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Poster

Accelerated Maturation of Human iPSC-Derived Cerebral Cortical and Peripheral Sensory Neurons

Poster showing the effects of the MATURATION MAXIMIZER supplement on accelerating maturation of Human iPSC-Derived Cerebral Cortical and Peripheral Sensory Neurons


Poster

Detection of drug-induced seizure-like activities using MEA system in cultured human iPSC-derived neurons: Report from multi-site pilot study of the HESI NeuTox Committee in collaboration with CSAHi and iNCENS

Human iPSC-derived cortical neurons (Axol) and astrocytes (Axol) were cultured on 24-wells MEA plate for extracellular recording using MED64 Presto. HESI twelve compounds (pentylenetetrazole, picrotoxin, 4- aminopyrdine, linopyridine, amoxapine, strychnine, pilocarpine, amoxicillin, chlorpromazine, enoxacin, phenytoin, and acetaminophen) and dimethyl sulfoxide (DMSO) were tested at 5 concentrations for each compound (n>10).

Poster

Modelling Alzheimer's disease: Development of a scalable, high-throughput-compatible assay to detect tau aggregates using iPSC-derived cortical neurons maintained in a 3D-culture format

We describe a robust, scalable and disease relevant model of tau aggregation using iPSC- derived cortical neurons that can be applied to drug discovery programs in neurodegeneration.


Poster

Using iPSC-derived neural stem cells as a CNS model to study neuronal behaviour in development and neurodegernation

Induced pluripotent stem cell (iPSC)-derived neural cells provide a powerful tool that can be used to model neuronal behaviour and disease pathology. The increased use of these cells in drug discovery promises to help accelerate current drug screening processes and reduce the use of in vivo models used at the earliest stages of testing. Importantly, the production of specific populations, such as cortical and dopaminergic neurons, has allowed researchers to investigate the activity of neural networks from particular regions of the brain. We developed a number of endpoint assays using human iPSC-derived neural stem cells to determine the functionality of these cells and their response to toxins or disease-relevant biomarkers in both Alzheimer’s disease and epilepsy. We have also manipulated the cells using Lentivirus and have demonstrated long-term expression of over 9 months. The methods developed offer a platform to facilitate our understanding of normal physiological functions and the causes of central nervous system (CNS) pathology


Poster

Implementation of high throughput screening on iPS cells

Induced pluripotent stem cells (iPSCs) belong to a growing list of stem cell populations that hold great potential for use in cell-based assay development and screening. iPSC-derived cells like cardiomyocytes and neuronal cells represent a reliable source of cellular material with robust assay performance and scalability which is essential to any HTS campaign and subsequent follow-up. Here we demonstrate the impact of iPSC-derived neurons in modern drug discovery. We present examples of assay automation and miniaturization of cellular assays based on high content imaging using the Operetta and Ca-flux using the FLIPR instruments. Our examples show the opportunities and benefits that iPSC-derived cells may provide in the search for new chemical starting points for drug discovery in the near future.

20 Qualified Hit List reports to the target owners. The over 40 HTS campaigns performed to date cover a wide range of target classes including more demanding cellular targets like ion channels and GPCR’s. Cellular HTS assays have been successfully miniaturized to 384- and 1536-well format in order to perform them in a cost-efficient manner. Induced pluripotent stem cells (iPSCs) belong to a growing list of stem cell populations that hold great potential for use in cell-based assay development and screening. iPSC-derived cells like cardiomyocytes and neuronal cells represent a reliable source of cellular material with robust assay performance and scalability which is essential to any HTS campaign and subsequent follow-up. Here we demonstrate the impact of iPSC-derived neurons in modern drug discovery. We present examples of assay automation and miniaturization of cellular assays based on high content imaging using the Operetta and Ca-flux using the FLIPR instruments. Our examples show the opportunities and benefits that iPSC-derived cells may provide in the search for new chemical starting points for drug discovery in the near future.


Poster

In vitro pain responses of dorsal root ganglion neurons using multi-electrode arrays

Dorsal root ganglion (DRG) sensory neurons are pain-related neurons and have a variety of sensory receptors that are activated by chemical, thermal, and mechanical stimuli. Establishment of pharmacological assay in pain research and drug screening is important issue. Here, we used the multi-electrode array (MEA) system to detect the electrophysiological responses by chemical and thermal stimuli in cultured DRG neurons. After 2 days of culture on the MEA, we observed spontaneous activities and chemical responses. Addition of the capsaicin, menthol and wasabi induced significant changes of the firing rate and concentration-dependent responses. Furthermore, temperature elevation increased the number of firings and it showed the largest increase at 43 degrees. We also detected the responses to temperature and capsaicin in hiPSC derived sensory neurons at 14 DIV. We confirmed that the typical response of DRG neurons can be easily obtained using MEA system. These results suggested that electrophysiological measurements in DRG neurons using a MEA system may be beneficial for clarifying the functions of DRG neurons and human iPSC derived sensory neurons in pain research and for drug screening applications.


