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.

CIRM Scholar Jessica Gluck on using stem cells to make biological pacemakers for the heart

As part of our CIRM scholar series, we feature the research accomplishments of students and postdocs that have received CIRM funding.

Jessica Gluck, CIRM Scholar

Jessica Gluck, CIRM Scholar

I’d like to introduce you to one of our CIRM Scholars, Jessica Gluck. She’s currently a Postdoctoral Fellow at UC Davis working on human stem cell models of heart development. Jessica began her education in textiles and materials science at North Carolina State University, but that developed into a passion for biomedical engineering and stem cell research, which she pursued during her PhD at UC Los Angeles. During her graduate research, Jessica developed 3D bio-scaffolds that help human stem cells differentiate into functioning heart cells.

We asked Jessica to discuss her latest foray in the fields of stem cells and heart development.


Q: What are you currently working on in the lab?

JG: I work as a postdoc at UC Davis in the lab of Deborah Lieu. She’s working on developing pacemaking cardiomyocytes (heart cells) from human induced pluripotent stem cells (iPS cells). Pacemaking cells are the cells of the heart that are in charge of rhythm and synchronicity. Currently, we’re able to take iPS cells and get them to a cardiomyocyte state, but we want to further develop them into a pacemaking cell.

So ultimately, we’re trying to make a biological pacemaker. We can figure out how we can make a cell become the cell that tells your heart to beat, and there’s two things we can get out of that. First, if we understand how we get these beating cells, the ones that are telling the other heart cells to beat, we might be able to understand how different heart diseases progress, and we might be able to come up with a new way to prevent or treat that disease. Second, if we understand how we’re getting these pacemaking cells, we could hopefully bioengineer a biological pacemaker so you wouldn’t necessarily need an electronic pacemaker. With a biological one, a patient wouldn’t have to go back to the doctor to have their battery replaced. And they wouldn’t have to have multiple follow up surgeries throughout their life.

Q: What models are you using to study these pacemaking cells?

JG: I’m looking at my project from two different directions. On one side, we’re using a pig model, and we’re isolating cells from the sinoatrial (SA) node, which is where the pacemaking cells actually reside in your heart. And there’s really not that many of these cells. You probably have about a billion cells in your heart, but there’s maybe 100,000 of these pacemaking cells that are actually controlling the uniform beating of the heart. So we’re looking at the native SA node in the pig heart to see if it’s structurally any different than ventrical or atrial heart tissue.

Diagram of the heart depicting the Sinoatrial Node. (Image from Texas Heart Institute.

Diagram of the heart depicting the Sinoatrial Node. (Image from Texas Heart Institute)

We’ve found that the SA node is definitely different. So we’re de-cellularizing that tissue (removing the cells but not the matrix, or support structure, that keeps them in place) thinking that we could use the native matrix as a scaffold to help guide these heart cells to become the pacemaking phenotype. On the other side, we’re taking dishes with a known elasticity and we’re coating them with different proteins to see if we can tease out if there’s something that an individual protein does or a certain stiffness that actually is part of the driving force of making a pacemaking cell. We’ve gotten some pretty good preliminary results. So hopefully the next phase will be seeing how functional the cells are after they’ve been on these de-cellularized matrices.

Q: Why does your lab work with pig models?

JG: Pig hearts are pretty close to the human heart – their anatomy is pretty similar. To give you context, a pig heart is slightly larger than the size of your two hands clasped together. But the SA node, when you isolate it out, is only a couple of millimeters squared. It’s a lot smaller than we originally thought, and if we had gone with a smaller animal model, we wouldn’t be able to tangibly study or manipulate the SA node area. Because we are at UC Davis, we have a Meat Lab on campus, and we are able to get the pig hearts from them.

Q: Have you run into any road blocks with your research?

JG: For anybody that’s working with cardiomyocytes, the biggest problem is getting stem cells to become mature cardiomyocytes. Some labs have shown that you can get cells to a more mature cardiomyocyte after it’s been in culture for almost 100 days, but that’s not exactly feasible or that helpful.

We’ve been able to isolate out a small population of cells that we’re pretty sure are pacemaking cells. Over the last year, we’ve realized that a lot of the information that we thought we knew about pacemaking cells isn’t necessarily specific to pacemaking cells. Many of the biological markers that people have published in the literature are present in pacemaking cells, but we realized that they are also present in other heart cells like atrial cells, just in a lower amount. So we haven’t really been able to pick one specific biomarker that we’ve been able to say, yes this is actually a pacemaking cell. Instead, we have a small percentage of cells that we’re able to study. But we’re trying to figure out if there’s a way that we could increase our yield, or if there’s something fundamentally different about the environment that would also increase the yield of these pacemaking cells. So we’ve had a lot of trouble shooting along the way.

Q: What was your experience like as a CIRM scholar?

JG: I became a CIRM scholar in the spring of 2014. It was through the UC Davis Stem Cell Training Program. The opportunity was very helpful for me because it was in my first year as a postdoc at Davis. I earned my PhD at UCLA, so I was dealing with being on a new campus, trying to figure out whose lab I could go to to borrow random things and where to find equipment that I needed to use. So it was helpful to be around a group of other people that were also doing stem cell projects. Even though a lot of us were focused on different areas, it was still helpful to talk to other people, especially if you get somebody’s perspective that isn’t necessarily in your field. They might come up with a random idea that you haven’t thought of before.

