TY - JOUR
T1 - Development of a 3-dimensional model to study right heart dysfunction in pulmonary arterial hypertension
T2 - First observations
AU - Llucià-Valldeperas, Aida
AU - Smal, Rowan
AU - Bekedam, Fjodor T.
AU - Cé, Margaux
AU - Pan, Xiaoke
AU - Manz, Xue D.
AU - Wijnker, Paul J.M.
AU - Vonk-Noordegraaf, Anton
AU - Bogaard, Harm J.
AU - Goumans, Marie Jose
AU - de Man, Frances S.
N1 - Funding Information: Funding: This research was financially supported by the Netherlands Organization for Scientific Research: NWO-VICI num. 918.16.610 (A. Vonk-Noordegraaf) and NWO-VIDI num. 917.18.338 (F.S. de Man). The work was also funded by the Dutch Heart Foundation Dekker senior post-doc grant num. 2018T059 (F.S. de Man), and the Netherlands CardioVascular Research Initiative: CVON-2017-10 DOLPHIN-GENESIS (A. Vonk-Noordegraaf, F.S. de Man, H.J. Bogaard and M.-J. Goumans), and CVON-2018-29 PHAEDRA-IMPACT (A. Llucià-Valldeperas, F.T. Bekedam, A. Vonk-Noordegraaf, F.S. de Man, H.J. Bogaard and M.-J. Goumans). Funding Information: This research was financially supported by the Netherlands Organization for Scientific Research: NWO-VICI num. 918.16.610 (A. Vonk-Noordegraaf) and NWO-VIDI num. 917.18.338 (F.S. de Man). The work was also funded by the Dutch Heart Foundation Dekker senior post-doc grant num. 2018T059 (F.S. de Man), and the Netherlands CardioVascular Research Initiative: CVON-2017-10 DOLPHIN-GENESIS (A. Vonk-Noordegraaf, F.S. de Man, H.J. Bogaard and M.-J. Goumans), and CVON-2018-29 PHAEDRA-IMPACT (A. Lluci?-Valldeperas, F.T. Bekedam, A. Vonk-Noordegraaf, F.S. de Man, H.J. Bogaard and M.-J. Goumans). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - Engineered heart tissue
KW - Induced pluripotent stem cells
KW - Pulmonary arterial hypertension
KW - Right heart dysfunction
UR - http://www.scopus.com/inward/record.url?scp=85121354694&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cells10123595
DO - https://doi.org/10.3390/cells10123595
M3 - Article
C2 - 34944102
SN - 2073-4409
VL - 10
JO - Cells
JF - Cells
IS - 12
M1 - 3595
ER -