Researchers moved closer to solving problems with treating heart disease by developing ways to build tissues and parts of a human heart using human stem cells.
Treating heart disease – given the differences between heart physiology in humans and other animals and the potentially dangerous side effects from drugs – poses particular challenges.
Two groups of researchers have moved a step closer to solving those problems by developing ways to build tissues and parts of a human heart using human stem cells, opening up new possibilities for drug testing, studying diseases and creating personalized treatments.
Researchers at Harvard University created a small-scale model of a heart’s left ventricle made from nanofibrous scaffolds through a process developed in Kit Parker’s Disease Biophysics Group lab. The technique, called pull spinning, uses a high-speed rotating bristle that pulls a solution of polyester and gelatin into a fiber that solidifies before detaching. It then moves onto a rotating cone-shaped collector that causes all of the deposited fibers to align in the same direction, which in turn will help align the human cells. The researchers then seed these scaffolds with human cardiomyocytes, the muscle cells that contract in the heart to keep it beating. The 3D structure acts as a template for the cells, which eventually assemble together to beat within the ventricular structure.
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“Using this technology, we can study healthy versus disease states at an organ level,” says Luke MacQueen, a bioengineering postdoc at Harvard University and first author on the study, recently published in Nature Biomedical Engineering. Physicians and researchers currently seek therapies using animal models, which are less than ideal since the physiology of those hearts differ from those of humans.
“Animals have different genetics than people and respond differently to various medications,” MacQueen says.
The researchers began by creating thin-walled chambers and seeding them with neonatal rat ventricular myocytes, which began to beat in synchrony after about four days. They were able to measure the pressure-volume loop and contractions within the ventricle using catheter sensors and electrocardiography equipment.
“A lot of cardiac function and cardiac diseases depend upon the connectivity of the cells,” MacQueen says. The heart cells in the artificial ventricle, like those in a real human heart, line up end to end so that electrical impulses can pass through in a certain direction.
The team built a self-contained bioreactor with chambers for valve inserts and access ports for catheters and ventricular assist capabilities so the researchers could better study the ventricles over time. Using human cardiomyocytes, they cultured and measured the behavior of the ventricles for six months.
To mimic cardiac arrhythmias, where structural abnormalities within the cardiac tissue sometimes cause irregular heartbeats as well as heart attacks, the researchers poked small holes in the ventricle and measured wave activity before and after the injury. Before the injury, the electric pulses moved in a wave along a plane. After the holes were added, the ventricles developed a spiral wave pattern.
In another system, the researchers introduced a drug called isoproterenol, which has similar effects to adrenaline, into the artificial ventricle, and the cells responded by increased beat rate. These exercises suggest that the ventricle model can be used to re-create heart attacks and cardiac arrhythmias. The model can also be used to test drugs and procedures that may lead to therapies for this potentially life-threatening abnormal beating of the heart and other forms of heart disease.
Another group is approaching therapeutics from a different angle, using cells but without heart-like structure. The company, InvivoSciences, grows living cardiomyocyte tissue from human induced pluripotent stem cells in a microplate format. It creates “human micro hearts” used to help drug companies test potential heart therapies. The company has a “palpator” that uses two different types of probes to measure the mechanical and electrical function of the heart tissue, which gives researchers essential information on the pressure-volume loop. It measures biological responses of the tissue connected to calcium and mitochondria that are essential to heart function. The palpator can also detect arrhythmias and heart failure, both of which are affected by injuries to the pressure-volume loop.
“In terms of heart function measurement, this is as comprehensive as it gets based on current technology,” says, Tetsuro Wakatsuki, InvivoSciences’ co-founder and chief scientific officer.
The “heart” is a fluid-filled bag that serves as a pump for the blood in our bodies. Any mechanical changes that affect the tissue, such as abnormalities in the cardiomyocytes, a loss of connectivity in the heart muscle cells (systolic heart failure), or a stiffening of the heart wall (diastolic heart failure), can result in changes in cardiac pressure that cause the pump to behave irregularly, resulting in arrhythmias or heart failure.
InvivoSciences has created a high-throughput analysis of the microplate system, which allows drug companies to test new potential drugs for heart failures and arrhythmias. It also allows companies to test the side effects of potential new drugs for heart disease, an important first step before clinical trials, Wakatsuki says. Company researchers are also working with the FDA to look at existing cancer drugs to address potential life-threatening side effects. Some cancer drugs have a high level of cardiotoxicity that can cause heart failure 10 to 20 years later in patients who had childhood cancer. Studying the effects of these drugs in a system such as this one may lead to new insights for minimizing the toxicity of these drugs.
Whether it’s heart muscle cell tissue beating on a plate or cardiomyocytes pumping in a small ventricle, heart part technologies still have room to grow. The cardiomyocyte tissue on the microplates has no structure. And while the cells beat synchronously, they are not pumping fluid.
The three-dimensional model of a human ventricle, a huge step forward towards building a whole heart, also has room to improve. For one, the researchers simplified the model as much as they could to keep the system as straightforward as possible while still making it functional. To maintain control of the cardiomyocytes, they also kept the tissue thin, so it generates less force while pumping than an actual animal ventricle would. The cardiomyocytes in these two systems also beat spontaneously. So developing a pacemaker of sorts — either using a node of human cells that regulate heartbeat or through artificial means — could mark a new area of research.
“It’s a starting point, but we have a long way to go,” MacQueen says.
Melissa Lutz Blouin is an independent technology writer.
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