Researchers at Harvard University have created a fish-like construct from human stem cell-derived cardiac muscle. The structure can beat and swim autonomously, and is inspired by zebrafish. So far, the researchers have shown that the fish can survive and swim for over 100 days, and they hope these new structures could provide insights into cardiac diseases, such as arrhythmias. However, the major prize in sight is an artificial heart that is suitable for transplantation, and the technology may represent a stepping stone to this eventual goal.
“Our ultimate goal is to build an artificial heart to replace a malformed heart in a child,” said Kit Parker, one of the leaders that developed the new technology. “Most of the work in building heart tissue or hearts, including some work we have done, is focused on replicating the anatomical features or replicating the simple beating of the heart in the engineered tissues. But here, we are drawing design inspiration from the biophysics of the heart, which is harder to do. Now, rather than using heart imaging as a blueprint, we are identifying the key biophysical principles that make the heart work, using them as design criteria, and replicating them in a system, a living, swimming fish, where it is much easier to see if we are successful.”
The structure consists of two muscle layers that lie on either side of the tail fin. The fish employs a clever mechanism that allows for continuous movement. When one side of the fish contracts, the other stretches. This stretching motion causes mechanosensitive proteins to open, stimulating the stretched side to immediately contract, stretching the other side, and triggering a chain reaction. This closed-loop beating motion is reminiscent of the mechanics of the human heart, and the researchers hope to use the fish to study cardiac disease.
“By leveraging cardiac mechano-electrical signaling between two layers of muscle, we recreated the cycle where each contraction results automatically as a response to the stretching on the opposite side,” said Keel Yong Lee, another researcher involved in the study. “The results highlight the role of feedback mechanisms in muscular pumps such as the heart.”
Strikingly, the fish has shown continuous motion for over 100 days, suggesting that it is robust and viable. The swimming motions improved over time, as the cells in the engineered muscle matured over time and the muscle became stronger. The Harvard team hopes that this technique could pave the way for something more complex and more valuable – an artificial heart for transplantation.
“I could build a model heart out of Play-Doh, it doesn’t mean I can build a heart,” said Parker. “You can grow some random tumor cells in a dish until they curdle into a throbbing lump and call it a cardiac organoid. Neither of those efforts is going to, by design, recapitulate the physics of a system that beats over a billion times during your lifetime while simultaneously rebuilding its cells on the fly. That is the challenge. That is where we go to work.”
See a video of the fish below.
Study in Science: An autonomously swimming biohybrid fish designed with human cardiac biophysics