search strategy: hiPSC OR iPSC OR iPS OR stem cells AND schizophrenia disorder OR personality disorder OR antisocial personality disorder OR psychopathy OR bipolar disorder OR major depressive disorder OR obsessive compulsive disorder OR anxiety disorder OR substance use disorder OR alcohol use disorder OR nicotine use disorder OR opioid use disorder OR eating disorder OR anorexia nervosa OR attention-deficit/hyperactivity disorder OR gaming disorder. Using the above search criteria, a total of 3515 studies were found. After screening, a final total of 56 studies were deemed eligible for inclusion in our study. Using iPSC technology, psychiatric disease can be studied in the context of a patient’s own unique genetic background. This has allowed great strides to be made into uncovering the etiology of psychiatric disease, as well as providing a unique paradigm for drug testing. However, there is a lack of data for certain psychiatric disorders and several limitations to present iPSC-based studies, leading us to discuss how this field may progress in the next years to increase its utility in the battle to understand psychiatric disease.

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Section: Introductionmentioning

confidence: 99%

Mental health dished up—the use of iPSC models in neuropsychiatric research

et al. 2020

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“…Following pioneering work by Brennand et al [19], the number of iPSC-based case/control studies on SCZ and BD has increased steadily over the last years (reviewed in [20,21,22]). These studies measured in neuronal cells from patients with SCZ (i) reduced neuronal connectivity, (ii) attenuated activity-dependent transcription, (iii) impaired mitochondrial function and increased oxidative stress, (iv) delayed NPC differentiation and neuronal maturation, and (v) altered miRNA expression.…”

Section: Introductionmentioning

confidence: 99%

Progress in iPSC-Based Modeling of Psychiatric Disorders

Hoffmann

Ziller

Spengler

2019

IJMS

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Progress in iPSC-based cellular systems provides new insights into human brain development and early neurodevelopmental deviations in psychiatric disorders. Among these, studies on schizophrenia (SCZ) take a prominent role owing to its high heritability and multifarious evidence that it evolves from a genetically induced vulnerability in brain development. Recent iPSC studies on patients with SCZ indicate that functional impairments of neural progenitor cells (NPCs) in monolayer culture extend to brain organoids by disrupting neocorticogenesis in an in vitro model. In addition, the formation of hippocampal circuit-like structures in vitro is impaired in patients with SCZ as is the case for glia development. Intriguingly, chimeric-mice experiments show altered oligodendrocyte and astrocyte development in vivo that highlights the importance of cell–cell interactions in the pathogenesis of early-onset SCZ. Likewise, cortical imbalances in excitatory–inhibitory signaling may result from a cell-autonomous defect in cortical interneuron (cIN) development. Overall, these findings indicate that genetic risk in SCZ impacts neocorticogenesis, hippocampal circuit formation, and the development of distinct glial and neuronal subtypes. In light of this remarkable progress, we discuss current limitations and further steps necessary to harvest the full potential of iPSC-based investigations on psychiatric disorders.

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“…This shortcoming raises the question of what cellular phenotypes are needed to enhance identification of causal mechanisms and genes in psychiatric disorders. Previous studies on patient-specific disease modeling were directed towards gene expression profiling, imaging, electrophysiology, proteomic approaches, and functional readouts such as proliferation, migration, and maturation (for recent reviews see [103][104][105]. Qualitative and quantitative improvements on these readouts are likely to improve further reproducibility and statistical power from case/control studies.…”

Section: Outlook and Discussionmentioning

confidence: 99%

Focus on Causality in ESC/iPSC-Based Modeling of Psychiatric Disorders

Hoffmann

Ziller

Spengler

2020

Cells

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Genome-wide association studies (GWAS) have identified an increasing number of genetic variants that significantly associate with psychiatric disorders. Despite this wealth of information, our knowledge of which variants causally contribute to disease, how they interact, and even more so of the functions they regulate, is still poor. The availability of embryonic stem cells (ESCs) and the advent of patient-specific induced pluripotent stem cells (iPSCs) has opened new opportunities to investigate genetic risk variants in living disease-relevant cells. Here, we analyze how this progress has contributed to the analysis of causal relationships between genetic risk variants and neuronal phenotypes, especially in schizophrenia (SCZ) and bipolar disorder (BD). Studies on rare, highly penetrant risk variants have originally led the field, until more recently when the development of (epi-) genetic editing techniques spurred studies on cause-effect relationships between common low risk variants and their associated neuronal phenotypes. This reorientation not only offers new insights, but also raises issues on interpretability. Concluding, we consider potential caveats and upcoming developments in the field of ESC/iPSC-based modeling of causality in psychiatric disorders.

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From the Psychiatrist’s Couch to Induced Pluripotent Stem Cells: Bipolar Disease in a Dish

Cited by 17 publications

References 109 publications

Mental health dished up—the use of iPSC models in neuropsychiatric research

Mental health dished up—the use of iPSC models in neuropsychiatric research

Progress in iPSC-Based Modeling of Psychiatric Disorders

Focus on Causality in ESC/iPSC-Based Modeling of Psychiatric Disorders

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