You are hereDecember 1, 2016
2016 STEM CELLS Translational Medicine Young Investigator Award Winner: Thorsten R. Döppner, MD, MSc
Meeting "The Right Person at the Right Time" Sets Researcher on Award-Winning Career
A German neurologist who helped lead a groundbreaking study on stroke is the winner of this year’s Stem Cells Translational Medicine (SCTM) Young Investigator Award. Launched in 2013, the award fosters advancements in the field of stem cells and regenerative medicine by honoring a young researcher who is principal author of an article published in SCTM, which over the course of a year is deemed to have the most impact and to push the boundaries of novel and insightful research.
Thorsten R. Döppner, MD, MSc, earned the award for “Extracellular Vesicles Improve Post-Stroke Neuroregeneration and Prevent Post-Ischemic Immunosuppression.” In the paper, he and his colleagues describe how they discovered that extracellular vesicles (EVs)—tiny membrane-enclosed structures that travel between cells—seem to work as well as adult stem cells in helping the brain recover from a stroke.
The study demonstrates convincing evidence through a side-by-side analysis that EVs act as a key agent in repairing the brain. It could lead to a new clinical treatment for ischemic strokes, as EVs carry far fewer risks than adult stem cell transplants. "The fact that intravenous EV delivery alone was enough to protect the post-stroke brain and help it recover highlights the clinical potential of EVs in future stroke treatment," Dr. Döppner said.
Dr. Döppner is a consultant and independent research group leader in the Department of Neurology at the University of Göttingen, Germany. He earned his MSc at the Max-Planck-Research-School, Göttingen, and his MD at the University of Duisburg-Essen, Essen, Germany. He also has been a visiting associate professor at Medipol University in Istanbul, Turkey, and a research fellow at the University of Wisconsin-Madison, in the United States.
Along with being a member of several professional organizations and a peer reviewer on many publications related to neurology, Dr. Döppner serves as editor of Brain Circulation and associate editor of the American Journal of Stem Cells and also of Frontiers in Cellular Neuroscience.
He took time from his busy schedule to answer SCTM’s questions about his work in stem cells and what led him to this point in his career. We share his responses here:
SCTM: Please describe the hypothesis you were testing in the research described in your award-winning paper?
Döppner: The causal therapy of stroke is hampered due to a narrow therapeutic time window and significant side effects. Experimental approaches thus strive to help increase the brain’s own neurorestorative capacity by transplanting adult stem cells such as mesenchymal stem cells (MSCs).
Although stem cells induce neuroprotection against stroke in various animal models, the grafted cells are not integrated in the residing neural network and do not replace lost tissue. Rather, stem cells mediate their beneficial effects via the secretion of growth factors, cytokines and others – a process called paracrine secretion.
However, more recent work suggests an involvement of extracellular vesicles (EVs) such as exosomes and others. In light of previous data, we wanted to analyze whether or not the application of EVs derived MSCs in our rodent stroke model counteracts the consequences of stroke. Provided a positive effect of EVs in terms of brain injury and neurological recovery, we then set out to systematically compare stroke outcomes of mice after EV treatment and MSC treatment. We hypothesized that the application of EVs in stroke mice is not inferior to the transplantation of MSCs themselves.
SCTM: Can you explain why investigating this hypothesis is important to stem cell research?
Döppner: Even though clinical trials have been under way demonstrating that MSCs appear to be safe in stroke patients for an observation period of one year and beyond, the long-term consequences such as tumor formation are still not known. As such, providing experimental evidence that EVs are the biological mediator of MSC-induced neuroprotection in stroke might pave the way for novel therapeutic concepts in stroke, avoiding the risks of cell transplantation in man.
SCTM: Briefly outline the approach you used to test your hypothesis.
Döppner: We exposed male C57BL6 mice to transient focal cerebral ischemia followed by an intravenous treatment of MSCs or MSC-EVs. The treatment started one day after stroke induction, and mice were sacrificed either at two days, six days or 28 days. At the time points given, brain injury was analyzed using immunohistochemistry, and post-stroke immune responses were measured using flow cytometry in blood and brain samples on day two and six. Finally, post-stroke neurological recovery was assessed using well-defined behavioral tests for which mice were trained before induction of stroke in order to ensure proper test performance.
SCTM: What was/were the most important finding(s) to come out of your study?
Döppner: Our study showed that the application of EVs is not inferior to MSC transplantation in our rodent stroke model. We could show that MSC-EV treatment stimulated post-stroke neuroregeneration and neurological recovery.
The latter was a consequence of EV-induced modulation of post-stroke immune responses. Although cerebral immune cell infiltration itself was not affected by EVs, the post-ischemic immunosuppression was attenuated in the peripheral blood at subacute stages of the disease, providing an appropriate external milieu for successful brain remodeling.
SCTM: Was there a specific methodological technique important to your work?
Döppner: The methodological basis for all of our work is the thread occlusion model in mice, which allows the induction of strokes in a well-defined manner without the need of opening the intact skull of the animal. Beside the latter, an experimental paradigm that provides sufficiently high EV enrichment was vital for our project. As such, we used the PEG precipitation method followed by subsequent ultracentrifugation in order to enrich EVs that could later be used for in vivo purposes.
SCTM: What does this mean for stem cell biology and its application?