Poster

In vitro electrophysiological drug testing using human induced-pluripotent stem cells

Human induced pluripotent stem cell (hiPSC)-derived neurons may be effectively used for drug discovery and cell-based therapy. We here used a multi-electrode array (MEA) system to investigate the functional characteristics of hiPSC-derived neurons on their long-term spontaneous activity and drug responsiveness over 300 days culture. We demonstrated that hiPSC-derived neurons allowed the culture to be maintained over 10 months with long-term spontaneous activity. After 70 days of culture, we observed synchronous burst firing activity due to synapse transmission within neuronal networks. Addition of the synapse agonist and antagonists kainic acid, bicuculline, CNQX and AP5 induced significant changes of the firing rate in spontaneous firings and electrical evoked responses. Furthermore, we demonstrated that epilepsy phenomenon was evoked by administration of pentylentetrazole (PTZ) and was inhibited by anti-epilepsy drug phenytoin and sodium valproate (VPA). High frequency synchronized bursts were evoked over PTZ 100 μM. These bursts were gradually decreased with the increasing the dose of anti-epilepsy drug, and disappeared over phenytoin 100μM or VPA 1 mM respectively. These results suggested that long-term electrophysiological measurements in hiPSC-derived neurons using a MEA system may be beneficial for drug screening applications.


Poster

Pharmacological responses in cultured human iPSC-derived cortical neurons using multi-electrode array

The functional network of human induced pluripotent stem cell (hiPSC)-derived neurons is a potentially powerful in vitro model for evaluating disease mechanisms and drug responses. However, the culture time required for the full functional maturation of individual neurons and networks is uncertain. We investigated the development of spontaneous electrophysiological activity and pharmacological responses for over 1 year in culture using multi-electrode arrays (MEAs). The complete maturation of spontaneous firing, evoked responses, and modulation of activity by glutamatergic and GABAergic receptor antagonists/agonists required 20–30 weeks. At this stage, neural networks also demonstrated epileptiform synchronized burst firing (SBF) in response to pro-convulsants and SBF suppression using clinical anti-epilepsy drugs. Our results reveal the feasibility of long-term MEA measurements from hiPSC-derived neuronal networks in vitro for mechanistic analyses and drug screening. However, developmental changes in electrophysiological and pharmacological properties indicate the necessity for the international standardization of culture and evaluation procedures.


Poster

Functional maturation and drug responses of human induced pluripotent stem cell-derived cortical neuronal networks in long-term culture

The functional network of human induced pluripotent stem cell (hiPSC)-derived neurons is a potentially powerful in vitro model for evaluating disease mechanisms and drug responses. However, the culture time required for the full functional maturation of individual neurons and networks is uncertain. We investigated the development of spontaneous electrophysiological activity and pharmacological responses for over 1 year in culture using multi-electrode arrays (MEAs). The complete maturation of spontaneous firing, evoked responses, and modulation of activity by glutamatergic and GABAergic receptor antagonists/agonists required 20–30 weeks. At this stage, neural networks also demonstrated epileptiform synchronized burst firing (SBF) in response to pro-convulsants and SBF suppression using clinical anti-epilepsy drugs. Our results reveal the feasibility of long-term MEA measurements from hiPSC-derived neuronal networks in vitro for mechanistic analyses and drug screening. However, developmental changes in electrophysiological and pharmacological properties indicate the necessity for the international standardization of culture and evaluation procedures.


Poster

Induction of plasticity phenomena in human induced pluripotent stem cell-derived cortical neurons

Long-term potentiation (LTP) and long-term potentiation depression (LTD) in neuronal networks has been analyzed using in vitro and in vivo techniques in simple animals to understand learning, memory, and development in brain function. Human induced pluripotent stem cell (hiPSC)- derived neurons may be effectively used for understanding the plasticity mechanism in human neuronal networks, thereby elucidating disease mechanisms and drug discoveries. In this study, we attempted the induction of LTP and LTD phenomena in a cultured hiPSC-derived cerebral cortical neuronal network using multi-electrode array (MEA) systems. High-frequency stimulation (HFS) produced a potentiated and depressed transmission in a neuronal circuit for 1 h in the evoked responses by test stimulus. The cross-correlation of responses revealed that spike patterns with specific timing were generated during LTP induction and disappeared during LTD induction and that the hiPSC-derived cortical neuronal network has the potential to repeatedly express the spike pattern with a precise timing change within 0.5 ms. We also detected the phenomenon for late-phase LTP (L-LTP) like plasticity and the effects for synchronized burst firing (SBF) in spontaneous firings by HFS. In conclusion, we detected the LTP and LTD phenomena in a hiPSC-derived neuronal network as the change of spike pattern. The studies of plasticity using hiPSC-derived neurons and a MEA system may be beneficial for clarifying the functions of human neuronal circuits and for applying to drug screening.