ABOVE: A new microfluidic heart-on-a-chip approach allows cardiomyocytes and vascular endothelial cells to communicate with each other. Arun Sharma

The simple, constant rhythm of a beating heart is a reassuring sign of life. With each lub-dub, blood brings life-sustaining oxygen throughout the body. But behind this steady beat is a busy orchestration of dozens of cell types that signal in tandem to stay in sync. When thrown off tempo, the consequences can be fatal. 

Scientists are fascinated by this carefully choreographed routine, but replicating it in a laboratory setting outside of the body has been a challenge. Even though technical advances have made it possible to grow many of the individual components in the lab—for example, heart muscle cells, or blood vessel cells—putting these cells together in an environment that mimics the heart is no small task.

Scientists at Cedars-Sinai Medical Center proposed a new way to use a microfluidic chip to mimic key features of a heart.1 By turning patient-derived stem cells into cardiovascular cells and growing them in a microfluidic chip, the team coaxed the cells to better mirror the morphology and function of cells in a human heart. This heart chip could serve as a patient avatar to simulate how his or her heart might respond to toxic chemotherapy drugs.

 “There's a lot of really exciting technologies that are emerging at the intersection of stem cell biology and tissue engineering that allow us to model heart disease in improved ways,” said Arun Sharma, a cardiovascular biologist at Cedars-Sinai Medical Center and coauthor of the study.

Sharma spent years developing methods to turn induced pluripotent stem cells (iPSC) into either cardiomyocytes or vascular endothelial cells.2 However, he noticed that the cells never quite matured to a degree where they closely resembled the cells found in a working human heart.

Nearby, his colleagues at Cedars-Sinai were building a brain-on-a-chip: a microfluidic chip that used different fluid channels to mimic the interactions between neurons and blood vessels at the blood-brain barrier.3 Sharma didn’t skip a beat and got to work using a similar approach for modeling the heart.

His team chose a commercial organ chip that contained two separate fluid channels.4 In one channel, they grew iPSC-derived cardiomyocytes to mimic heart muscle tissue, and in the other channel, they grew iPSC-derived vascular endothelial cells to mimic blood vessels. At the point where the two channels crossed, a porous membrane allowed molecules to diffuse between the two types of cells, emulating cross-talk that the cells might experience in a human body.

The chip also allowed Sharma’s team to manipulate the cells further. For example, they placed the chip on a system that stretched the cells, similar to the movements of a beating heart. They also pushed fluid through the channels to mimic blood flow.

“We’re basically giving the cells a workout on the chip,” Sharma said.

This workout seemed to help the cells mature. Visually, they began to take on the structures of human heart tissue, and the cardiomyocytes beat harder. A genetic analysis showed that these cells expressed genes found in mature cells.

In parallel, Sharma wanted to understand how some cancer drugs damage the heart, and realized that the heart-chip could help find the answer. In particular, the tyrosine kinase inhibitor (TKI) class of chemotherapy drugs is toxic for some patients. When his team flowed the TKI sorafenib through the heart chip, the cells died in the same way that they do in an actual heart. By measuring the electric impulses that drive the cardiomyocytes to beat, they saw that the cells fell out of sync. 

“Compared to other heart-on-a-chip platforms, this system is more biomimetic in that it tests for cardiotoxicity in the presence of normal mechanical processes like shear and stretch,” said Ngan Huang, a cardiovascular researcher at Stanford University who was not involved in this study.

According to Sharma, obtaining more mature cells was key to seeing a realistic toxicity response, which he hopes will make this more useful for clinical applications. His team is working on incorporating more cell types to make a more complex chip that they could link up with chips that simulate other organs that cancer drugs damage, such as the liver and brain.

“Increasing the complexity of the cellular makeup of organs-on-chip is an important challenge,” said Sara Vasconcelos, a cardiovascular researcher at the University of Toronto who was not involved in this study. She also noted that drug toxicities vary across people, so fully understanding this diversity will require heart chips from people with genetic differences.

This is ultimately Sharma’s goal. “We call it a patient avatar on a chip,” he said. He envisions using individual patients’ cells to generate iPSC and differentiate them into the relevant heart cells. “We want preclinical models to be able to better identify cardiotoxic drugs in a predictive way,” he said. “That's really a dream for personalized medicine.”

References

  1. Mozneb M, et al. Multi-lineage heart-chip models drug cardiotoxicity and enhances maturation of human stem cell-derived cardiovascular cells. Lab Chip. 2024;24(4):869-881.
  2. Sharma A, et al. Differentiation and contractile analysis of GFP-sarcomere reporter hiPSC-cardiomyocytes. Curr Protoc Hum Genet. 2018;96:21.12.1-21.12.12.
  3. Vatine GD, et al. Human iPSC-derived blood-brain barrier chips enable disease modeling and personalized medicine applications. Cell Stem Cell. 2019;24(6):995-1005.
  4. Huh D, et al. Microfabrication of human organs-on-chips. Nat Protoc. 2013;8(11):2135-57.