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Heart regeneration using stem cells: Why irregular heartbeats occur after transplantation

MATSUMOTO (JP), August 2020 - Stem cells are studied around the world with the hope of reviving damaged body parts unable to regenerate themselves ¾ including the cardiac muscle injured during a heart attack. Once this tissue is damaged, there is no truly effective treatment option for restoring the heart’s function to its previous capacity.

However, stem cells hold promise because they can be manipulated to generate healthy cells to replace damaged or diseased cells. Still, a few issues must be cleared before such treatments can be implemented clinically. A major one is understanding why irregular heartbeats occur two to four weeks after heart muscle cells derived from induced pluripotent stem cells (iPSCs) are transplanted to the heart. The heartbeat stabilizes on its own after 12 weeks, but researchers have set out to find why the arrhythmia occurs.

Arrhythmia during a heart attack is often the result of what is called "re-entry," which occurs when the electricity inside the heart goes haywire and loops around inside the heart. Two previous groups who studied arrhythmia in hearts treated with transplanted cells thought the irregularity was not caused by re-entry, but from the activity of the transplanted cells.

That led to this latest study, published recently in Scientific Reports, in which a team led by Hajime Ichimura, M.D., of Shinshu University, proposed that the reason for this phenomenon might be a change in the properties of the cells after transplantation. To investigate, they prepared heart muscle cells from iPSCs (producing both working type cells, which as the name implies, contract and relax to produce exertion, and "nodal-like" muscle cells, which act like an electric pacemaker) and transplanted them in rats. This included one group of animals with induced heart attacks and another group that did not undergo a heart attack, as a control. The experiment was also done in vitro (lab culture).


They then observed the results at intervals of two, four and 12 weeks. What they found was that immediately after transplantation, the iPSC grafts in the rats were very small. However, by week 12 the grafts had grown and, interestingly, consisted mainly of working-type cells. There was also a noted decrease in arrhythmia at this point, which the researchers believe was because the number and activity of the nodal-like cells had decreased, which in turn resulted in a lessening of extra electrical activity. This was confirmed through in vitro testing, too.

“Perhaps if doctors could remove the nodal-like cells before transplantation, arrhythmia would not occur during future transplantation of heart cell grafts,” said corresponding author Yuji Shiba, M.D., Ph.D.

The researchers observed several electric parameters such as the beating rate. The nodal-like cells beat a little faster than the working-type cells. The dV/dt acts like the starting software. The APD is the breadth. The SHOX2+ Cells are the nodal-like cell markers. Troponin T (cTNT) is the marker for such cardiomyocytes. Their abundance is one (nodal-like) to nine (working-type). The MLC2V is the mature working-type cell. MLC2A can be found in nodal-like and immature working-type cells. MLC2A is found mostly in vitro, immature working-type and nodal-like cells.

Image courtesy of © 2020, Springer Nature.

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DOI: 10.1038/s41598-020-68373-9