CIRM scholar Ke Wei talks heart regeneration

Ke Wei

Ke Wei

“How do you mend a broken heart?” was the topic of one of our recent Stem Cellar blogs highlighting a stellar CIRM-funded publication on the regenerative abilities of the protein FSTL1 following heart injury. One of the master-minds behind this study is co-first author Ke Wei. Ke is a postdoc in Dr. Mark Mercola’s lab at the Sanford Burnham Prebys Medical Discovery Institute located in balmy southern California. He also happens to be one of our prized CIRM scholars.

KeWeipatch

Cross sections of a healthy (control) or injured mouse heart. Injured hearts treated with patches containing FSTL1 show the most recovery of healthy heart tissue (red). Image adapted from Wei et al. 2015)

Upon hearing of Ke’s important and exciting accomplishments in the field of regenerative medicine for heart disease, we called him up to learn more about his scientific accomplishments and aspirations.

Q: Tell us about your research background and how you got into this field?

KW: I went to UCLA for my graduate school PhD, and I studied under Dr. Fabian Chen focusing on heart development. At that time, I mainly worked on very early heart development and other tissues like smooth muscle cells. For my graduate thesis work, I found that particular genes were important for smooth muscle development.

So I was trained as a heart developmental biologist, but after my PhD, I came to the Burnham Institute and I joined two labs: Dr. Mark Mercola and Dr. Pilar Ruiz-Lozano. They co-mentored me for the first couple of years of my postdoc. Mark is interested in using stem cells and high throughput screens to identify pharmaceutical compounds for inducing heart regeneration and treating heart diseases. Pilar is interested in the epicardium, the outer layer of the heart, which is known to play important roles during heart development. When I joined their labs, they had combined forces to study how the epicardium affects heart development and heart diseases.

In their labs, I used my developmental biologist background to combine in vitro stem cells based screening studies (Mark) and in vivo mouse embryonic heart development studies (Pilar) to dissect the function of the epicardium on heart development and disease.

Q: Tell us about your experience as a CIRM scholar and what you were able to accomplish.

KW: My two years of CIRM fellowship were separated but my focus was the same for both CIRM-funded periods: to understand the effect of the epicardium on heart development and diseases.

In my first project in 2008, we tried to generate an in vitro model of mouse epicardial cells and used those cells to study their influence on cardiac differentiation using both in vitro and in vivo experiments. We ran into a lot of technical difficulties, so at that time, we decided to switch to using existing in vitro epicardial cell lines, and using those to study their influence on cardiomyocytes (heart muscle cells).

In my second year of CIRM funding in 2011, we identified the genes and proteins that can promote immature cardiomyocytes to proliferate, and put them in vivo and it worked. So the success of our publication all started from my second year of CIRM-fellowship.

Q: What benefits did you experience as a CIRM scholar?

KW: I’ve really enjoyed being a CIRM scholar and took advantage of the resources they provided me over the years. One of the benefits I enjoyed the most was attending the CIRM annual meetings and retreats. I was able to talk with a lot of scientists with different backgrounds, and that really expanded my horizons.

As you can see from our paper in Nature, it’s definitely not only a developmental biologist paper. It’s actually very clinical and collaborative, and it was done by many different groups working together. By going to CIRM conferences and meeting all the other CIRM fellows, I got a lot of new ideas, and those ideas encouraged me to collaborate with more scientists. These events really encouraged me to look beyond the thoughts of a developmental biologist.

Our paper is co-authored by me and Vahid Serpooshan from Stanford. We co-first authored this paper, and my work mainly involved the in vitro studies that identified the regenerative proteins and their function in heart injury. Vahid’s approach was more bioengineering focused. He produced the FSTL1 patch, put it in the rodent heart, and conducted all the other in vivo studies. It was a perfect collaboration to push this project for publication in a high level journal like Nature.

Q: What is the big picture of your research and your future goals?

KW: I plan to stay in academia. The key thing about heart diseases is that heart regeneration is very limited. Using our approach, we found one particular protein that’s important to the regenerative process, and in reality, its concentration is very low in the heart when it’s infarcted (injured). I think we have set up a pretty good system to test all possible therapeutic means in the lab, including proteins from the epicardium, small molecules, microRNAs and other compounds to activate cardiomyocyte proliferation. I plan to focus on understanding the mechanisms for why cardiomyocytes stop proliferating in the adult heart, and what new approaches we can pursue to promote their expansion and regenerative abilities. The FSTL1 story is the start of this, and I will try to find new factors that can promote heart regeneration.

Q: Will your work involve human stem cell models?

KW: To make this study clinically relevant, we included the swine models. We are definitely testing FSTL1 in human cells right now. Currently we can produce a huge amount of the human cardiomyocytes. They seem to be at a different stage than rodent cells so we are optimizing the system to perform screens for human cell proliferation. When that system is set up, then anything that comes out of the screen will be much more relevant to clinical studies in humans.

