Stem Cell Therapy for Ischemic Stroke

What have you been working on during your time as a Ph.D. student?

“What I do is stem cell therapies. In the lab, we focus on ischemic stroke which is a disease that currently has no effective treatment after the first few hours. Beyond physical exercise or rehabilitation, there’s little that can repair the damaged brain. So, our lab works on developing stem cell–based approaches for stroke recovery.

To do that, we generate cortical neurons, the brain cells typically affected by stroke, and more recently, oligodendrocytes, a type of glial cell found in the central nervous system. We work with two cell sources: embryonic stem cells, which are pluripotent and can give rise to any cell type in the body, and neuroepithelial stem (NES) cells, which are multipotent and can only form brain cells. 

Throughout my thesis, I used these cell sources for different aims. One major part of my work was to establish an ex vivo platform using adult human cortical tissue which has helped us to bridge the gap between animal research and human biology. In science, much of the research is done in vivo, using animals, but often when we attempt to translate findings from animal models into a human context, many clinical trials fail when translating findings to humans due to fundamental differences between animal and human systems.

This platform helps to overcome this issue. We receive brain tissue from our collaborator, neurosurgeon Johan Bengzon. During certain surgeries, he removes a small piece of healthy cortex to access deeper damaged regions of the brain. We culture these tissue slices in the lab, keeping them alive for as long as possible. Then, we transplant our lab-generated cortical neurons and oligodendrocytes into this tissue to see how they behave in a human environment. This setup helps us validate findings from animal models and better predict whether a new therapy will work in humans, which is an important step toward clinical translation. It is about as close as we can get to studying human brain repair in a preclinical setting.

So, in my thesis, you will first find the characterization of this ex vivo platform and how it can be used for developing cell therapies and testing drugs. The next two papers focus on stem cell transplantations in ischemic stroke, where we use a mix of cortical neurons and oligodendrocytes, and test them separately – only cortical neurons. Here, we wanted to see if these transplanted cells could survive in an animal setting, and if they matured and integrated into the brain’s circuitry to help rewire the whole system and restore function.

Finally, the last part of my thesis focuses on optimizing the generation of oligodendrocytes in the lab, trying to make this process faster and more efficient. Current protocols take a relatively long time (60-100 days) or yield low numbers of cells, so we aimed to develop a quicker method that produces pure oligodendrocytes. This protocol could also benefit research into other diseases like multiple sclerosis, where the main issue is that the oligodendrocytes are damaged.”

Were you always interested in neuroscience, stroke, and stem cell therapies?

“Not at all. My background is in biology, pure biology. I did my bachelor’s degree in biology with a thesis in immunology. But looking back, I think I was always drawn to the brain. Whenever I had to pick a project or essay topic, I would think, ‘Neuro sounds fun,’ and choose that.  There is just so much that we do not know about the brain, and that mystery always fascinated me.

During my master’s, I became interested in stem cells and Advanced Therapy Medicinal Products (ATMPs), and one of my courses focused on neuroscience. So, when it came time to find a master’s thesis, I knew I wanted to work with stem cells, and if it involved the brain, even better.”

What brought you from Spain to Lund?

“I am from Madrid, and like I said, I did both my bachelor’s and master’s there. During my bachelor’s, I did not get to go on Erasmus, so for my master’s, I knew that I really wanted to do my thesis abroad. That also just so happened to be when the COVID-19 pandemic hit.

While I was searching for where to do my internship, some friends and I came across Lund Stem Cell Center. At first, I could not remember what I had heard about Lund, but then it clicked, ‘ah that’s’ why it sounded familiar. I remembered learning about Lund in one of my courses, learning about Olle Lindvall and Anders Björklund and the clinical trials they did with a stem cell–based therapy for Parkinson’s in the 1980s and ’90s.

Lund University was also one of the few places still accepting students during the pandemic. I came here in September 2020 for a six-month thesis project. When my project ended, I was not ready to go back to Spain. It was still during lockdown, and I did not know what I would do there, so I asked my supervisor, Zaal Kokaia, if I could stay a bit longer. He agreed, and soon after, a new PhD position opened in his lab. I was not sure what to do at first, I had always been more interested in industry, mainly because academia is harder to pursue in Spain. I asked some PhD students who were around at the time about their experience, and decided to take a leap and stay. Four years later, I am still here.”

Speaking of Olle Lindvall, he and Zaza have been long-time collaborators, and Olle is active in the lab. Did you expect to work so closely with Olle when you first arrived?

“Not at all! I did not even realize he was still so active in science. The first time I met him, I was struck by how humble and passionate he still is about science. He is still very involved in the lab, always ready to teach and share his experience, and still curious about everything. It is incredible to see how much science has advanced since he began. I mean, he was doing science before I was even born, and he has adapted with it. It has really been an honor to have him around.”

Can you tell us more about your thesis cover?

