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

Ikuro Suzuki, Associate Professor at Tohoku Institute of Technology, Japan who recently published his work with Axol Human iPSC-Derived Cerebral Cortical Neurons in Nature’s Scientific Reports (Odawara et al., 2016), presented our Innovation Showcase in collaboration with Alpha MED Scientific.

Prof Suzuki discussed the following results from his research:

  • Morphology in long-term culture
  • Development of spontaneous burst firings
  • Pharmacological properties
  • Induction of epileptiform activity & effects of anti-epilepsy drugs
  • Induction of long-term potentiation and depression

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Human iPSC-derived cardiomyocytes: A comparison with primary cells and applications in standard and 3D culture models

Ventricular cardiac muscle cells, the cardiomyocytes, not to be confused with smooth muscle myocytes of the arterial wall or myoblasts of skeletal muscle, are the working muscle cells of the heart that relentlessly maintain the body’s circulation during a lifetime. Their high metabolic activity and low ischemic tolerance, sensitivity to changes in extracellular calcium, refractoriness to DNA transfection and limited lifespan in culture, notably without proliferation, make these cells a demanding in vitro model system. This issue is compounded by the absence of immortalized cell lines with characteristics comparable to primary human cardiomyocytes. The technology of reprograming somatic human cells into induced- pluripotent stem cells (hiPSC), which theoretically allows the production of cardiomyocytes and other cardiovascular cell types in unlimited amounts, has become popular as an alternative to primary rodent cells for disease modeling and toxicology. Furthermore, in vitro studies are now possible with hiPSC-derived cardiomyocytes from patients with specific disease-causing genotypes and genetic backgrounds, sometimes with access to their entire medical history.

Applications of hiPSC include general toxicology, drug efficacy and safety testing, cell physiology, disease modeling, 3D culture models and tissue engineering, and basic science. The only currently remaining concern with these cells is their comparably immature developmental state, showing features of the fetal or neonatal heart. In addition, there is heterogeneity in the cell population regarding expression patterns of different chambers of the heart or of the electrical conduction system. Also, some cellular features are less well formed such as T-tubules and the expression levels of connexins, depending on the properties of the original hiPSC-cell lines in comparison with the fully differentiated cells of the adult human heart. Several academic groups and companies are currently developing protocols and strategies to improve maturation and purity of hiPSC-derived cardiomyocytes. Our lab, at the University Hospital Bern, has been active in the field of cardio-toxicity for some years now, first with isolated cardiomyocytes from adult rats, using human samples from cardiac surgery, and now we are using hiPSC-derived cardiomyocytes from several commercial sources. As we are interested in the mechanisms of cancer therapy-associated cardiotoxicity, and want to study this in cardiomyocytes, we always endeavor to use the most relevant in vitro culture systems. Therefore, we have recently started to develop a 3D-culture model using hiPSC-derived cardiomyocytes and have tested this system in comparison with mature primary cells.

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Modelling Alzheimer's Disease

Dr Alfredo Cabrera, Janssen Pharmaceutica, presented a robust, scalable and disease relevant model of tau aggregation using induced pluripotent stem cell (iPSC)-derived cortical neurons that can be applied to drug discovery programs in neurodegeneration. The resulting assay is highly reproducible across users and works in different commercially available iPSC-lines, providing a reliable tool for better understanding TAU pathophysiology and the identification of novel treatments against Alzheimer’s disease.

Dr Cabrera covers the following in this tutorial:

  • iPSC and related initiatives in Europe: European Bank for Induced Pluripotent Stem Cells (EBiSC)
  • Introduction to Alzheimer’s disease & tau aggregation
  • Modelling tau aggregation using iPSCs

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The use of iPSC-derived cells and primary cells as in vitro models for toxicity screening

Toxicologists have access to a range of iPSC-derived cell types, including cardiomyocytes, hepatocytes and renal cells, used in toxicity screening. We discuss how these models are accurate and representative cell models, and how they can phase out inconsistencies and reduce the use of in vivo models.

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Modelling Alzheimer's disease using stem cells

Dr Eric Hill, Aston University, presented his research on brain hypometabolism in Alzheimer's disease progression during Research & Innovation 2016.

Currently, the majority of studies on Alzheimer's disease have used transgenic animal models or imaging studies of the human brain. It is difficult to validate these findings using human tissue. Whilst animal models have been central to our understanding of human physiology, human stem cell-based models may help us to further our understanding of human physiology and tackle devastating diseases such as Alzheimer's disease.

Dr Hill covers the following in this presentation:

  • Brain hypometabolism is a major feature of Alzheimer's disease, appearing decades before cognitive decline and pathological lesions.
  • Human stem cell-derived neuron and astrocyte cultures treated with oligomers of amyloid beta display a clear hypometabolism, particularly with regards to utilisation of substrates such as glucose, pyruvate, lactate and glutamate.
  • As many neuronal functions, such as memory formation and protection from oxidative stress require energy formed from oxidative phosphorylation, these cells are at high risk of hypometabolism.
  • Further research using models derived from iPSCs may elucidate the mechanisms associated with amyloid beta-induced hypometabolism and therefore expedite the discovery of novel biomarkers and mechanisms associated with disease progression.

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Rising to the challenges of human iPSC-derived cells for tox & drug screening

We presented 'in the field' data on our portfolio of human iPSC and primary cells demonstrating their proven ease of use, reliability and consistency as meaningful drug discovery tools. Here, we overcome the challenges of cell line variability and address the needs for cell scale-up in assay campaigns.

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