Heart assembloids give researchers a new way to study heart valve disorders

A multidisciplinary, multi-institutional group of researchers focused their expertise in genetics, mechanics, chemistry and biology on a chip the size of a postage stamp in order to model a particular class of heart conditions.

In a first for the field, a team led by Guang Li, associate professor in the School of Medicine’s Department of Cell Biology, has grown heart valves on organoids — miniature, simplified versions of a human heart chamber. This work, published August 11 in the journal Cell Stem Cell, is an important step toward better understanding and treating a number of serious heart disorders.

This kind of research often depends on animal models, which allow researchers to study the development of heart valves that grow much quicker than those of humans, which take nearly 10 weeks to fully develop.

Also, Li said, “human valves are very different from animal valves.” Imagine the physiological and genetic differences between a person and, for instance, a zebrafish. “To study human valve diseases, we need human valve models.”

Grown from pluripotent, adult human stem cells, organoids offer just such a model. The stem cells can be generated from skin, blood or other cells, then coaxed into developing into cells from a body part of interest. In this case, a human heart. Different types of organoids can be combined into “assembloids” to better model complex organs that natively originate from combinations of different tissues.

But a living, functioning heart is more than a cluster of certain types of cells. Its development and continued operation is dependent, among other things, on a complex interaction of different forces. To build analogs of those forces into the model, Li sought the engineering expertise of colleagues, including Lance Davidson, the William Kepler Whiteford Professor in the Swanson School of Engineering’s Department of Bioengineering, and Si-Yang Zhen, a professor of biomedical engineering at Carnegie Mellon University.

“This kind of project is really a hallmark of the community of researchers in Pittsburgh,” Davidson said. 

To create a model, Li grew a valve on the surface of a heart assembloid — two organoids made from different types of heart cells that were combined into one platform. Then the team went on, able to stimulate growth by designing ways to mimic the forces that would act on an embodied heart: a flowing medium to simulate blood, an endothelial culture to act as the cells that line heart valves and even a set of magnetized beads that moved according to the placement of a magnetic belt to mimic muscle contraction.

With the organoid working to replicate a heart with valves, the team now had a model they could use to study four types of valve disorders, including mitral valve prolapse (MVP), a genetic disorder affecting 7 million to 8 million individuals in the United States at any given time.

When Li introduced a mutation associated with the disease, the developing valves showed signs of MVP. In other cases, damage was simulated or introduced to mirror the damage that can occur to a person’s valves throughout life in conditions such as valve calcification, cryo-injury, and complications from hypoglycemia and diabetes.

Li was able to begin studying the organoids, identifying some pathways responsible for the development problems associated with MVP and ways they can be corrected. He was also able to develop models for the acquired deficiencies and will go on to look for ways to treat them.  

Next, he plans to add complexity to his assembloids, growing two chambers with valves inside them, instead of on the surface, to better model a real human heart.