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Vascular and Regenerative Medicine

Research

Combining different disciplines, Leiden University researchers work together to formulate innovative solutions to societal problems. Below is an example from the field of health and wellbeing.

Overview research dossiers

Vascular and Regenerative Medicine

Repairing damaged organs

Methods of treatment for chronic illnesses are limited. Doctors and researchers at Leiden University Medical Center (LUMC) and Leiden University are working on new therapies as an alternative for organ transplants. The goal is to cure the illnesses by restoring organs to their original function. Stem cells play an important role in this process.

<p>Photo: Brigitte Wieles, LUMC.</p>

Photo: Brigitte Wieles, LUMC.

A new approach

Patients with chronic conditions such as diabetes and arteriosclerosis are seldom cured of their illness. Usually doctors cannot do much more for them than keep the illness under control and limit damage to organs as far as possible. Regenerative medicine aims to use a completely new approach, namely to repair damaged organs, returning them to their original state and function. Through vascular research, Leiden scientists are looking for factors that point to disease at an early stage, to be able to predict when people are getting ill.

Repairing organs instead of replacing them

In the past a complete organ, such as a heart or kidney, would be replaced in a transplant operation. Nowadays specialists are more inclined to explore whether there is a mechanism in the body itself that can repair the damage. The capacity is often already there, but this mechanism does not function well. For example, the repair mechanism can be activated by introducing stem cells. These are cells that still have the potential to grow into different types of somatic cells. Within LUMC, a great deal of research is being conducted on possible therapeutic applications of these stem cells for regenerating tissues. Among the types of patients that could benefit from this sort of treatment are those suffering from Graft-versus-Host disease and type 1 diabetes.

Organ-on-a-chip

In addition to therapeutic applications, stem cells are also important for scientific research into new medications. With the help of so-called organ-on-a-chip technology, researchers grow stem cells into a small piece of an organ. These pieces can then be used to test substances that could lead to the development of new medications.

Precursor

Leiden University Medical Centre has many research facilities in the area of regenerative medicine. In 2011, LUMC was the first to have a facility for growing induced pluripotent stem cells, and it has a very extensive Good Manufacturing Practice facility for the production of stem cells for therapeutic applications. At Leiden University and LUMC there is good interaction with cell biologists, physicians and technicians at the surrounding technical universities.

More information:
Vascular and Regenerative Medicine LUMC

Stromal cells suppress immune response symptoms

A new therapy for the serious Graft-versus-Host disease


Researchers at LUMC have developed a new therapy for Graft-versus-Host disease, a serious condition, based on mesenchymal stromal cells. Research into the effectiveness of this therapy is already in its final phase. To achieve a therapy that is generally available to patients, effectiveness is being tested on a large group of patients in a so-called phase III study.

Graft-versus-Host

Stem cell transplantation is a commonplace treatment, such as for patients with leukaemia. Unhealthy stem cells in the bone marrow are replaced with healthy stem cells, which usually come from a donor. Unfortunately, this sort of transplant procedure always carries the risk of an immune response. The patient’s body may reject the donor’s stem cells, but conversely, the donor’s stem cells can also exhibit an immune response to the patient’s body. The latter situation can lead to Graft-versus-Host disease, a serious condition that is fatal for many patients.

The surprising effects of stromal cells

Over the last few years, researchers in Leiden have developed a new treatment for this Graft-versus-Host disease, based on mesenchymal stromal cells (MSCs). MSCs are special cells that can be extracted from bone marrow, fat tissue or the umbilical cord. They can grow to become bone, cartilage or fat tissue. One of these cells’ special properties is that they do not trigger an immune response, and in fact they can even suppress such a response. The immune-suppressing properties of these cells were first demonstrated in Graft-versus-Host disease.

Professor Wim Fibbe and his colleagues achieved promising results with MSCs extracted from donor bone marrow. In a clinical study with a group of fifty-five patients, 70 to 80 per cent of them were cured of Graft-versus-Host disease after receiving these MSCs. The results for children were even slightly better than for adults. Doctors who collaborated on the study were completely surprised by what they saw.

From the lab table to the patient

Before a new method of treatment becomes generally available for patients, it must first go through a long clinical test phase. Tests are conducted to determine whether it is feasible to give the cells to patients (phase I), whether it is safe (phase II) and finally whether the treatment is actually effective (phase III). The effectiveness is shown in a large randomised study: a study in which patients are arbitrary divided into test groups. One of the test groups is given the therapy, and the other group is given a placebo. In order to identify a sufficient number of patients with Graft-versus-Host disease for the study, LUMC is collaborating with hospitals throughout the Netherlands and with colleagues in six other countries in the European Union. This study, sponsored by the EU under the name RETHRIM, began in 2015 and will continue for about five years.

