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.

CIRM Scholar Spotlight: Matt Donne on Lung Stem Cells

CIRM has funded a number of educational and research training programs over the past ten years to give younger students and graduate/postdoc scholars the opportunity to explore stem cell science.

Two of the main programs we support are the Bridges and the CIRM Scholars Training Program. These programs fund future scientists from an undergraduate to postdoctoral level with a goal of creating “training programs that will significantly enhance the technical skills, knowledge, and experience of a diverse cohort of… trainees in the development of stem cell based therapies.”

The Stem Cellar team was interested to hear from Bridges and CIRM scholars themselves about their experience with these programs, how their careers have benefited from CIRM funding, and what research accomplishments they have under their belt. We were able to track some of these scholars down, and will be publishing a series of interview-style blogs featuring them over the next few months.

Matt Donne

Matt Donne

We start off with a Matt Donne, a PhD student at the University of California, San Francisco (UCSF) in the Developmental and Stem Cell Biology graduate program. Matt is a talented scientist and has a pretty cool story about his research training path. I sat down with Matt to ask him a few questions.


Q: Tell us how you got into a Stem Cell graduate program at UCSF.

MD: I was fortunate to have Dr. Carmen Domingo from San Francisco State support my application into the CIRM Bridges Program. I’d been working for Dr. Susan Fisher at UCSF for a couple of years and realized that I wanted to get a PhD and go to UCSF. I thought the best way to do that was improve my GPA and get a masters degree in stem cell biology. I applied to the CIRM program at SF State, and was accepted.

The Bridges Program has been a great feeder platform to get students more science experience exposure than they would have otherwise received, and prepares them well to move on to competitive graduate schools.

After receiving my Masters degree, I was admitted into the first year of the Developmental and Stem Cell Biology program at UCSF. When the opportunity to apply for a training grant from CIRM came about between my first and second year of at UCSF, I knew I had to give it a chance and apply. With the help of my mentor, Dr. Jason Rock, I wrote a solid proposal and was awarded the fellowship.

While at SF State, Carmen was extremely supportive and always available for her students. Since then, many of us still keep in touch and more have joined the UCSF graduate school community.

Q: Can you describe your graduate research?

MD: The field of regenerative medicine is searching for ways to allow us to repair injuries similar to how the Marvel Comic Wolverine can repair his wounds in the movies. One interesting fact which has been known for several decades, but has not been able to be investigated more deeply until now, is the innate ability for the adult lung to regrow lost lung tissue without any sort of intervention. My thesis focuses on defining the molecular mechanisms and stem cell niches that allow for this normal, healthy adult lung tissue growth. The working hypothesis is if we can understand what makes a cell undergo healthy tissue proliferation and differentiation, we could stimulate this response to cure individuals who suffer from diseases such as chronic obstructive pulmonary disease (COPD). Similarly, if we understand how a cell decides to respond in a diseased way, we could stop or revert the disease process from occurring.

One of the models we use in our lab is a “pneumosphere” culture. We essentially grow alveoli, which are the site of gas exchange in the lung, in a dish to attempt to understand how specific alveolar stem cells signal and interact with one another. This information will teach us how these cells behave so we can in turn either promote a healthy response to injury or, potentially, stop the progression of unhealthy cell responses. The technique of growing alveoli in a dish allows us to cut down on the “noise” and focus on major cellular pathways, which we can then more selectively apply to our mouse model systems.

Pneumospheres. (Photo by Matt Donne)

Pneumospheres or “lung cells in a dish”. (Photo by Matt Donne)

Lung cells.

Lung pneumospheres under a microscope. (Photo by Matt Donne)

We are now in the process of submitting a paper demonstrating some of the molecular players that are involved in this regenerative lung response. Hopefully the reviewers will think our paper is as awesome we as believe it to be.

Q: How has being a CIRM scholar benefited your graduate research career?

MD: Starting in my second year at UCSF, I was awarded the CIRM fellowship. I think it helped the lab to have the majority of my stipend covered through the CIRM fellowship, and personally I was very excited about the $5,000 discretionary budget. These monies allowed me to go to conferences every year for the past three years, and also have helped to support the costs of my experiments.

The first conference I attended was a Gordon Conference in Italy on Developmental Biology. There I was able to learn more about the field and also make friends with many professors, students, and postdocs from around the world. Last year, I went to my first lung-specific conference, and attended again this year. That has been one of the highlights of my PhD career. While there, one is able to speak and interact with professors whose names are seen in many textbooks and published papers. I never thought I would be able to so casually interact with them and develop relationships. Since then, I have been able to work on small collaborations with professors from across the US.

It was great that I could go to these conferences and establish important relationships with professors without being a major financial burden to my Professor. Plus, it has been hugely beneficial for my career as I now have professors whom I can reach out to as I look towards my future as a scientist.

Q: What other benefits did the CIRM scholars program provide you?

MD: Dr. Susan Fisher has been in charge of the CIRM program at UCSF. She organized lunch-time research talks that involved both academic as well as non-academic leaders in the field. I enjoyed the extra exposure to new fields of stem cell biology as well as the ability to learn more about the start-up and non-academic world. There are not many programs that offer this type of experience, and I felt fortunate to be a part of it. Also, the free lunches on occasion were a nice perk for a grad student living in San Francisco!

I attended the CIRM organized conferences whenever they happened. It’s always great presenting at or attending poster sessions at these events, seeing familiar faces and meeting new people. I took full advantage of the learning and networking that CIRM allowed me to do. The CIRM elevator pitch competition was really cool too. I didn’t win, came in third, but I enjoyed the challenge of trying to break down my thesis project into a digestible one-minute pitch.

Q: Where do you see the field of lung biology and regenerative medicine heading?

MD: My take away from the research conferences I have attended with the help of CIRM-funding is that we are in a very exciting time for lung stem cell research. The field overall is still young, but there are many labs across the world now working on a “lung mapping project” to better define stem cell populations in the lung. I see this research in the future translating in to regenerative therapies by which diseased cells/tissue will be targeted to actually stop the disease progression, and in turn possibly repair and regenerate healthy new tissue. This research has wide reaching implications as it has the potential to help everyone from a premature baby more quickly develop mature healthy lungs, to adults suffering from COPD brought on by environmental factors, such as air pollution. As many scientists are often quoted, “This is a very exciting time for our field.”

Q: What are your future plans?

MD: I expect to graduate in about a year’s time. In the future, I want to pursue a career focusing on the social impact of science. I aspire to be someone like UCSF’s former chancellor Dr. Susan Desmond-Hellmand. It’s really cool to go from someone who was the president of product development at Genentech, to chancellor at UCSF, to now president of the Bill and Melinda Gates Foundation. Bringing science to impact society in that way is what I hope to do with my future.


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