Harvard researchers successfully used a human heart-on-chip to demonstrate that endothelial extracellular vesicles — particles released from cells lining the surface of blood vessels — are able to keep cardiac cells viable both during and after oxygen deprivation due to a heart attack.
The results, published last week in Science Translational Medicine, indicate that EEVs have the capacity to both rescue cardiac tissues damaged by lack of oxygen and serve as a potential multitargeted therapy for such damage. The successful use of heart-on-chip technology may also signal an emerging replacement to animal studies commonly used in biological experiments.
The researchers were based out of Harvard’s School of Engineering and Applied Sciences, The Wyss Institute for Biologically Inspired Engineering, Harvard Medical School, and the Harvard Center for Mass Spectrometry Proteomics.
Moran Yadid, the first author on the paper, began work on the research as a SEAS postdoctoral fellow in Bioengineering and Applied Physics professor Kit Parker’s lab; she now works as a research associate at Tel Aviv University.
Yadid said in an interview that the first of the study’s two main components entailed establishing an in vitro model for studying diseases and conditions that can affect cardiac tissues.
“This model is based on a heart-on-chip technology that we developed in the lab,” Yadid said. “In this technology, we utilize tissue engineering approaches and biofabrication to build tissues on soft substrates that can be good substrates to grow cardiac cells.”
In these chips, the researchers integrated special sensors that enabled them to continuously monitor the contracting function of the cardiac tissue in the heart, according to Yadid.
Johan U. Lind — another author on the paper who researched in Parker’s lab and is now an assistant professor at the Technical University of Denmark — said he worked extensively with the technological development of the heart-on-chip.
“One of the things that I think is exciting is this fundamental idea that we can study human tissue in the laboratory, and that might be a shortcut to new therapies,” Lind said. “So rather than taking the long route, where we do animal studies that don’t turn out much to actually predict what we’re looking for, to go straight to what’s human, and then test something new.”
The second part of the study focused on using the technology to study extracellular vesicles secreted from endothelial cells. In that phase, the researchers replicated a model for ischemia reperfusion injury — oxygen-deprivation damage that can lead to cell death — on the heart-on-chips and examined the impact of the EEVs.
Usually, when heart tissues or muscular tissues are deprived of oxygen, they cannot produce mechanical contractions, according to Yadid. But with EEVs present, the research team observed cell contraction even in the absence of oxygen.
“We saw that when you add these vesicles to cardiac features, they can increase their maximum respiration capacity, so they can work harder. They can better withstand and survive stress,” Yadid said. “When we actually induce the injury, we saw a significant decrease in cellular death. The tissue was much more viable after the injury. We also saw that they kept their mechanical function.”
Bogdan Budnik, a co-author of the paper and principal scientist at the Harvard Center for Mass Spectrometry, brought his expertise on single-cell proteomics to the team to analyze the EEVs, which require an ultra-sensitive type of analysis due to the limited amount of the material.
“Now, in this particular case, it’s the heart damage area of biology. But I do believe that extra vesicles-type of analysis will be applied to a lot of areas of cancer,” Budnik said. “I think that would be the big next step for proteomics.”
For Yadid, the research has two overarching takeaways. First, while previous efforts to treat failing hearts have focused on using one molecule to target one process, the group’s findings on EEVs indicate a solution to target many processes related to heart failure at once. Second, heart-on-chip or general organ-on-chip technology may come to replace animal studies as a more accurate method of testing new treatments.
“When we tested the same treatment with a rodent chip, we obtained different results,” Yadid said. “It’s more relevant to use human in vitro models rather than animal in vitro models to test different diseases.”