Development of a 3-Dimensional Model to Study Right Heart Dysfunction in Pulmonary Arterial Hypertension: First Observations

Cells, vol. 10, pp. 3595

Abstract

Pulmonary arterial hypertension (PAH) patients eventually die of right heart failure (RHF). Currently, there is no suitable pre-clinical model to study PAH. Therefore, we aim to develop a right heart dysfunction (RHD) model using the 3-dimensional engineered heart tissue (EHT) approach and cardiomyocytes derived from patient-induced pluripotent stem cells (iPSCs) to unravel the mechanisms that determine the fate of a pressure-overloaded right ventricle. iPSCs from PAH and healthy control subjects were differentiated into cardiomyocytes (iPSC-CMs), incorporated into the EHT, and maintained for 28 days. In comparison with control iPSC-CMs, PAH-derived iPSC-CMs exhibited decreased beating frequency and increased contraction and relaxation times. iPSC-CM alignment within the EHT was observed. PAH-derived EHTs exhibited higher force, and contraction and relaxation times compared with control EHTs. Increased afterload was induced using 2× stiffer posts from day 0. Due to high variability, there were no functional differences between normal and stiffer EHTs, and no differences in the hypertrophic gene expression. In conclusion, under baseline spontaneous conditions, PAH-derived iPSC-CMs and EHTs show prolonged contraction compared with controls, as observed clinically in PAH patients. Further optimization of the hypertrophic model and profound characterization may provide a platform for disease modelling and drug screening.

Authors 11

1. Aida Llucià Valldeperas

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · Vrije Universiteit Amsterdam

   Affiliation as printed

   PHEniX Laboratory, Department of Pulmonary Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, 1081 HZ Amsterdam, The Netherlands

2. Rowan Smal

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · Vrije Universiteit Amsterdam

   Affiliation as printed

   PHEniX Laboratory, Department of Pulmonary Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, 1081 HZ Amsterdam, The Netherlands

3. Fjodor T. Bekedam

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · Vrije Universiteit Amsterdam

   Affiliation as printed

   PHEniX Laboratory, Department of Pulmonary Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, 1081 HZ Amsterdam, The Netherlands

4. Margaux Cé

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · Vrije Universiteit Amsterdam

   Affiliation as printed

   PHEniX Laboratory, Department of Pulmonary Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, 1081 HZ Amsterdam, The Netherlands

5. Xiaoke Pan

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · Vrije Universiteit Amsterdam

   Affiliation as printed

   PHEniX Laboratory, Department of Pulmonary Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, 1081 HZ Amsterdam, The Netherlands

6. Xue Daphne Manz

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · Vrije Universiteit Amsterdam

   Affiliation as printed

   PHEniX Laboratory, Department of Pulmonary Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, 1081 HZ Amsterdam, The Netherlands

7. Paul J.M. Wijnker

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, 1081 HZ Amsterdam, The Netherlands

8. Anton Vonk Noordegraaf

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · Vrije Universiteit Amsterdam

   Affiliation as printed

   PHEniX Laboratory, Department of Pulmonary Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, 1081 HZ Amsterdam, The Netherlands

9. Harm Jan Bogaard

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · Vrije Universiteit Amsterdam

   Affiliation as printed

   PHEniX Laboratory, Department of Pulmonary Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, 1081 HZ Amsterdam, The Netherlands

10. Marie‐José Goumans Aachen Department of Cell and Chemical Biology

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Cell and Chemical Biology, Leiden UMC, 2300 RC Leiden, The Netherlands

11. Frances S. de Man corresponding

    Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · Vrije Universiteit Amsterdam

    Affiliation as printed

    PHEniX Laboratory, Department of Pulmonary Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, 1081 HZ Amsterdam, The Netherlands