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

Knowing that the information I acquire through experiments is new to mankind, and that my actions expand the horizon of combined human knowledge, even just for a tiny bit, is a huge satisfaction to me as a scientist.

Patching up a Broken Heart with FSTL1

Get-Over-Heartbreak-Step-08How do you mend a broken heart? It’s a subject that songwriters have pondered for generations, without success. But if you pose the same question to a heart doctor, they would give you a number of practical options that focus on the prevention or management of the physical symptoms you are dealing with.

That’s because heart disease is complicated. There are many different types of diseases that affect the health and function of the heart. And once damage happens to your heart, say from a heart attack, it’s really hard to fix.

New regenerative factor for heart disease

Scientists from Stanford University, the University of California, San Diego, and the Sanford-Burnham-Prebys Medical Discovery Institute have teamed up to figure out how to fix a broken heart. In a CIRM-funded study published today in the journal Nature, the group reported that the gene follistatin-like 1 (FSTl1) has the ability to regenerate heart tissue when it’s delivered within a patch to the injured heart.

2004_Heart_Wall

The different layers of the heart.

The wall of the heart is made up of three different layers: the endocardium (inner), myocardium (middle), and epicardium (outer). The epicardium not only protects the inner two layers of the heart, but also supports the growth of the fetal heart.

The group decided to study epicardial cells to determine whether these cells produced specific factors that protect or even regenerate adult heart tissue. They took epicardial cells from rodents and cultured them with heart cells (called cardiomyocytes), and found that the heart cells divided and reproduced much more quickly when cultured with the epicardial cells. This suggested that the epicardial cells might secrete factors that promote the expansion of the heart cells.

Patching up a broken heart

They next asked whether factors secreted from epicardial cells could improve heart function in mice after heart injury. They designed and engineered tiny patches that contained a cocktail of special epicardial factors and sewed them onto the heart tissue of mice that had just experienced the equivalent of a human heart attack. When they monitored these mice two weeks later, they saw an improvement in heart function in mice with the patch compared to mice without.

When they analyzed the cocktail of epicardial factors in the patch, they identified one factor that had potential for regenerating heart tissue. It was FSTL1. To test its regenerative abilities, they cultured rodent heart cells in a dish and treated them with FSTL1 protein. This treatment caused the heart cells to divide like crazy, thus proving that FSTL1 had regenerative qualities.

Moving from the dish into animal models, the scientists explored which layers of the heart FSTL1 was expressed in after heart injury. In healthy hearts, FSTL1 is expressed in the epicardium. However, in injured hearts, they found that FSTL1 expression was missing in the epicardium and was instead present in the middle layer of the heart, the myocardium.

FSTL1 to the rescue

patch

Cross sections of a healthy (control) or injured mouse heart. Injured hearts treated with patches containing FSTL1 show the most recovery of healthy heart tissue (red). Image adapted from Wei et al. 2015)

In a eureka moment, the scientists decided to add a FSTL1 protein back to the epicardial layer of the heart, post heart injury, using the same patch system they used earlier in mice, to see whether this would promote heart tissue regeneration. Their guess was correct. FSTL1 delivery through the engineered epicardium patch system resulted in a number of beneficial effects to the heart including better function and survival, reduced scar tissue build up (a consequence of heart injury), and increased blood flow to the area of the patch.

Upon further inspection, they found that the FSTL1 epicardial patch caused heart cells to divide and proliferate. The same effect did not happen when FSTL1 is expressed in the myocardium layer of the injured heart.

To make sure their findings translated to other animal models, they studied the regenerative effects of FSTL1 in a pig model of heart injury. They applied patches infused with FSTL1 to the injured heart and as expected, observed that FSTL1 delivery improved symptoms and caused heart cells to divide.

No more heartbreak?

The authors concluded that heart injury turns off the activity of an important factor, FSTL1, in specific heart cells needed for heart regeneration. By turning on FSTL1 back on in the epicardium after injury, heart cells will receive the signal to divide and regenerate heart tissue.

Co-first author and CIRM postdoctoral scholar Ke Wei spoke to CIRM about the next steps for this study and its relevance:

Ke Wei

Co-first author, Ke Wei

In the future, we hope that our engineered epicardium patch technology can be used as a clinical platform to deliver drugs or cells to the injured heart. This strategy differs from conventional tools to treat heart attack, and may provide a novel approach in our repertoire battling heart diseases.

Thus it seems that scientists have found a potential way to patch-up a broken heart and to extend a lifeline for those suffering from heart disease. It’s comforting to know that the regenerative abilities of FSTl1 will be explored in human models and will hopefully reach clinical trials.

Ke Wei (UCSD, Sanford-Burnham-Prebys) and Vahid Serpooshan (Stanford) were co-first authors on this study. The senior authors were Daniel Bernstein (Stanford), Mark Mercola (UCSD, Sanford-Burnham-Prebys), and Pilar Ruiz-Lozano (Stanford). Both Ke Wei and Mark Mercola received CIRM funding for this study.


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