See the RETHRIM-website for more information on this research.

Repair a bad kidney or make a new one to order

Searching for ways to delay the need for a transplant and trying to build kidneys to order.


Kidney disease

The Netherlands has some 60,000 kidney patients. The kidneys of more than a quarter of these patients work so poorly that they depend on dialysis or a transplant. But kidney dialysis is only a partial replacement for the kidney’s most important function: purifying the blood. About 70% of these patients dependent on kidney dialysis die within five years. For this reason a large proportion of these patients are on a waiting list for a kidney from a donor. The chances of survival with a donor kidney are much greater. However, the number of available donor kidneys is small, and with an increase in the number of kidney patients the waiting period is only getting longer.

Repairing kidneys with stromal cells

The mesenchymale stromal cells (MSCs), which are so promising for treating Graft-versus-Host disease, are also being investigated for treating patients with kidney diseases. Their immune-suppressing property is currently being tested on patients undergoing a kidney transplant. In this way the researchers hope to figure out whether the chance of a transplanted kidney being rejected can be reduced. Patients undergoing a kidney transplant need to take a lot of medicines to suppress their immune system. These medicines often have serious side effects. A kidney transplant in combination with MSCs would provide a way to reduce the quantity of medications and thus also reduce the associated side effects.

In addition to the aforementioned MSCs, Ton Rabelink’s group is also working on organ-specific MSCs. These are MSCs extracted from the kidney. Within the EU-sponsored STELLAR project, researchers are studying whether these kidney MSCs are better equipped to regenerate a sick kidney. One would be able to make the sick kidney a bit better, so to speak, allowing the need for dialysis to be postponed or even making dialysis unnecessary.


A new kidney made to order

In close collaboration with a group in Australia, Ton Rabelink’s research group is investigating whether it is possible to produce custom-made kidneys. To do this they use pig kidneys from which all the cells are removed. This process results in a kidney consisting of nothing more than its ‘skeleton’. This kidney skeleton is then covered with cells from the patient. All the individual components needed to construct a kidney are already available, but cobbling a kidney together is a very complicated process. The cells used to cover the skeleton have to undergo a complicated procedure to get the stem

A pig kidney from which all the celss are removed (photo: Ton Rabelink).

A pig kidney from which all the celss are removed (photo: Ton Rabelink).

cell to grow into various kidney-specific cells. Furthermore, the right cells need to be produced in sufficient quantities and then be correctly positioned in the skeleton. Much more research is still needed before the first made-to-order kidney can be transplanted. But when we do reach that point, it will be a medical breakthrough: a solution for the kidney donor shortage.

For more information on this research, see the STELLAR-website.

From islet transplants to stem cell therapy for diabetes patients

Stem cells can be differentiated into insulin-producing cells.


Type 1 diabetes, a frequently occurring form of diabetes, can be cured with a transplantation of the pancreas or the islets of Langerhans. These transplants yield good results, but unfortunately very few donor pancreases are available. This is why Leiden researchers are developing a new method of treatment based on stem cells, allowing the treatment of multiple patients using a single donor’s pancreas.

Insulin injections

When a person eats carbohydrates, the hormone insulin prevents the glucose level in his blood from rising too high. This hormone is produced by insulin-producing cells in the pancreas. Together, these cells are called the islets of Langerhans. In patients with type 1 diabetes, these islets have been destroyed by their own immune system, preventing them from producing insulin. This is why these patients are forced to take insulin injections. However, this does not protect them from the risk of developing serious secondary symptoms, such as kidney and heart failure.

The islets of Langerhans.

The islets of Langerhans.

Pancreas transplants

Curing diabetes is currently possible either by transplanting the entire pancreas, which is a very invasive operation, or by transplanting the islets of Langerhans. These transplants yield very good results. After an islet transplantation, sixty to seventy per cent of patients treated no longer need insulin injections. With the remaining patients, the disease is much easier to control. Leiden University Medical Centre is the only Dutch medical centre where pancreas and islet transplants are performed. Each year around 20–25 patients are treated with a pancreas transplant and 5–6 patients receive an

islet transplant. Professor Ton Rabelink explains: ‘A pancreas transplant is a difficult operation due to the digestive juices. It’s a very complex surgical procedure. It’s very difficult to remove the organ from the donor without the digestive juices leaking. This is why so few donor pancreases are available. Sometimes we are also offered pancreases that aren’t suitable for transplantation. Fortunately we can still use those to extract the islets of Langerhans for an islet transplant.’