“Back home, I live outside of Madrid, closer to the mountains and having nature close by has always been something that I have appreciated. In Sweden, I have always been captivated by the fact that no matter where you go, there is always a little piece of nature to go to. So, before starting the cover, I knew I wanted something inspired by nature. For me, Sweden is nature, and all about the seasons. You can really feel each one of them pass here, unlike in Spain, where it’s mostly warm and summer-like before, ‘BOOM,’ it is suddenly winter. 

I wanted to connect the seasons with neurodegeneration and regeneration. The background of the cover is autumn, which represents neurodegeneration. In the foreground, it is spring which represents renewal. Between them is a yellow brick road, because I am slightly obsessed with Wicked and The Wizard of Oz, which symbolizes time and the journey we take as we get older.

As you move along the path, you go from youth and renewal to aging and degeneration, but my research has focused on how we can reverse that path. That’s why the spring side is in focus: it’s about renewal and regeneration through stem cell therapy.

In the center is a flower made of the two cell types I used in my research - a neuron forms the stem, and an oligodendrocyte is placed in the center of the flower and forms its petals. The flower grows up through the path, symbolizing how stem cell therapy breaks through degeneration, initiating the process of regeneration or renewal.

A former PhD student here, Edoardo Sozzi, drew it for me. I just gave him my ideas and sketches, including one of the oligodendrocyte images that I liked, and he took it from there.”

What have you enjoyed most about your PhD?

“The people, and the network, how interactive the Stem Cell Center is. That has been the most enjoyable. The Center has provided so many opportunities for networking and collaborations, which have been where I have found people that I know I am going to have with me for life. Through programs like the Professional Development Program led by Christine and Jenny, all the seminars, and the annual meetings, they have all been great chances to connect with others and share ideas and I’ve met so many different people from different backgrounds through them. 

Those connections have been one of the highlights of my PhD and that is why I will always recommend others to come to the Lund Stem Cell Center if they can. Whether they join as a student or a postdoc, I always encourage people to come here because I feel like they do a really good job at connecting people and bringing people together. The community and collaboration here are something special. 

And then of course there is UniSTEM Day! I have always enjoyed the organization around the event and the opportunity to talk with high school students, potential future scientists. I know there have been a few students at the Center who first came as high school visitors and later returned as interns, master’s, and PhD students. Hearing these stories, that we helped to inspire others to pursue science, it feels like a full circle moment.”

What has been most challenging?

“At first, being far from home and without a support system. That was hard. Over time, I built one here with people I have met during my time here, but it took a while.

Another challenge was multitasking and trying to allocate time for everything that needs to be done in a day, and prioritizing things – these have always been challenging for me as a PhD student. I have always been curious and eager to learn, but that sometimes meant saying yes to too many things when I should have probably said no. That I think is a learning process every PhD student has, though, and so I have had to learn to prioritize. 

Luckily, I have had supervisors, Zaza and Sara, who have always trusted and supported me. Our lab is small, and we work well as a team, each helping each other through the long days or experiments, and that makes a big difference. I am really proud of where I have landed and the team that we have built altogether.”

What’s next after the defense?

“That is the question that everyone is asking. For now, I know that I will stay in the lab until December. After that, I am still figuring it out. I would love to stay in academia, but I do not see myself as a PI. I am also curious about the industry and want to see what is out there. 

What I do know is that I do not want to move countries again. It took time to establish myself; to build a life here and I do not want to have to start over somewhere else. So, my plans are to stay in the area, especially since the Öresund region is so strong in the life science sector, both in academia and industry, and the connection between the two is strong and continues to grow closer. Maybe I would consider crossing the bridge to Denmark for work, but I am not going further than that.

I also know that a purely desk job, 9-to-5, would not suit me. I need something hands-on, creative, and social. I love mixing lab work with other tasks, but sitting at a computer all day just is not for me. I learned that during the pandemic, when everything was shifted online. While writing my thesis, I knew I would need to sit at a desk and write, so I tried to mix in other tasks so that I could leave the computer for a bit. I found that helped my motivation.”

That last bit is a good piece of advice. Do you have any other advice you would like to share with future PhD students?

“Even when it feels tough, keep going. Be gentle with yourself. Talk to your friends and peers, especially other PhD students, they understand what you’re going through. 

Reflecting on my own experience, I know I used to be too hard on myself, and I have learned these last four years how important open communication is. To talk about how you feel and not bottle it up, because that is mentally and physically not good for anyone. Everyone needs an outlet, a stress release. For me, sometimes it’s just a five-minute cry and then I can move on. But I have also seen how much better I feel if I communicate with others how I am feeling before it gets to that point. 

Then I think it is also really important to stay connected to people, both inside and outside science. Talking to people outside academia can really put things in perspective. When we are in the environment that we are in, there's always pressure, there's always stress, there's always something and they might have a different perspective on how to manage things, or how to deal with that stress or the pressure you are feeling. We can get so deep into our projects that we lose sight of the bigger picture. 

So, communicate, reach out, and don’t be afraid to lean on others. It makes the journey much lighter.”