Over the course of the year, we had a journal club, which was always interesting to see what’s going on in the field. I also went to the annual International Society for Stem Cell Research meeting in Vancouver using CIRM funding. And as part of the program, we also worked with the CIRM Bridges program between UC Davis and Cal State Sacramento. There were Bridges master’s students that were there with us. It was interesting to hear their take on everything, and they were very enthusiastic. We have had two master’s students work in our lab. I think it was very beneficial to them because they got a lot of hands on training and both have gone on to jobs in the regenerative medicine field.

Q: What is the future of stem cell research?

JG: If you’re looking at heart disease and stem cell treatments, there’s been some interesting clinical trials that have come out that have some promising results. I think that for a couple of those studies, people might have jumped the gun a little getting the treatments into the clinic. There’s still a lot that people should study in the lab before we move on to clinical trials. But I do think that we will see something in the next 20 years where stem cell research is going to have a huge therapeutic benefit. The field is just moving so quickly, and I think it will be really interesting to see what advances are made.

For our research, I’ve always been fairly realistic, and unfortunately, I don’t think we will see this biological pacemaker any time soon. But I think that the research that we produce along the way will be very beneficial to the field and our work will hopefully improve the foundation of what is known about pacemaking cells. What I think is really interesting about our lab’s work, is that we are moving into a 3D culture environment. Cells behave very differently in the body as opposed to on a plastic petri dish. So I think it’s very encouraging that we are seeing a lot more labs moving towards a more physiologically relevant model.

Q: What are your future goals?

I’ve been lucky that I’ve been able to work with very well established professors and also brand new faculty. But I’ve seen how difficult the funding climate is – it’s very daunting. So I’m really not sure what will happen next, and I’m keeping my options open.

I’ve really enjoyed working with our undergraduate and graduate students. I’ve gotten involved with outreach programs in Sacramento that promote science to young kids. It’s something that I’ve really enjoyed, and it’s very interesting telling people that I work in stem cells. Middle school kids seem to think that stem cells are magic. It’s fun to explain the very basics of stem cells and to see the light bulb moment where they understand it. I’m hoping to end up in a career that is still within the stem cell field but more towards teaching or outreach programs.

Q: What is your favorite thing about being a scientist?

JG: The thing I really like is having a puzzle that you’re trying to figure out the answer to. It’s great because every time you answer one question, that answer is going to lead you to at least three or four more new questions. I think that that’s really interesting especially trying to figure out how all the puzzle pieces fit together, and I’ve really enjoyed getting to work with people in very different fields. My parents think its funny because they said even as a little kid, I hated not knowing the answers to questions – and still do! They were completely understanding as to why I stayed in school as long as I did.

You can learn more about Jessica’s research by following her on Twitter: @JessicaGluckPhD

Finding your Inner Rhythm: Cedars-Sinai Cardiologists Create Biological “Pacemakers” in the Heart

If your heart has trouble keeping a steady rhythm, you normally get a pacemaker: a small device that is inserted into your body and attached to your heart. About 300,000 people receive a pacemaker each year. But what if we could harness the body’s own cells to do what an external device does today?

Cedars-Sinai cardiologists have discovered a new way to keep the heart beating in rhythm.

Cedars-Sinai cardiologists have discovered a new way to keep the heart beating in rhythm.

In research published today in Science Translational Medicine, cardiologists from the Cedars-Sinai Heart Institute have found a way to reprogram one type of heart cell into another type that actually keeps the heart beating at a steady rate. These findings, performed in animal models, open the door to replacing an artificial pacemaker with a natural, biological one.

Dr. Eduardo Marbán, CIRM-grantee and the study’s lead author, explained the importance of their research:

“We have been able, for the first time, to create a biological pacemaker using minimally invasive methods—and to show that the biological pacemaker supports the demands of daily life. We also are the first to reprogram a heart cell in a living animal in order to effectively cure a disease.”

In this study, researchers injected a gene called TBX18 into the hearts of laboratory pigs. They then monitored any changes in heart rhythms of those pigs, comparing them to the hearts of pigs that did not receive the injection.

In just two days, the pigs that had received the injection showed stronger, faster rhythms, compared to the controls. And even more importantly—that strong rhythm persisted for the entire duration of the study (14 days), indicating that the therapy could be sustainable as a longer-term alternative to traditional, artificial pacemakers.

Intriguingly, the research team argues that their new method could be especially useful in cases where a traditional pacemaker is not an option, such as in newborns. Dr. Eugenio Cingolani, another member of the Cedars-Sinai team explained:

“Babies still in the womb cannot have a pacemaker, but we hope to work with fetal medicine specialists to create a life-saving catheter-based treatment for infants diagnosed with congenital heart block. It is possible that one day, we might be able to save lives by replacing hardware with an injection of genes.”

In addition to newborns, this new method could help a variety of other heart disease patients unable to receive traditional pacemakers—such as those who would suffer certain negative effects, or more complex heart arrhythmias—should the research proceed to clinical trials, which they hope to begin in approximately three years.

Added Marbán:

“Originally, we thought that biological pacemaker cells could be a temporary bridge therapy for patients who had an infection in the implanted pacemaker area. These results show us that with more research, we might be able to develop a long-lasting biological treatment for patients.”