Evaluation of established human iPSC-derived neurons to model neurodegenerative diseases

Meneghello, Giulia; Verheyen, A.; Ingen, M. Van; Kuijlaars, Jacobine; Tuefferd, Marianne; Wyngaert, Ilse Van den; Nuydens, Rony

doi:10.1016/j.neuroscience.2015.05.071

Cited by 18 publications

(14 citation statements)

References 52 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Presence of sufficient glutamatergic neurons seems to be critical for maturity and function of a network41. However, GABAergic signaling has been shown to be as important for maturation and network development42.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Sustained synchronized neuronal network activity in a human astrocyte co-culture system

Kuijlaars

Oyelami

Diels

et al. 2016

Sci Rep

127

101

View full text Add to dashboard Cite

Impaired neuronal network function is a hallmark of neurodevelopmental and neurodegenerative disorders such as autism, schizophrenia, and Alzheimer’s disease and is typically studied using genetically modified cellular and animal models. Weak predictive capacity and poor translational value of these models urge for better human derived in vitro models. The implementation of human induced pluripotent stem cells (hiPSCs) allows studying pathologies in differentiated disease-relevant and patient-derived neuronal cells. However, the differentiation process and growth conditions of hiPSC-derived neurons are non-trivial. In order to study neuronal network formation and (mal)function in a fully humanized system, we have established an in vitro co-culture model of hiPSC-derived cortical neurons and human primary astrocytes that recapitulates neuronal network synchronization and connectivity within three to four weeks after final plating. Live cell calcium imaging, electrophysiology and high content image analyses revealed an increased maturation of network functionality and synchronicity over time for co-cultures compared to neuronal monocultures. The cells express GABAergic and glutamatergic markers and respond to inhibitors of both neurotransmitter pathways in a functional assay. The combination of this co-culture model with quantitative imaging of network morphofunction is amenable to high throughput screening for lead discovery and drug optimization for neurological diseases.

show abstract

Section: Resultsmentioning

confidence: 99%

“…This might explain why it is challenging to obtain synchronized oscillations3241. During early cortical development, GABA is predominantly excitatory45, followed by a switch to inhibitory properties during further maturation4647.…”

Section: Discussionmentioning

confidence: 99%

Sustained synchronized neuronal network activity in a human astrocyte co-culture system

Kuijlaars

Oyelami

Diels

et al. 2016

Sci Rep

127

101

View full text Add to dashboard Cite

show abstract

“…iCell ® neurons are a mixture of postmitotic GABAergic and glutamatergic cortical neurons that are more characteristic of relatively immature forebrain neurons than the sensory neurons found in the DRG 17,18 . Peri.4U ® neurons are more peripheral-like, expressing IIItubulin, peripherin, MAP2 and vGLUT2, but have been minimally characterized with respect to functional properties 10,19 .…”

Section: Introductionmentioning

confidence: 99%

Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel

Xiong

Chua

Stage

et al. 2020

Preprint

View full text Add to dashboard Cite

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse event associated with treatment with paclitaxel and other chemotherapeutic agents. The prevention and treatment of CIPN are limited by a lack of understanding of the molecular mechanisms underlying this toxicity. In the current study, a human induced pluripotent stem cell-derived sensory neuron (iPSC-SN) model was developed for the study of chemotherapy-induced neurotoxicity. The iPSC-SNs express proteins characteristic of nociceptor, mechanoreceptor and proprioceptor sensory neurons and show Ca 2+ influx in response to capsaicin, ,-meATP and glutamate. iPSC-SNs are relatively resistant to the cytotoxic effects of paclitaxel, with IC 50 values of 38.1 M (95% CI: 22.9 -70.9 M) for 48 hr exposure and 9.3 M (95% CI: 5.7 -16.5 M) for 72 hr treatment. Paclitaxel causes dose-and time-dependent changes in neurite network complexity detected by III-tubulin staining and high content imaging. The IC 50 for paclitaxel reduction of neurite area was 1.4 M (95% CI: 0.3 -16.9 M) for 48 hr exposure and 0.6 M (95% CI: 0.09 -9.9 M) for 72 hr exposure. Decreased mitochondrial membrane potential, slower movement of mitochondria down the neurites and changes in glutamate-induced neuronal excitability were also observed with paclitaxel exposure. The iPSC-SNs were also sensitive to docetaxel, vincristine and bortezomib.Collectively, these data support the use of iPSC-SNs for detailed mechanistic investigations of genes and pathways implicated in chemotherapy-induced neurotoxicity and the identification of novel therapeutic approaches for its prevention and treatment.

show abstract

“…Still, even if cultured on astrocytes, neurons did not exhibit matured synaptic activity before the third week, and cells on laminin were further delayed. Astrocyte-conditioned [ 125 ], ascorbic acid [ 126 ] and cAMP supplemented [ 123 ] culturing medium or the application of graphene oxide nanomaterial [ 127 ] also accelerates differentiation.…”

Section: Evidence-based Questionsmentioning

confidence: 99%

“…An additional hampering factor might be the time-consuming derivation and characterization of neurons from somatic cells accompanied by several technical pitfalls. Research industry offers several genetically modified iPSC-derived neurons which can be a faster model for drug development after thorough validation [ 125 ].…”

Section: Evidence-based Questionsmentioning

confidence: 99%

A Dishful of a Troubled Mind: Induced Pluripotent Stem Cells in Psychiatric Research

Kálmán

Hathy

Réthelyi

2015

Stem Cells International

View full text Add to dashboard Cite

Neuronal differentiation of induced pluripotent stem cells and direct reprogramming represent powerful methods for modeling the development of neurons in vitro. Moreover, this approach is also a means for comparing various cellular phenotypes between cell lines originating from healthy and diseased individuals or isogenic cell lines engineered to differ at only one or a few genomic loci. Despite methodological constraints and initial skepticism regarding this approach, the field is expanding at a fast pace. The improvements include the development of new differentiation protocols resulting in selected neuronal populations (e.g., dopaminergic, GABAergic, hippocampal, and cortical), the widespread use of genome editing methods, and single-cell techniques. A major challenge awaiting in vitro disease modeling is the integration of clinical data in the models, by selection of well characterized clinical populations. Ideally, these models will also demonstrate how different diagnostic categories share overlapping molecular disease mechanisms, but also have unique characteristics. In this review we evaluate studies with regard to the described developments, to demonstrate how differentiation of induced pluripotent stem cells and direct reprogramming can contribute to psychiatry.

show abstract

Evaluation of established human iPSC-derived neurons to model neurodegenerative diseases

Cited by 18 publications

References 52 publications

Sustained synchronized neuronal network activity in a human astrocyte co-culture system

Sustained synchronized neuronal network activity in a human astrocyte co-culture system

Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel

A Dishful of a Troubled Mind: Induced Pluripotent Stem Cells in Psychiatric Research

Contact Info

Product

Resources

About