Döppner: The results obtained in our study challenge the need of stem cell transplantation for therapeutic approaches under at least some well-defined conditions. Thus, we should not only concentrate on analyzing and modifying both survival and differentiation patterns of grafted stem cells, but also to better understand the biological characteristics of stem cells in terms of their secretion products.
If the latter indeed turns out to be the biologically relevant mediators, which has to be confirmed in further studies, it could provide the path for a novel view of stem cell application under therapeutic aspects such as stroke.
SCTM: What's the best scenario that you would like to see come out of your study?
Döppner: The experimental approach chosen in our study was unusual in the sense that we did not intend to follow a “bench-to-bedside” paradigm, but vice versa. As a matter of fact, we have previously applied MSC-EVs in a non-stroke patient who apparently did not show any side effects from EVs during the observation period of six months. Thus, the best scenario we would like to see from our study is the adjuvant stroke therapy of patients using infusion kits containing EVs in addition to the well-established thrombolysis of ischemic strokes.
SCTM: Let’s turn the spotlight on you for a bit. Why did you choose to go into stem cell research?
Döppner: First of all, I did not “choose” to go into stem cell research in the first place. As I will explain later on, I was lucky to be involved in an ongoing project focusing on post-stroke neuroregeneration when I was enrolled in the neurosciences program of the Max-Planck-Research-School of Göttingen.
When I got involved with the phenomenon of endogenous neurogenesis in the mammalian brain back in 2005, I was immediately fascinated by its complexity and the putative therapeutic potential that lies within it. This fascination has now been ongoing for years, being a key element that motivates me and my colleagues in order to strive to better understand the mechanisms involved in post-stroke neuroregeneration and stem cell transplantation
SCTM: Can you talk about your training, any mentors who might have influenced you and what motivates you today?
Döppner: Looking back, I appeared to be lucky enough to meet the right persons at the right time during my career so far. In that sense, I remember one of my professors claiming that there is hardly any other profession where chance plays a more decisive role than in science. He might be right after all.
During my medical studies at the University of Duisburg-Essen (Essen, Germany), I had the chance to be part of a work group focusing – among other things – on apoptotic pathways after ischemic/ reperfusion injury of the liver, which was located at the Institute of Physiological Chemistry. Under the supervision of Prof. Rauen, it was there that I got acquainted with laboratory work and fundamental research. That experience turned out to be vital for my career.
Being fascinated by the nervous system and neurological disorders, I decided that I needed more knowledge in the field of neurosciences if I was to make a career in that field. So after graduating from medical school, I enrolled in an international neurosciences program at the Max-Planck-Research-School in Göttingen. There, I made contact with my then and now boss, Prof. Mathias Bähr, who is head of the Department of Neurology at the University of Göttingen.
Expressing my interests in analyzing fundamental mechanisms underlying ischemic stroke, I was given the chance to participate in a well-funded project focused on post-stroke neurogenesis in 2005. Keeping on with my project, I developed a deep interest in neurogenesis and the application of stem cells for pathological conditions like stroke.
After obtaining a MSc degree, I started to develop an expertise in the field of translational stroke research, working both as a clinician and a researcher in Göttingen. Several years later, chance again played a major role in my career when I was offered the opportunity to build up my own independent research group at my former home, the University of Duisburg-Essen. Under the guidance of Prof. Hermann, I was able to further specialize in the field of post-stroke stem cell application and neuroregeneration. I strictly followed that path, working hard both as a clinician and as a fundamental neuroscientist during the years to come.
After spending some time abroad in 2015 as a visiting associate professor in Turkey and as a research fellow in Wisconsin (USA), I then decided to move back to Göttingen to keep on following my research track in the excellent scientific environment of the city.
SCTM: Tell us a bit about your current position.
Döppner: I am a consultant and independent research group leader at the Department of Neurology of the University of Göttingen (Prof. Bähr). I am fully involved in clinical routine, supervising young doctors who take care of both outpatients and admitted patients. I also run my own research group that focuses on analyzing mechanisms of post-stroke neuroregeneration.
As such, you could say that I am truly at the interface between clinical neurology and fundamental neurosciences, thus reflecting the idea of a translational scientific approach.
SCTM: Is there anything else that you think is important to bring up about your paper, your work and what you think should happen next?
Döppner: The work that is described in the paper, for which quite a few people have done a great job, has to be regarded as a proof-of-concept study. We wanted to know whether or not EVs are indeed equal to MSCs with regard to their therapeutic potential in our stroke model.
Once having clarified this, a great deal of work lies ahead of us. We need to further understand the mechanisms involved in EV application, including possible side effects that we have not yet observed.
SCTM: Why did you select the journal STEM CELLS Translational Medicine to publish your paper?
Döppner: The journal STEM CELLS Translational Medicine is the ideal platform for publishing my kind of research. Being a translational scientist myself at the interface between bench and bedside, as is the journal. Currently I can hardly think of any other journal that better suits my kind of scientific approach in the field of post-stroke neuroregeneration.
SCTM: How do you think the Young Investigator Award might affect your career?
Döppner: Any award that you obtain during your career is, I think, important. Yet, this award is something very special to me as it appreciates the great work that we have done in the previous years.
I hope that this award might give me the opportunity to bring our research to new levels in the future.