Modeling psychiatric disorders using patient stem cell-derived neurons: a way forward

Vadodaria, Krishna C.; Amatya, Debha N.; Marchetto, Maria C.; Gage, Fred H.

doi:10.1186/s13073-017-0512-3

Cited by 94 publications

(70 citation statements)

References 10 publications

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“…Although all integration-free methods are prominent for iPSC application in the clinic, it should be noted that optimisation is required before being applied in clinical trials. [56], [57]. Therefore, I…”

Section: Integration-free Mediated Reprogrammingmentioning

confidence: 95%

An in vitro model of lissencephaly: expanding the role of DCX during neurogenesis

et al. 2017

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Lissencephaly comprises a spectrum of brain malformations due to impaired neuronal migration in the developing cerebral cortex. Classical lissencephaly is characterized by smooth cerebral surface and cortical thickening that result in seizures, severe neurological impairment and developmental delay. Mutations in the X-chromosomal gene DCX, encoding doublecortin, is the main cause of classical lissencephaly. Much of our knowledge about DCX-associated lissencephaly comes from post-mortem analyses of patient's brains, mainly since animal models with DCX mutations do not mimic the disease. In the absence of relevant animal models and patient brain specimens, we took advantage of induced pluripotent stem cell (iPSC) technology to model the disease. We established human iPSCs from two males with mutated DCX and classical lissencephaly including smooth brain and abnormal cortical morphology. The disease was recapitulated by differentiation of iPSC into neural cells followed by expression profiling and dissection of DCX-associated functions. Here we show that neural stem cells, with absent or reduced DCX protein expression, exhibit impaired migration, delayed differentiation and deficient neurite formation. Hence, the patient-derived iPSCs and neural stem cells provide a system to further unravel the functions of DCX in normal development and disease.

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Section: Integration-free Mediated Reprogrammingmentioning

confidence: 95%

An in vitro model of lissencephaly: expanding the role of DCX during neurogenesis

et al. 2017

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“…There are growing opportunities arising from phenotyping neurons differentiated from patient-derived stem cells (induced pluripotent stem cells [iPSCs]) for modeling disease, screening for treatment options, detecting biomarkers, or even acting as biomarkers of disease risk in their own right (Gendron et al, 2017;Schrenk-Siemens et al, 2018;Vadodaria et al, 2018;Wainger et al, 2014;Xu et al, 2018). iPSCs contain, of course, the genetic background of the patients, but not the epigenetic marks derived from environmental interaction or the effects of aging.…”

Section: Patient-derived Neurons As Pain Biomarkersmentioning

confidence: 99%

Composite Pain Biomarker Signatures for Objective Assessment and Effective Treatment

Tracey

Woolf

Andrews

2019

Neuron

177

184

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“…Based on our cellular analyses, we established (1) a developmental delay during neural differentiation, (2) a dynamic GABA/glutamate imbalance, associated with autism. However, there has been criticism of the induced pluripotent stem cell technology, one of the arguments against it being insufficient recapitulation of in vivo and adult cellular phenotypes 44 , thus, making it unsuitable for studying many neuropsychiatric conditions. There has also been criticism of the study of non-syndromic autism using an iPSC model system 45 , and the presence of a heterogeneous genetic background in non-syndromic autism has been speculated to likely introduce confounds.…”

Section: Atypical Neurodevelopmental and Immune Pathways Revealed Inmentioning

confidence: 99%

Atypical neurogenesis in induced pluripotent stem cell (iPSC) from autistic individuals

Adhya

Swarup

Nagy

et al. 2018

Preprint

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30Autism is a heterogenous collection of disorders with a complex molecular underpinning. 31Evidence from post mortem studies using adult brains have identified atypical co-expression 32 of genes which may occur during the prenatal period. Recent studies using induced pluripotent 33 stem cells (iPSCs) generated from autistic individuals have suggested that prenatal 34 development is a critical period for the emergence of pathophysiology associated with this 35 condition. However, how early during development these differences emerge and whether such 36 alterations can be seen across the development of multiple brain regions is unclear. In this study 37 we investigated whether early prenatal stages of neurodevelopment differ between iPSCs 38 generated from typically developing and autistic individuals. We specifically selected autistic 39 individuals unrelated to each other with a heterogeneous genetic background and no known 40 comorbidities, to probe for common molecular phenotypes. Differentiation of iPSCs towards a 41 cortical lineage revealed abnormal cell fate acquisition from an early stage of development. 42Interestingly, abnormal differentiation occurred in the absence of alteration in cell proliferation 43 during cortical differentiation, differing from previous studies. Moreover, these effects 44 appeared specific for the acquisition of a cortical fate, as differentiation of iPSCs towards a 45 midbrain lineage was not accompanied by differences in neurogenesis between typically 46 developing and autism iPSC lines. RNA-sequencing on a subset of our cohort further revealed 47 autism-specific signatures during cortical differentiation similar to that observed in post 48 mortem studies, indicating a potential common biological mechanism. Together, these data 49 suggest unique developmental differences associated with autism may establish at an early 50 prenatal stage. 51 52 53 4 54 Recent methodological advances in the field of induced pluripotent stem cell (iPSC) 75technology [15][16][17][18][19][20] has made it possible to study prenatal cellular behaviour in autism in detail, 76 something that was not possible using post mortem brains. IPSCs have similar abilities to 77 5 embryonic stem cells to generate any tissue of the body. These can then be differentiated into 78 neurons of various lineages 15-17, 19, 20 . As the neurons contain the same genetic information as 79 the individual from whom it was derived, typical or autistic, its cellular behaviours is 80 influenced by its genetic background. Using these methods, studies have shown significant 81 anomalies in cellular/molecular behaviour during prenatal-equivalent periods of development 82 in autistic individuals [21][22][23] . One such study generated iPSCs from autistic individuals who were 83 comorbid for macrocephaly, and demonstrated: (1) atypical cortical differentiation and 84 increased cell proliferation of cortical neural precursor cells (NPCs) from iPSCs, and (2) an 85 imbalance in excitatory (glutamate-producing) and inhibitory (GABA-produ...

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Modeling psychiatric disorders using patient stem cell-derived neurons: a way forward

Cited by 94 publications

References 10 publications

An in vitro model of lissencephaly: expanding the role of DCX during neurogenesis

An in vitro model of lissencephaly: expanding the role of DCX during neurogenesis

Composite Pain Biomarker Signatures for Objective Assessment and Effective Treatment

Atypical neurogenesis in induced pluripotent stem cell (iPSC) from autistic individuals

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