Researchers have built a fully autonomous artificial fish from human heart muscle cells. The biohybrid construction is powered by the contractions of heart muscle cells and mimics the swimming movements of a zebrafish. The model illustrates how important feedback mechanisms are for the functioning of muscle pumps such as the heart. In the future, it can also be used to research heart diseases such as cardiac arrhythmias in more detail. It also represents a further step towards the development of an artificial heart for humans.
In the course of a human lifetime, our heart beats around three billion times. In order for the blood to be pumped optimally through our body, the muscles must contract in a precisely defined pattern. The sinus node acts as a clock generator, stimulating the muscle cells with electrical signals. They also react to physiological requirements through internal, mechano-electrical feedback systems. This system is so sophisticated and complex that researchers have only partially succeeded in artificially replicating it. Although they can grow tiny beating heart organoids, they are still a long way from an actually functioning heart.
Hybrid fish as heart model
A team led by Keel Yong Lee from Harvard University in Boston is now approaching this goal with a different approach: “Instead of focusing on reproducing the anatomical features of the heart, we let the biophysics of the heart inspire our design.” , says Lee’s colleague Kevin Kit Parker. “We identify the key biophysical principles that make the heart work, use them as design criteria, and recreate them in a system that makes it easier to see if we’re succeeding: an artificial swimming fish.”
To do this, Lee and his team first grew human heart muscle cells from stem cells. They grew these together to form two layers, one on each side of their artificial fish’s tail. They also isolated special heart muscle cells, from which they constructed a clock generator inspired by the sinus node and connected it to the double layer of muscles. They built the body of the fish, which is about the size of a fingernail, out of paper, gelatine and a plastic fin.
Internal and external stimulation
When arranging the two muscle layers, the researchers were inspired by the muscle drive in insect wings. This is constructed in such a way that movement in one direction gives the impetus for movement in the other direction. Cardiac muscle cells are also suitable for such a system. As part of the mechanoelectrical feedback system, they have specific receptors that respond to mechanical stretching and subsequently trigger a contraction. In the biohybrid fish, Lee and his colleagues attached the muscle layers in such a way that a contraction of the muscles on one side caused a stretch on the other side – in response to which those muscles in turn gave an impulse to contract and those on the opposite side stretched.
“This enabled the generation of continuous rhythms to regulate the antagonistic muscle pair to produce a spontaneous but coordinated swimming drive with the caudal fin,” the researchers report. In order to be able to control the hybrid fish externally as well, they genetically modified the muscle cells so that they react to light impulses: red light led to contraction in muscles on the left side of the hybrid fish, blue light in muscles on the right side. Using alternating red and blue light pulses, the researchers were able to coordinate the movements of the fish: when the light pulses changed quickly, it swam faster, and slower when the light pulses changed slowly. “This is reminiscent of the force-frequency relationship in the human heart,” say Lee and his team.
platform for further research
The hybrid fish worked for 108 days – longer than any previous model. Over time, he even improved his performance: “The amplitude of muscle contractions, maximum swimming speed and muscle coordination increased in the first month and were maintained for a total of 108 days,” the researchers write. The swimming performance of the hybrid fish was similar to that of real zebrafish. “Our results clarify the role of feedback mechanisms in muscle pumps like the heart,” says Lee. His colleague Sung-Jin Park adds: “This new research provides a model to study mechanoelectrical signaling as a therapeutic target for cardiac rhythm management. It also helps to understand which processes play a role in diseases such as cardiac arrhythmias.”
Source: Keel Yong Lee (Harvard University, Boston, Massachusetts) et al., Science, doi: 10.1126/science.abh0474