A safe and effective treatment for myocardial infarction and heart failure.
Scientists at the University of Washington School of Medicine in Seattle have successfully designed stem cells that do not produce hazardous arrhythmias, a complication that has previously hindered the development of stem-cell treatments for damaged hearts.
Silvia Marchiano, a postdoctoral fellow in the laboratory of Chuck Murry at the UW Medicine Institute for Stem Cell and Regenerative Medicine, said, “We have identified the key area we need to address to ensure the safety of these cells.”
Marchiano is the lead author of a paper published in the journal Cell Stem Cell today, which outlines the study’s findings.
The research was conducted in collaboration with the Seattle-based firm, Sana Biotechnology.
In prior research, Murry’s team utilized stem cell-derived heart muscle cells to mend heart muscle destruction resulting from myocardial infarction. This type of heart attack happens when the blood supply to the heart muscle is impeded, causing heart cells to perish. Since heart cells do not regenerate, scar tissue replaces the damaged muscle, impairing the heart’s ability to pump blood and weakening it. In severe cases, heart failure and death may occur.
To create their therapeutic heart cells, the Seattle-based researchers employed pluripotent stem cells. These cells have the potential to become any cell type in the body, unlike adult stem cells that have already specialized into particular cell types.
Between 2012 and 2018, the team in Seattle effectively transplanted pluripotent stem cells into injured heart walls to produce new muscle that could replace what was lost during an infarction. Through animal studies, they demonstrated that the implanted cells could fuse with the heart muscle, beat in synchronization with other heart cells, and improve the heart’s contractility. These discoveries revealed that stem cell therapy could be potentially used to rescue damaged hearts.
However, there was one significant obstacle. During the initial weeks of engraftment, the hearts would frequently beat at a dangerously high rate. Unless a solution was found to prevent or suppress this issue, stem cells could not be deemed a safe treatment for myocardial infarction and heart failure.
“Our goal is to create working contractile cells that would not try to set their own pace,” Murry adds.
Specialized cells called pacemaker cells regulate the heart rate in a mature heart. These cells generate electric signals at regular intervals that induce other heart cells to contract. In pacemaker cells, voltage oscillates between negative (hyperpolarized) and positive (depolarized). Murry compares this process to a metronome with positive ions moving in and out of the cell through channels. The heart rate is determined by the rate at which this repolarization and depolarization cycle occurs.
Nonetheless, in early embryonic hearts, the system in which only a few cells have become specialized pacemaker cells while others have become inactive contractile cells has not yet formed. All the cells act as pacemakers. Murry and his team hypothesized that the implanted stem cells were mimicking early embryonic cells, resulting in chaotic signal generation and causing hazardous heart rhythms.
To unravel the reason behind the aberrant behavior of these cells, the scientists employed RNA-sequencing, a technique that determines which ion channels are produced at various stages of cell maturation. The sequencing results indicated that specific ion channels emerge in the early stages of development and later vanish as the cell matures, while other types of ion channels surface in the later stages of development. This provided the researchers with their list of potential culprits, much like a puzzle gradually coming together.
To identify the ion channels responsible for the arrhythmia-causing current, the researchers utilized CRISPR-based genome editing to methodically delete depolarizing genes or activate repolarizing genes. This process turned out to be more intricate than anticipated. The team initially theorized that there would be a single ion channel responsible for the arrhythmia, but none of the single-gene edits could entirely eradicate the rapid heart rhythms. Subsequently, they undertook a meticulous process of testing “combinations” by conducting double and triple gene edits. Unfortunately, none of these edits eliminated the arrhythmia, and some appeared to exacerbate it, causing frustration among the researchers.
Ultimately, the researchers developed a stem cell line in which they knocked out three depolarizing genes and activated one repolarizing gene. This strategy proved effective. The cardiac muscle cells generated from these stem cells were electrically quiescent, similar to adult heart muscle, but they contracted when exposed to an electrical signal to simulate a natural pacemaker. These cells were dubbed “MEDUSA” (modifying electrophysiological DNA to understand and suppress arrhythmias) cardiomyocytes. The MEDUSA cardiomyocytes could engraft in the heart, mature into adult cells, electrically integrate with heart muscle, and beat synchronously with natural pacemaking, all without generating hazardous heart rhythms. Murry describes this as the sine qua non for heart regeneration.
Murry notes that further experimentation with the modified cells is necessary. However, he believes that “I think we’ve overcome the biggest roadblock to regenerating the human heart.”
Source:10.1016/j.stem.2023.03.010
Image Credit: Michael McCarthy