New stem cell therapy

Recently, Rabelink and his colleagues have developed a new method with which they hope to be able to help many more diabetes patients. It is a treatment based on stem cells. The pancreas contains stem cells that can be differentiated into insulin-producing cells. When the islets are extracted from a donor pancreas for an islet transplant, Rabelink and his colleagues can also extract these stem cells. They have recently been able to show that these stem cells can be made to grow into insulin-producing cells in the lab. This means that they can probably be used for a transplant in the same way as extracted islets. Rabelink explains: ‘The advantage is that you can continue to cultivate these cells for a long time, allowing you to help multiple patients using a single donor pancreas.’ It may be that in the long term the same technology can be used to grow islets based on the patient’s own stem cells, obviating the patient’s need for medications to suppress the immune system. But that is still a long way off.

Blood vessels on a chip make the cause of dementia visible

New technology offers many new possibilities for research, such as on dementia.


‘Organ-on-a-chip’ is a new technology in which small bits of organ are grown out of stem cells on a small plastic plate. A small piece of blood vessel, heart or nerve offers many new possibilities for research, such as on dementia.

Better models for pharmaceutical research

You can’t simply take a new medication and test it on humans. This is why researchers often use mice to study the effects of new medications. There have been a great number of potential medications that seemed successful on mice, but proved not to work well on humans. For some illnesses it is not even possible to test medications on mice, such as when the illness doesn’t occur in mice. For this reason there is a great need for better models for pharmaceutical research. ‘Organs-on-a-chip’ provide a new solution to this problem.


Mini-organs

‘Organ-on-a-chip’ is a technology in which cultivated organ cells are joined together on a small plastic plate. The chip contains tiny channels carrying liquids to and from these cells. Using advanced equipment, researchers can then perform all sorts of measurements, such as to see how the organ cells contract (as in the case of a piece of heart tissue), where inflammation reactions occur or what the effect is when medicines are applied to 

Organ-on-a-chip:  cultivated organ cells joined together on a small plastic plate

Organ-on-a-chip: cultivated organ cells joined together on a small plastic plate

them. Growing a piece of organ like this requires cells from either a patient or a healthy test subject. That could be either skin tissue or blood cells, for example. By adding four genes, these cells are transformed into stem cells, also called induced pluripotent stem cells (iPS). That means that these cells can grow into (almost) any desired type of cell type. LUMC has a special iPS facility to cultivate these types of stem cells. It is already possible to get the stem cells to grow into many different types of tissues, such as a fragment of blood vessel, kidney, heart, nerve or pancreas.

The role of blood vessels in dementia

‘Organs-on-a-chip have a great many advantages,’ says Leiden Professor Christine Mummery. ‘For example, in practice you often see people using a lot of different medications, which sometimes have a negative effect on each other. It used to be difficult to test all the different combinations. But with a chip with a thousand or so prints you can do that quite simply, in various series of concentrations.’

One of the ways Mummery uses the organ-on-a-chip technology is to study vascular dementia. She mainly looks at a hereditary variant of this condition, which is caused by a malfunction in the blood supply in the brain. Mummery explains: ‘We have used patient material to grow pieces of blood vessel in which we can see exactly what is going wrong. This made it immediately clear that this condition really is a blood vessel problem rather than a problem with the nerves. Unfortunately we can’t cure this disease, but what we can do is investigate whether there are medicines that we can give patients preventively in order to prevent or delay dementia.’ She can eventually also derive from these trials information relevant for patients with a non-hereditary form of this disease.

Find more information about pharmaceutical research in our research dossier Effective Drug Development.

Searching for disease indicators in healthy people

LUMC researchers are looking for factors that point to illness at an early stage.


Prevention is better than cure. In order to be able to predict who will become ill, LUMC researchers are looking for factors that point in this direction at an early stage. The Netherlands Epidemiology of Obesity (NEO) study is following nearly 7,000 overweight patients in order to identify predicting factors for the development of diabetes, cardiovascular disease, kidney failure, osteoarthritis and lung disease. The first research results were published recently.

Nearly half of the Dutch adult population falls within the overweight range. This is associated with health risks, including an increased risk of contracting diabetes and cardiovascular disease. It is unclear why some overweight people develop a chronic disease while others do not. This also makes timely intervention difficult in people who are at high risk, especially since they form such a substantial population.

