Useful information about stem cells. Focusing on stem cells from the umbilical cord

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1 Useful information about stem cells Focusing on stem cells from the umbilical cord

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3 Useful information about stem cells Focusing on stem cells from the umbilical cord What is a stem cell?... 4 Categories of stem cells What are stem cells currently used for?... 9 How do stem cells work? The need for tissue compatibility Milestones in research and treatment Facts and figures on stem cells from the umbilical cord How do you get access to stem cells? Future prospects Challenges Private versus public? How is the area regulated? Glossary Notes and references Find out more

4 Stem cells an area of strong development Useful information about stem cells Focusing on stem cells from the umbilical cord 2 In recent years much has been spoken and written about stem cells. We now know that many diseases are linked to damaged or defective cells, tissue and organs, and that stem cells have the potential to cure a variety of diseases. Each month publications appear with results of new research and treatment. We often hear about people who travel the world in the anticipation that stem cell treatment may save them from an incurable disease, and we are continuously following the many clinical trials and the results achieved. Many of these trials are conducted at university hospitals throughout the world. Also in Denmark, research within the field of stem cells has intensified in recent years. Thus, the national stem cell centre, DanStem, was established in 2010, and in recent years several major projects are underway to examine the possibility of using stem cells to treat a variety of diseases. Rigshospitalet (Copenhagen University Hospital) has e.g. conducted several studies where stem cells have been used to treat patients with heart problems. These trials have shown to produce positive results, and currently the first trials are being followed up by new trials on patients with various forms of heart disease. In Denmark, developments will steadily increase within several

5 fields of diseases over the coming years. In recent years there is a growing interest in using stem cells from umbilical cord blood. Umbilical cord blood is the blood that remains in the placenta/afterbirth, when the umbilical cord has been cut. If you are expecting a baby, you have particular reasons to be interested in the subject, because it is during pregnancy that you have to decide whether you wish to store the stem cells from your baby s umbilical cord. In the USA, it has been possible to store stem cells from umbilical cord blood in private cord blood banks since 1992, in Europe since 1997 and in Denmark since In 24 states in the USA it is required by law to inform pregnant women of the possibility to get umbilical stem cells deepfrozen. 1 This information will hopefully be required or more common here in Denmark, but currently, it is up to individual parents to familiarise themselves with this subject. The stem cell field is constantly evolving and is complicated to grasp. Hopefully, with this booklet, we will be able to increase the overview of the vast area that stem cells include. Magnification of human mesenchymal stem cells that express GFP (Green Fluorescent Protein). 3

6 What is a stem cell? Bone cells Heart cells muscel cells Stem cell Mesenchymal stem cell Nerve cells Red blood cells Immune system cells White blood cells Blood stem cell Useful information about stem cells Focusing on stem cells from the umbilical cord 4 Cells are the smallest living component of an individual, and the cells are specialised in relation to the tissue they are in. There are a total of 200 different cell types in the body. Our bones contain e.g., cells, which are capable forming new bone tissue, whilst in the heart there are cells capable of repairing narrowed blood vessels, defective heart muscles, or normalise a heart that is out of rhythm, to again beat regularly. Furthermore, in the body, we have stem cells, which are capable of repairing disorders arising in the brain and in nerve tissue, as well as stem cells for building up other tissue and organ parts in the body. Common for all the specialised cells of the body is that all originate from a single cell type: The stem cell. Stem cells are immature cells that can replicate themselves and have the potential to develop into any cell of the body. In other words, stem cells are the body s ultimate producer of building blocks. They are found in early embryos (embryonic stem cells, ESC), in tissue and organs from the newborn, in the placenta and in the umbilical cord, as well as in young people and adults (has been identified in many types of tissue or organs in the body, such as bone marrow, muscle tissue and fatty tissue). Stem cells comprise irrespective of the source of the stem cell mainly two types: Blood-forming stem cells (hæmatopoietic stem cells, HSC) and mesenchymal stem cells (MSC). When stem cells mature, they develop into several types of specialised cells of which the body is composed, e.g. blood cells, nerve cells, liver cells, muscle cells, etc.

