Stem cell-derived pacemaker cells could help weak hearts keep the beat

In an average lifetime, the human heart dutifully beats more than 2.5 billion times. You can thank an area of the heart called the sinoatrial node, or SAN, which acts as the heart’s natural pacemaker. The SAN is made up of specialized heart muscle cells that, like a conductor leading an orchestra, dictates the rate which all other heart muscle cells will follow. But instead of a conductor’s baton, the cells of the SAN send out an electrical signal which stimulates the heart muscle cells to beat in unison.

Stem cell-derived pacemaker cells (blob in center) stimulate the layer of heart muscle cells  underneath to beat in unison (video: McEwen Centre for Regenerative Medicine).

Artificial pacemakers: an imperfect remedy for irregular heart beats
Certain inherited mutations as well as the aging process can foul up this natural pacemaker signal which usually results in slower, erratic heart rates and leads to poor blood circulation. The current remedy for irregular heart rhythm in these cases is the implantation of an artificial electronic pacemaker into the body. But these devices have their drawbacks: they can’t respond to hormone signals received by the heart, the implantation itself carries a risk of infection and the pacemaker’s battery life is limited to about 7 years so replacement surgeries are needed. Also, for children needing artificial pacemakers, there’s no effective way to adjust the device to adapt to a child’s growing heart.

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X-Ray of implanted electronic pacemaker (Image: Wikipedia)

Now, a Canadian research team at the McEwen Centre for Regenerative Medicine in Toronto aims to create a pacemaker from stem cells to one day provide a biological alternative to current electronic options. In their Nature Biotechnology report published last week, the team describes how they used their expertise in the developmental biology of the heart to successfully devise a method for transforming human embryonic stem cells into functioning pacemaker cells.

If you’ve been following the stem cell field for a while, you’ve probably watched lots of cool videos and read countless stories about beating heart cells grown from stem cells. Then what’s so special about this report? It’s true, you can readily make beating heart muscle cells, or cardiomyocytes, from embryonic stem cells. But usually these methods generate a mixture of various types of cardiomyocytes. The current report instead focused on specifically transforming the stem cells into the SAN pacemaker cells.

Look Ma, no genes inserted!
In 2015, another research team published work showing they had nudged stem cells to become cells with SAN-like pacemaker activity. But that study relied on the permanent insertion of a gene into the cells’ DNA which carries a risk of promoting tumor formation and would not be suitable for clinical use in the future. To generate cells that more closely correspond to the natural pacemaker found in healthy individuals, the researchers in this study created their cells by relying on a gene insertion-free recipe that included the addition of various hormones and growth factors. Stephanie Protze, the first author in the report, explained in a University Health Network press release, the challenge of finding the right ingredients:

“It’s tricky, you have to determine the right signaling molecules, at the right concentration, at the right time to stimulate the stem cells.”

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First author Dr. Stephanize Protze and senior author Gordon Keller, Director of the McEwen Centre
(Photo: McEwen Centre for Regenerative Medicine)

A replacement biological pacemaker: one step closer to reality
Analysis of their method showed that 90% of the human stem cell-derived SAN cells had the correct pacemaker activity. They went on to show that these cells could act as a natural pacemaker both in the petri dish and in rats. These results are an exciting step towards providing a natural pacemaker for people with irregular heartbeat disorders. Still, it’s important to realize that human clinical trials are at least 5 to 10 years down the road because a lot of preclinical animal studies will need to examine safety and effectiveness of such a therapy.

In the meantime, the team is eager to use their new method to grow patient specific pacemaker cells from human induced pluripotent stem cells. This approach will give the researchers a chance to study heart arrhythmia in a petri dish to better understand this health problem and to test drugs that could potentially improve symptoms.

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