Vials for blood extracted from test subjects.

Vials for blood extracted from test subjects.


‘We did what could not be done’

To investigate this further, the LUMC launched the Netherlands Epidemiology of Obesity (NEO) study in 2008 under the leadership of Professor Frits Rosendaal. In the first four years, Rosendaal and his colleagues examined nearly 7,000 patients from the Leiden region, most of whom fell within the overweight range (BMI of 27 or higher).

Rosendaal explains: ‘What was remarkable was that we examined these people in great detail. Usually, with such large groups, researchers only take blood samples and ask the subjects to complete some questionnaires. We carried out an extensive examination of each patient that took about four hours and included an MRI scan, a lung function test, a cardiogram and a nutritional test. Nothing like this had ever been done before. We did what could not be done.’ What is also remarkable is that these are healthy people whose entire health profile is being monitored, together with the potential development of any condition. ‘This is an investment that allows us to create a treasure trove of data,’ he says enthusiastically.

Life-long study

‘Ideally we would like to follow these people throughout their life. Last year we did a follow-up via the participants’ GPs to find out which ones had become ill. We may ask people to return for a more extensive examination at some point, but that depends on funding. We hope that we will also be able to observe the effects of changes over time.’


Fat around organs is worse

The study has been going for a number of years, so the first results are coming in. One of the discoveries is that our health depends on where exactly fat is stored: just under the skin or around the organs. The two look the same from the outside. ‘We can use the MRI scans to determine the

Some people store fat just under the skin, others deeper around the organs.

Some people store fat just under the skin, others deeper around the organs.

distribution of fat. It turns out that people with fat around their organs suffer more frequently from reduced insulin sensitivity, which is an early form of diabetes.’

New therapy

Ultimately, Rosendaal hopes to be able to establish many more such links. ‘Nearly all diseases occur more frequently in people who are overweight. This is not something that we really understand at this point. It looks as though all illnesses start out in the same way, and in this study we hope to discover whether this is indeed the case. This knowledge can then be used to develop new therapies and drugs.’

Experts

Scientists working in this research area

  • Prof dr. Douwe Atsma
  • Prof. dr. Wim Fibbe
  • Prof. dr. Christine Mummery
  • Prof. dr. Ton Rabelink
  • Prof. dr. Pieter Reitsma
  • Dr. Paul van der Boog

Prof dr. Douwe AtsmaProfessor of Cardiology

Topics: Cardiology, cardial cell therapy, cardiogenetics, heart, stem cells, stem cell therapy

+31 (0)71 52 6 12 73

Prof. dr. Wim FibbeProfessor of Hematology

Topics: Mesenchymal stem cells, Graft-versus-Host disease, stem cell transplant

+31 (0)71 52 6 3800

Prof. dr. Christine MummeryProfessor of Developmental Biology

Topics: Stem cells, heart and vascular disease, human heart cells, human vascular development, heart development

+31 (0)71 52 6 9301

Prof. dr. Ton RabelinkProfessor of Internal Medicine

Topics: Nefrology, vascular medicine, kidney transplant

+31 (0)71 52 6 2148

Prof. dr. Pieter ReitsmaProfessor of Experimental Molecular Medicine

Topics: Experimental Molecular Medicine, Coagulation, blood vessels, thrombosis, haemorrhage, heredity

+31 (0)71 52 6 6985

Dr. Paul van der BoogMedical specialist kidney diseases

Topics: Kidneys, transplantation of kidneys

+31 (0)71 526 2148

Education

Students learn directly from researchers

Regenerative medicine is a multi-faceted area of research that is developing at a staggering pace. Students can acquaint themselves with research in regenerative medicine through the ‘Transfusion Medicine’ and ‘Vascular Medicine’ minors. Here they receive broad-based training in the field of stem cell biology and its possible clinical applications. In lectures that are frequently organised for students, researchers give updates on the latest developments and show the challenges they come up against in their research.
The researchers concerned want to share their enthusiasm outside the university as well. For this reason they are also involved in the education of high school students. One of the ways they do this is by supervising them as they write their profile paper.

Ton Rabelink giving a lecture to students (Photo: Brigitte Wieles, LUMC) Ton Rabelink giving a lecture to students (Photo: Brigitte Wieles, LUMC)

Outreach & News

Science at the heart of society

Our research extends further than the academic world alone. Our researchers share their knowledge online, at events, in schools and museums, at companies and via accessible public symposiums. In this way they bring science into the heart of society.

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