Two teams of researchers have developed miniature models of the human heart that beat and function like the full-size organ. The team from Michigan State University (MSU) and Washington University in St. Louis developed a human heart organoid (hHO) that recapitulates embryonic heart development, providing an unmatched view into congenital heart defects. The organoid created by the researchers at the Medical University of South Carolina (MUSC) and Clemson University mimics the tissue dysfunction that occurs following a heart attack.

Organoids are self-assembling, 3D multicellular constructs that exhibit organ properties and structure to various degrees. Several processes have been developed to create them in recent years.

The MSU teams heart includes all the primary types of heart cells, as well as functional chambers and vascular tissues. These minihearts constitute incredibly powerful models in which to study all kinds of cardiac disorders with a degree of precision unseen before, said Aitor Aguirre, the studys senior author and assistant professor of biomedical engineering at MSUs Institute for Quantitative Health Science and Engineering.

Results of the groups work created quite a stir when it appeared on the preprint server bioRxiv and highlights were presented at the 2020 International Society for Stem Cell Research Annual Meeting. Weve received a lot of calls from researchers who want to use our process, Aguirre told BioWorld. The NIH and the American Heart Association provided funding for the study.

To create the approximately 1-mm diameter hHOs, the team combined several approaches developed over the last decade. They start with induced pluripotent cells ordinary cells from adults that are induced by the introduction of several genes to become pluripotent stem cells or master cells. The team then provides chemical signals that stimulate the cells to differentiate and mimic the process used in fetal development to create a heart.

In 15 to 20 days, the developmentally directed approach takes an undifferentiated ball of cells and gets to the point that the heart beats, has chambers, has cells organized in the way those cells are organized in the heart. At a molecular and cellular level, we are creating a heart, Aguirre noted.

The process is much simpler and easier to recreate than tissue engineering, as hundreds can be created simultaneously with minimal operator involvement and without the need for expensive machinery. Aguirre said the equipment required would be present already in any standard cell laboratory.

Currently, the team is using the miniaturized model heart to study developmental heart disorders. Thats crucial because, while congenital heart affects 1% of all newborns, there have been no good ways to study fetal heart development. You cant tell a pregnant woman, we want to take a biopsy, so its hard to study first-hand, Aguirre explained. With this process, the team can replicate much of fetal heart development without using fetal cells, bypassing all ethical concerns.

Since the publication of their initial results, Aguirre and his team have made further advances to more closely model the human heart. By further improving the development conditions, the researchers are now giving the organoids structural and locational cues needed to organize themselves better. Those new conditions have led to the formation of two chambers with heart looping, creating a shape that resembles a sausage more than a ball. In addition, they are growing hearts that are more sophisticated and demonstrate functioning of a somewhat older heart.

The researchers also are working on the development of vasculature that will enable the minihearts to grow larger and to create a multiorgan system in vitro that would be especially useful in studying pediatric cardiopulmonary development. Beyond gaining a better understanding of the basics of early heart development, the team hopes the model will provide greater insight into the impact of various chemicals and conditions, including environmental contaminants, maternal diabetes and medications.

The South Carolina process

Researchers at the MUSC and Clemson University took a somewhat different approach to creation of their human cardiac organoid. Like the MSU team, they began with induced pluripotent stem cells that divide and self-assemble. The spherical organoids are fabricated in vitro using four defined cell types that range in maturity from early stage to adult in ratios found in the heart. The process gives the microtissue a range of functionality but does not reproduce the developmental process of a heart.

The greater maturity of some of the tissue has an advantage for the teams research, however. The South Carolina contingent has focused on creating heart organoids that parallel the physiological conditions present during and immediately following a heart attack. Their work recently appeared in Nature Biomedical Engineering.

The model demonstrates the key features of pathological metabolic shifts, fibrosis and calcium handling. Furthermore, our transcriptomic analysis showed that there are comparable disease characteristics that are similar to that of the diseased adult heart, lead author Dylan Richards, a graduate of the MUSC Clemson bioengineering program and now a computational biologist at The Janssen Pharmaceutical Companies of Johnson & Johnson, told BioWorld.

To model the heart after a heart attack, we used low oxygen culture to create an oxygen-diffusion gradient in cardiac organoids combined with noradrenaline stimulation, Richards said. This method resulted in a structural and functional gradient, similar to that of a heart after a heart attack (dying tissue in the middle surrounded by dysfunctional regions surrounded by functional regions).

Using the model, the team found that the experimental drug JQ1 reduces the fibrotic and arrhythmic properties seen in diseased post-heart attack organoids. They also demonstrated that doxorubicin, commonly used in breast cancer treatment, had greater cardiotoxic impact in diseased hearts, in keeping with previous findings of greater risk associated with the chemotherapy in women with pre-existing cardiovascular disease.

The team is looking at drug-exacerbated cardiotoxicity and COVID-19-induced cardiac diseases. It will also be enhancing the model to include immune cells, to better understand the role the immune system plays in restructuring heart tissue after damage from oxygen-deprivation.

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Human heart organoids provide unmatched insight into cardiac disease and dysfunction - BioWorld Online