Miniaturized engineered heart tissues from hiPSC-derived triple cell type co-cultures to study human cardiac function

Miniaturized engineered heart tissues from hiPSC-derived triple cell type co-cultures to study human cardiac function

Windt, L. M. (Leiden University Medical Center)
Wiendels, M. (Leiden University Medical Center)
Dostanić, M. (Leiden University Medical Center)
Bellin, M. (Leiden University Medical Center; Università degli Studi di Padova; Veneto Institute of Molecular Medicine)
Sarro, Pasqualina M (TU Delft Electronic Components, Technology and Materials)
Mastrangeli, Massimo (TU Delft Electronic Components, Technology and Materials)
Mummery, C. L. (Leiden University Medical Center)
van Meer, B.J. (TU Delft Electronic Components, Technology and Materials; Leiden University Medical Center; Sync Biosystems)

2023

Human heart tissues grown as three-dimensional spheroids and consisting of different cardiac cell types derived from pluripotent stem cells (hiPSCs) recapitulate aspects of human physiology better than standard two-dimensional models in vitro. They typically consist of less than 5000 cells and are used to measure contraction kinetics although not contraction force. By contrast, engineered heart tissues (EHTs) formed around two flexible pillars, can measure contraction force but conventional EHTs often require between 0.5 and 2 million cells. This makes large-scale screening of many EHTs costly. Our goals here were (i) to create a physiologically relevant model that required fewer cells than standard EHTs making them less expensive, and (ii) to ensure that this miniaturized model retained correct functionality. We demonstrated that fully functional EHTs could be generated from physiologically relevant combinations of hiPSC-derived cardiomyocytes (70%), cardiac fibroblasts (15%) and cardiac endothelial cells (15%), using as few as 1.6 × 10⁴ cells. Our results showed that these EHTs were viable and functional up to 14 days after formation. The EHTs could be electrically paced in the frequency range between 0.6 and 3 Hz, with the optimum between 0.6 and 2 Hz. This was consistent across three downscaled EHT sizes tested. These findings suggest that miniaturized EHTs could represent a cost-effective microphysiological system for disease modelling and examining drug responses particularly in secondary screens for drug discovery.

Cardiac contraction
Cardiomyocytes
Engineered heart tissues
hiPSCs
Microphysiological system

http://resolver.tudelft.nl/uuid:d4e08e5c-1fae-4d83-8294-e096e6b455d9

https://doi.org/10.1016/j.bbrc.2023.09.034

0006-291X

Biochemical and Biophysical Research Communications, 681, 200-211

Institutional Repository

journal article

© 2023 L. M. Windt, M. Wiendels, M. Dostanić, M. Bellin, Pasqualina M Sarro, Massimo Mastrangeli, C. L. Mummery, B.J. van Meer