Human cardiomyocytes derived from iPS cells for preclinical drug studies

Why use human cardiomyocytes ?

Healthy human heart cells are very rare and only available in very small quantities for obvious reasons of accessibility. Human cardiomyocytes derived from induced pluripotent stem cells (iPS-​hCMs) allow to access human ventricular-​like myocytes more easily. Due to their origin, these cells present the same functional and electrophysiological characteristics as human cardiomyocytes and offer a good alternative to ex vivo and in vivo models for drug development.

Human cardiomyocytes & cardiac safety studies

Human cardiomyocytes derived from iPS cells provide a good solution to study the repercussion of ion channels effects on cardiac electrical activity during preclinical studies. This human in vitro model can be used to evaluate the cardiac safety of newly developed drugs and is currently validated by the CiPA initiative for cardiac preclinical safety assessment.

Action potential recordings

To measure the effects of newly developed drugs on cardiac safety, we study their action potential, i.e. we measure ion movements through the different transmembrane ionic channels. The modification of the shape of the action potential gives information about ion channel effects. The advantage of this technique is that it allows to only select ventricular-type cells within the general cardiomyocyte population. This selection is important, since ventricular-type cardiomyocytes help detect ventricular dysfunction.

Technique

  • Manual Patch Clamp (current clamp configuration)
  • Non-cumulative concentrations

Study model

  • Cor.4U® from Axiogenesis or Pluricyte® from Pluriomics
  • 3 to 6 treated cells

Reference product

  • E-4031
  • Nifedipine
  • Dofetilide
  • Bepridil

Measured parameters

  • Resting Potential (mV)
  • Amplitude (mV)
  • Action Potential Duration at 20% and 90% repolarisation (ADP20, ADP90) (ms)

Cor.4U® cardiomyocytes

Cor4U human cardiomyocytes, typical results with Nifedipine
Cor4U human cardiomyocytes, typical assay results with Bepridil

Pluricyte® cardiomyocytes

Pluricyte human cardiomyocytes typical assay results with Nifedipine
Pluricyte cardiomyocytes typical assay results with Bepridil

Typical effects of nifedipine and bepridil on human cardiomyocytes derived from iPS (action potential recordings) on Cor.4U® and Pluricyte® cardiomyocytes.

Main cardiac ion channel recordings

The voltage-clamp technique allows to record the three specific currents (Ik, INa, ICa) that are involved in the action potential on individual human cardiomyocytes.

Technique

  • Manual Patch Clamp (voltage clamp configuration)
  • Non-cumulative concentrations

Study model

  • Cor.4U® from Axiogenesis
  • 3 to 6 treated cells

Calcium current recordings

Calcium current recordings typical results

Sodium current recordings

Sodium current recordings typical results

Potassium current recordings

Potassium current recordings typical result curves

Impedance measurements (outsourced to date)

The measurement of electrical impedance is non-invasive and assesses real-time changes in cellular morphology and attachment quality. We use the high-throughput method to assess cardiomyocyte contractility and viability in the presence of different drugs. This system allows the evaluation of both short-term and long-term (chronic exposure) cardiotoxicity for cardiac safety. 

Microelectrode array (outsourced to date)

MicroElectrode Array (MEA) recordings are a non-invasive way to measure integrated ion channel activity. The MEA system provides ECG-like results and detects modifications in beat rate, pro-arrhythmic events and other adverse effects.

Advice from our expert scientists

Human cardiomyocytes derived from iPS cells have the appropriate ventricular electrophysiology profile for cardiac safety assessment but these cells present certain limits (absence of some currents). This model has the advantage to give a drug profile on human cells but results must be completed with additional tests:

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