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iPSC-derived Heart-on-a-Chip System Takes Another Step Forward

Review ofEstablishment of a heart-on-a-chip microdevice based on human iPS cells for the evaluation of human heart tissue functionfrom Scientific Reports by Stuart P. Atkinson

The use of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes in drug discovery can provide information at the single-cell level [1]; however, this approach fails to entirely recapitulate the behavior/responses of native myocardial tissues. Recent research from the laboratory of Hidetoshi Masumoto (RIKEN Center for Biosystems Dynamics Research, Kobe/Kyoto University, Kyoto, Japan) has employed various human iPSC-derived cardiovascular cells and temperature-responsive culture dishes to create three-dimensional biomimetic cardiac microtissues as a heart tissue surrogate in the hope of advancing drug screening efforts [2].

The authors next sought to combine their cardiac microtissues with “Micro Electro Mechanical Systems” technology to create a polydimethylsiloxane-based microfluidic “heart-on-a-chip” system that would allow for a highly sensitive bioassay system for drug discovery and cardiac toxicity tests. In their new study, researchers from the Masumoto laboratory report on their current progress and system validation via an analysis of responses to electrical stimulation and drug administration [3].

Abulaiti et al. prepared cell sheet-shaped human iPSC-derived cardiac microtissues as previously described [4-6], which comprised approximately 15 layers of cells with a 100 µm-thick cardiomyocyte layer and a multilayered extracellular matrix to support stiffness. The authors then placed the cardiac microtissues within the microfluidic chip [7], accompanied by appropriate maintenance medium, and noted spontaneous beating on the following day, and then confirmed physiological cardiac pump functionality by correlating the displacement distance and speed of administered fluorescent particles with a frequency of electrical stimulation relevant to the physiological condition of the human heart rate at rest [8]. 

Finally, using versatile open-source software to quantify cardiomyocyte and cardiac muscle contraction within the heart-on-a-chip (MUSCLEMOTION) [9], the team validated the utility of their heart-on-a-chip by demonstrating a correlation between the contractile function of cardiac microtissues with calcium oscillation patterns in cardiomyocytes and the highly accurate pharmacological response to treatment with a β-adrenoceptor agonist.

While the authors provide robust evidence for the utility and sensitivity of their iPSC-derived heart-on-a-chip system, they underscore the need for further validation with candidate drugs and chemicals and the need to induce the additional maturation of iPSC-derived cardiomyocytes to further promote tissue maturation and change the intrinsic contractile properties of cardiac microtissues.

For more on the potential of iPSCs and organ-on-a-chip technology, stay tuned to the Stem Cells Portal!

References

  1. Kitaguchi T, Moriyama Y, Taniguchi T, et al., CSAHi study: Evaluation of multi-electrode array in combination with human iPS cell-derived cardiomyocytes to predict drug-induced QT prolongation and arrhythmia — Effects of 7 reference compounds at 10 facilities. Journal of Pharmacological and Toxicological Methods 2016;78:93-102.
  2. Kawatou M, Masumoto H, Fukushima H, et al., Modelling Torsade de Pointes arrhythmias in vitro in 3D human iPS cell-engineered heart tissue. Nature Communications 2017;8:1078.
  3. Abulaiti M, Yalikun Y, Murata K, et al., Establishment of a heart-on-a-chip microdevice based on human iPS cells for the evaluation of human heart tissue function. Scientific Reports 2020;10:19201.
  4. Masumoto H, Ikuno T, Takeda M, et al., Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration. Scientific Reports 2014;4:6716.
  5. Masumoto H, Nakane T, Tinney JP, et al., The myocardial regenerative potential of three-dimensional engineered cardiac tissues composed of multiple human iPS cell-derived cardiovascular cell lineages. Scientific Reports 2016;6:29933.
  6. Nakane T, Masumoto H, Tinney JP, et al., Impact of Cell Composition and Geometry on Human Induced Pluripotent Stem Cells-Derived Engineered Cardiac Tissue. Scientific Reports 2017;7:45641.
  7. Tanaka Y, Morishima K, Shimizu T, et al., An actuated pump on-chip powered by cultured cardiomyocytes. Lab on a Chip 2006;6:362-368.
  8. Endoh M, Force–frequency relationship in intact mammalian ventricular myocardium: physiological and pathophysiological relevance. European Journal of Pharmacology 2004;500:73-86.
  9. Sala L, van Meer Berend J, Tertoolen Leon GJ, et al., MUSCLEMOTION - A Versatile Open Software Tool to Quantify Cardiomyocyte and Cardiac Muscle Contraction In Vitro and In Vivo. Circulation Research 2018;122:e5-e16.