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Mini-hearts from hiPSC promote cardiomyocyte maturation and make low-cost platform for drug discovery and disease modelling

Wednesday, 10 June

Researchers from Leiden University Medical Center (group of hDMT PI Christine Mummery, Milena Bellin and Valeria Orlova) developed a microphysiological system that behaves as a "mini-heart" using cardiomyocytes, endothelial cells and cardiac fibroblasts all derived from human induced pluripotent stem cells (hiPSCs). These mini-hearts can be produced using only 5000 cells and without the need for any specialized equipment. This places them among the low-cost, low tech platforms for cardiac drug discovery and disease modelling. The results are just published in Cell Stem Cell.

Teamwork

This study could not have been done without collaboration among a group of young scientists (postdocs Viviana Meraviglia and Giulia Campostrini with PhD student Elisa Giacomelli) who worked together over many months to develop different aspects of the model. They are now continuing to build upon this model that will lead to additional publications. One, with LUMC colleague Sjaak Neefjes and collaborators on molecular variants of the chemotherapeutic drug doxorubicin that do not cause heart failure, is currently in press with PNAS. The mini-hearts used in a small part of this study showed a similar ability to distinguish cardiac toxic compounds as mouse models.

Cardiac fibroblasts as the "culprit" cell type in a genetic form of cardiac arrhythmia

The multicellular nature of mini-hearts makes them an excellent model to study multicellular cardiac diseases and to reveal disease-causing cells that might otherwise have been missed. This was elegantly demonstrated using hiPSCs from patients with Arrhythmogenic cardiomyopathy (ACM). When "healthy" cardiac fibroblasts were replaced with "diseased" cardiac fibroblasts from hiPSC, mini-hearts showed arrhythmias, even though the cardiomyocytes are perfectly normal. This could be applied to other forms of genetic disease and other complex heart conditions for which the causative mutation is unknown.

Complex readouts made simple

Mini-hearts were demonstrated to be an excellent model for multiplexing biological readouts ranging from electrophysiology, metabolomics, and single-cell transcriptomics to advanced imaging that allows cellular organization and cell-cell interactions to be studied. The researchers were not only able to look at how well the cardiomyocyte contractile apparatus was organized but also to see how endothelial cells formed vascular networks inside the mini-hearts. This is clearly evident in a 3D reconstruction video of mini-hearts imaged with a spinning disk microscope (cardiomyocytes are shown in green and vessels in red). The video was made by another postdoc in the group: Amy Cochrane, who is also a co-author. (click on the picture to start the video)

Building up the model for future advances

The group believes that the model can be further advanced by integrating inflammatory cell types, such as macrophages that can also be generated from hiPSCs (Cao et al. Stem Cell Reports 2019). Integration of mini-hearts in the organ-on-chip platform for controlled perfusion with patient-derived blood or serum could further reveal the role of circulating factors in the development of cardiovascular disease or assist in screening for early-stage markers of heart failure. In addition, the mini-heart format can be incorporated into Organ-on-Chip platforms. The low cost of mini-hearts can facilitate high-throughput compound screens for personalized medicine.

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