Enhanced conversion of induced neuronal cells (iN cells) from human fibroblasts: Utility in uncovering cellular deficits in mental illness-associated chromosomal abnormalities

Passeri, Eleonora; Wilson, Ana; Primerano, Amedeo; Kondo, Mari A.; Sengupta, Srona; Srivastava, Rupali; Koga, Minoru; Obie, Cassandra; Zandi, Peter P.; Goes, Fernando S.; Valle, David; Rapoport, Judith L.; Sawa, Akira; Kano, Shin-ichi; Ishizuka, Koko

doi:10.1016/j.neures.2015.07.011

Cited by 14 publications

(9 citation statements)

References 23 publications

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“…The transfected M17 and SY5Y cells were differentiated with DMEM/F12 plus 1% FBS, 1% penicillin/streptomycin (Gibco), and 10 μM of retinoic acid (RA) at a density of 1 × 10 4 cells/cm 2 in poly- L -lysine-coated 24-well tissue culture dishes. The non-transfected M17 cells were differentiated in a similar way to the transfected M17 cells except that two additional small molecules, SB431542 (10 μM) and Db-cAMP (1 mM), were added to the culture medium to accelerate neuronal differentiation ( Passeri et al, 2015 ). The P19 cells were maintained in α-modified minimum essential medium (α-MEM, Invitrogen, Carlsbad, CA, United States) supplemented with 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

CBX2 Inhibits Neurite Development by Regulating Neuron-Specific Genes Expression

Wang

et al. 2018

Front. Mol. Neurosci.

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Polycomb group (PcG) proteins regulate the epigenetic status of transcription regulatory states during development. Progression from pluripotency to differentiation requires the sequential activation and repression of different PcG target genes, however, the relationship between early patterning signals, PcG expression, and the development of the central nervous system is still unclear. Using various models of neuronal differentiation, we provide evidence that CBX2 is a negative regulator of neuronal differentiation. Knock-down of CBX2 expression promotes neurite development, while overexpression of CBX2 inhibits neurite development. Further, we found that CBX2 is a direct target gene of miR-124. During neuronal differentiation, CBX2 was decreased while miR-124 was increased. Mechanistically, CBX2 directly interacts with the promoter region of several neuro-associated genes and regulates their expression. We found that the neuron-specific GAP-43 gene could contribute to the stimulating effect on neurite development associated with inhibition of CBX2.

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Section: Methodsmentioning

confidence: 99%

CBX2 Inhibits Neurite Development by Regulating Neuron-Specific Genes Expression

Wang

et al. 2018

Front. Mol. Neurosci.

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“…These type of adult iNs have been generated using four main methods: (i) by the forced expression of transcription factors (Caiazzo et al, 2011 ; Pfisterer et al, 2011b ; Iovino et al, 2014 ; Mertens et al, 2015a ; Passeri et al, 2015 ; Siegert et al, 2015 ; Liu et al, 2016 ), (ii) by knocking down of the RNA-binding proteins PTB/nPTB (Xue et al, 2016 ) or p16-p19 (Sun et al, 2014 ), (iii) by the forced expression of neuronal specific microRNAs (Victor et al, 2014 ; Richner et al, 2015 ; Huh et al, 2016 ), (iv) by chemically manipulating pathways involved in neuronal fate and functions (Hu et al, 2015 ) or by a different combination of these strategies (Ambasudhan et al, 2011 ; Liu et al, 2013 ; Hsu et al, 2014 ; Wang et al, 2014 ; Xu et al, 2015 ; Drouin-Ouellet et al, 2017 ) (Figure 1 ). Each of these methods has been proven effective in generating functional neurons in which it is possible to evoke action potentials as well as observe spontaneous synaptic activity within a timeframe ranging from 4 to 12 weeks when co-cultured with astrocytes or primary cortical neurons or after transplantation (Hu et al, 2015 ; Huh et al, 2016 ; Liu et al, 2016 ; Xue et al, 2016 ; Drouin-Ouellet et al, 2017 ), and even spontaneous action potentials in some cases (Mertens et al, 2015a ).…”

Section: How To Define An In?mentioning

confidence: 99%

Direct Neuronal Reprogramming for Disease Modeling Studies Using Patient-Derived Neurons: What Have We Learned?

et al. 2017

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Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows for the possibility of generating patient-derived neurons. A unique feature of these so-called induced neurons (iNs) is the potential to maintain aging and epigenetic signatures of the donor, which is critical given that many diseases of the CNS are age related. Here, we review the published literature on the work that has been undertaken using iNs to model human brain disorders. Furthermore, as disease-modeling studies using this direct neuronal reprogramming approach are becoming more widely adopted, it is important to assess the criteria that are used to characterize the iNs, especially in relation to the extent to which they are mature adult neurons. In particular: i) what constitutes an iN cell, ii) which stages of conversion offer the earliest/optimal time to assess features that are specific to neurons and/or a disorder and iii) whether generating subtype-specific iNs is critical to the disease-related features that iNs express. Finally, we discuss the range of potential biomedical applications that can be explored using patient-specific models of neurological disorders with iNs, and the challenges that will need to be overcome in order to realize these applications.

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“…Passeri et al . () observed a significantly higher transformation efficiency in cells derived from patients carrying the del(16p.11.2) mutation compared to healthy subjects using single‐step transformation in an improved medium.…”

Section: Findings Suggesting Disturbed Neurodevelopmentmentioning

confidence: 96%

Are reprogrammed cells a useful tool for studying dopamine dysfunction in psychotic disorders? A review of the current evidence

Sauerzopf

Sacco

Novarino

et al. 2016

Eur J of Neuroscience

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Since 2006, reprogrammed cells have increasingly been used as a biomedical research technique in addition to neuro-psychiatric methods. These rapidly evolving techniques allow for the generation of neuronal sub-populations, and have sparked interest not only in monogenetic neuro-psychiatric diseases, but also in poly-genetic and poly-aetiological disorders such as schizophrenia (SCZ) and bipolar disorder (BPD). This review provides a summary of 19 publications on reprogrammed adult somatic cells derived from patients with SCZ, and five publications using this technique in patients with BPD. As both disorders are complex and heterogeneous, there is a plurality of hypotheses to be tested in vitro. In SCZ, data on alterations of dopaminergic transmission in vitro are sparse, despite the great explanatory power of the so-called DA hypothesis of SCZ. Some findings correspond to perturbations of cell energy metabolism, and observations in reprogrammed cells suggest neuro-developmental alterations. Some studies also report on the efficacy of medicinal compounds to revert alterations observed in cellular models. However, due to the paucity of replication studies, no comprehensive conclusions can be drawn from studies using reprogrammed cells at the present time. In the future, findings from cell culture methods need to be integrated with clinical, epidemiological, pharmacological and imaging data in order to generate a more comprehensive picture of SCZ and BPD.

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Enhanced conversion of induced neuronal cells (iN cells) from human fibroblasts: Utility in uncovering cellular deficits in mental illness-associated chromosomal abnormalities

Cited by 14 publications

References 23 publications

CBX2 Inhibits Neurite Development by Regulating Neuron-Specific Genes Expression

CBX2 Inhibits Neurite Development by Regulating Neuron-Specific Genes Expression

Direct Neuronal Reprogramming for Disease Modeling Studies Using Patient-Derived Neurons: What Have We Learned?

Are reprogrammed cells a useful tool for studying dopamine dysfunction in psychotic disorders? A review of the current evidence

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