“We need to get to know these cells much better”

Carlijn Voermans started working for Sanquin in 1996 as a PhD student at the Department of Experimental Immunohematology (IHE) and obtained her PhD in 2001. In that same year she became head of the laboratory for Stem Cell Transplantation of Sanquin. After a one and halve year leave to the Duke University Medical Center in Durham as a Postdoc, she returned to Sanquin in 2006, again as head of the laboratory for Stem Cell Transplantation (now called Laboratory for Cell Therapy) and group leader within the department of IHE. She currently works as a group leader within the department of Hematopoiesis. The projects she and her group are working on are focused on the bone marrow micro-environment.

You are a specialist in the area of bone marrow micro environment, and one of your specialties is studying several aspects of mesenchymal stromal cells. Could you explain why these MSCs are important for our health?
In the early seventies mesenchymal stromal cells (MSCs) were described as the cells that form the environment in the bone marrow, where they support hematopoietic stem cells (HSCs) that proliferate and undergo self-renewal. Now, however, it turns out that MSCs are not only present in the bone marrow but in several other tissues as well. They have three capacities; in addition to their hematopoietic support capacity they also have a regenerative capacity. This is observed in patients with osteogenesis imperfecta and in people with complicated fractures in which mesenchymal stromal cells increase healing of the bone. The third capacity is that MSCs can modulate the immune system probably because they secrete a lot of cytokines and growth factors. Due to these capacities, MSC are now widely clinically applied.
Using MSCs for clinical applications is done for several years now and has become some sort of hype. For example, world wide there are 301 ongoing trials in which MSCs are given to patients as a therapy. However, MSCs used in these trials are very heterogenic; they can not be described by one specific marker and are therefore difficult to recognize. In other words, we do not exactly know what we are giving to these patients, and for that reason, our research focuses on better defining mesenchymal stromal cells.
Something we studied in the past and we are still doing today are the effects of culturing. MSCs are very rare; to give them clinically we have to culture them for 3-6 weeks. This is a long time and during this culturing the characteristics change slightly, among other their migration capacity. Thus, the longer you culture them the worse they migrate, and that is something you do not want for some of the applications. At the moment we are investigating the heterogenic soup of cultured MSCs to see if we can make a better distinction right after isolation. We want to know if it is possible to determine: ‘these MSCs are optimal for immune modulation; these are for hematopoietic support and these cells you can use for their regenerative capacity’. We specifically study some of the proteins secreted by mesenchymal stromal cells, the so called WNT-proteins and we want to know which WNT-proteins are important for maintaining the bone marrow microenvironment.

What happens when the MSCs do not do their work properly?
Because we do not exactly now what we are giving to patients, there is a possibility that not all patients in a trial respond to the therapy. For example, to treat graft-versus-host disease (GVHD), a reaction that is seen after allogenic stem cell transplantation, a lot of MSCs are given with the intention to influence the immune system and inhibit the rejection reaction. In general, children respond better to the treatment then adults. There can be two reasons for this; either we are not giving the right MSCs, or we did not treat them in the right way. I leave that open for discussion. Nonetheless, it is obvious that this can have major clinically consequences. Eventually people might say that MSCs only work in half the patients, while we believe that a better definition of MSCs and a specification on what kind of MSC are transplanted should result in a firm conclusion on their clinical capacities.

Why is the treatment successful in children but not in all adults?
That is not really known. It could be because the immune system of children is different than that of adults. However, it can also be something completely different. What the MSCs research field is missing is a large complete trial in which mesenchymal stromal cells cultured under the same conditions are given to every patient. This varies a lot in the current situation because the MSCs come from different labs; some people give them fresh, so without being frozen while in the Netherlands they are often given after a period of frozen storage. Hence, there are many possible causes for different responses but the biggest problem is the heterogenicity of mesenchymal stromal cells. When they do not perform optimally for the applications you use them for, it can have major consequences.

What are the most important lines of research/approaches that have developed in your field over the past 5 or 10 years?
I find that difficult to say. I think that in our area of research it was important that we became more aware of the fact that we need to investigate these mesenchymal stromal cells much better. There are several articles on this topic published in prominent journals and it is also the focus of some leading labs in the United States as well. So I think we became more aware of the necessity to investigate what and how before we continue with clinical applications.
Another breakthrough in MSC research is the finding of one specific marker for MSCs in a mouse model. In mice you define mesenchymal stromal cells slightly different than in humans. For humans this marker applies to lesser extent, but in our field this was an important publication. Nevertheless, the awareness of further research, which is supported worldwide, is particularly the most important breakthrough.

What is, according to you, the biggest challenge in current research in your field?
That is in line with my previous answer. We need to get to know these cells much better. Many groups are working on this. I believe the challenge is to come to a more tailor-made product per patient, and to reduce culture time. Culturing takes a long time, is very expensive and labor-intensive. We could make some real progress when we succeed in this. However, to get it all clinically applied is another big challenge which requires cooperation from two sides. In first instance from basic research, to figure out what we are exactly looking at. The second is to see if we can translate these findings to the clinic.

Why does your line of research matter? In other words, why should people put money into it?
I believe that is twofold. Since 40 years, doctors perform stem cell transplantations, and since the beginning there is a growing group op people who qualify for a transplantation. The protocols have changed in ways which also allow older people to undergo transplantation. Nevertheless, a major disadvantage of allogenic transplantations is the complication graft-versus-host disease. Still, many people die from GVHD. By reducing these complications and making transplantations more applicable by using mesenchymal stromal cells can be, I believe, beneficial for many patients. I also believe that large groups of patients will benefit from treatment of bone diseases or from facilitating acceptation of a hematopoietic transplant. This is where the greater importance lies.

Who or what will benefit from your research?
Eventually the patient will benefit from this research. This can be the case for many applications. For example, we not only look at cancer patients but we also are developing MSCs for patients with Crohn’s disease. In this disease application of MSCs has an immune modulating function; they can inhibit the immune system at certain places so patients suffer less or sometimes the symptoms completely disappear. It is a whole different area of research but again you are using one of the capacities of MSCs. We still not know how these MSCs can do this, thus this is also a challenge for us. So in the end, large groups of patients will really benefit from our research.

How does your research suits Sanquin?
We have a just opened the new facility of the Laboratory for Cell Therapy within Sanquin. Here we process hematopoietic transplants for over 40 years now. For people that undergo an allogenic transplantation it is line to culture MSCs. Unfortunately, you cannot make cellular products without basic knowledge. For the final application it is of much importance to develop this basic knowledge. You need to know what you are working with before you can develop a clinically applied product. I think this basic knowledge suits Sanquin perfectly.

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