Researchers tackle major obstacle to stem-cell heart repair
Researchers have engineered stem cells that do not generate dangerous arrhythmias, a complication that has to date thwarted efforts to develop stem-cell therapies for injured hearts.
“We have found what we have to tackle to make these cells safe,” said Silvia Marchiano, a postdoctoral fellow in the laboratory of Chuck Murry at the UW Medicine Institute for Stem Cell and Regenerative Medicine (ISCRM).
Marchiano is the lead author of a paper describing the findings published Thursday, April 6, in the journal Cell Stem Cell. The work was done in collaboration with the Seattle company Sana Biotechnology.
In previous studies, Murry’s team used heart muscle cells created from stem cells to repair heart muscle damage caused by myocardial infarction.
To create their therapeutic heart cells, the Seattle researchers used pluripotent stem cells. Unlike adult stem cells, which have specialized to become specific cell types, pluripotent stem cells can become any type of cell in the body.
From 2012 to 2018 the Seattle team successfully injected pluripotent stem cells into damaged heart walls to create new muscle to replace that lost during an infarction.
But there was one major complication. During the early weeks of engraftment, the hearts tended to beat at a dangerously high rate. Unless a way could be found to prevent or suppress this problem, stem cells could not become 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 said.
To sort out what was causing these cells to behave this way, the researchers used a technique called RNA-sequencing to find out which ion channels were being made at different times as the cells matured.
To determine which ion channels were the culprits carrying the arrhythmia-causing current, the scientists used CRISPR-based genome editing to systematically knock out depolarizing genes or to activate repolarizing genes.
Finally, the scientists created a stem cell line in which three depolarizing genes were knocked out and one repolarizing gene was activated. That did the trick. Cardiac muscle cells generated from these stem cells were electrically quiescent, like adult heart muscle, but they contracted when given an electrical signal to mimic a natural pacemaker.
Murry cautions that additional testing with the engineered cells will need to be done, but, he adds, “I think we’ve overcome the biggest roadblock to regenerating the human heart.”
Excerpts from an article written by Michael McCarthy.