7 Categories of stem cells pluripotent stem cells 8 days after fertilisation The inner cell mass is isolated in the laboratory Stem cells are found in: 1. The early embryo (embryonic stem cells) 2. Fully developed organs in children and adults (adult stem cells) 3. Umbilical cord blood (umbilical cord stem cells) Embryonic stem cells Stem cells taken from fertilised eggs are grown in small bowls in the laboratory. Embryonic stem cells Stem cells from fertilised eggs are unique, as they are pluripotent and therefore, in principle, capable of differentiating into any of the cell types of the body. The cell mass, which is created when the fertilised egg begins to divide is called an embryo (or embryos). The embryo gives rise to all the cells of the body and to the placenta and the amniotic membrane that protects and nourishes the baby in the uterus. Embryonic stem cells have been removed from the fertilised egg 8 days after fertilisation and as the removal of embryonic stem cells thus involves the destruction of embryos, research in and practical use of embryonic stem cells is an ethical problematic area. In Denmark scientists are only permitted to carry out research on the fertilised eggs left over to be discarded in connection with in-vitro fertilisation. No clinical trials have been conducted with these cells, and a possible option for routine treatment based on embryonic stem cells is actually far away. It has further been found that human embryonic stem cells in long-term storage as well as in connection with freezing and defrosting can develop abnormalities, which potentially could change into unwanted and atypical cell types such as e.g. cancer cells. 2 5

8 Removal of stem cells from bone marrow requires surgical intervention. Bone marrow Stem cells Useful information about stem cells Focusing on stem cells from the umbilical cord Adult stem cells Adult stem cells are further advanced in their development than embryonic stem cells and have more limited development potential (multipotent stem cells). Adult stem cells are found in virtually all types of tissue, such as muscles, fat, the brain, teeth and heart. In addition, there are stem cells in the bone marrow itself, and they are used routinely in conjunction with bone marrow transplants. Bone-marrow stem cells can be divided into two stem cell types, blood-forming stem cells and mesenchymal stem cells. Blood-forming stem cells can turn into all types of blood cells and can be used e.g. in connection with treatment of blood-related diseases such as leukaemia (blood cancer) while the mesenchymal stem cells can be used for regenerative treatments. Mesenchymal stem cells may actually develop into a number of different specialised cell types, such as heart cells, bone cells, nerve cells and blood vessel cells. It is expected that mesenchymal stem cells (regardless of source) within a few years will be used to treat a variety of common diseases such as arthritis and rheumatism, bone formation, heart and brain disorders. 3,4,5 6

9 Mesenchymal stem cells Isolation of stem cells Blood stem cells Stem cells are removed from the umbilical cord immediately after the birth without any risk to child or mother. Stem cells from umbilical cord blood Blood from the umbilical cord and placenta contains stem cells, which are readily available and are usually discarded as waste when placenta and umbilical cord are discarded after the birth. These stem cells are the earliest that can be collected without damaging the foetus. The stem cells in umbilical cord blood, like the stem cells present in the bone marrow, can be divided into two types: Blood-forming stem cells and mesenchymal stem cells. Research indicates that there are several differences between the two types of stem cells in the umbilical cord, and those found in the bone marrow. For example, it has been shown that stem cells from umbilical cord blood can develop into more types of cells than adult stem cells. This is believed to be due to the fact that stem cells from cord blood are younger, more immature and undifferentiated than stem cells obtained from the bone marrow of an adult patient 6, as the stem cells in general age together with the body they are in, and due to exposure to the environment. Stem cells from umbilical cord blood are accepted far more easily by the body s immune system than stem cells from bone marrow 7. It is important if a patient is to be treated with stem cells from a donor who is a stranger or unrelated to the patient (recipient) (i.e. in connection with allogeneic not unrelated transplant treatment). Umbilical cord stem cells are considered to be zero years old and will continue to be, if they are collected at birth and frozen for long-term storage. 8 In recent years, researchers have successfully returned mature adult cells to the stem cells, from which they were developed (reprogramming). However, 7

10 such induced pluripotent stem cells (ips) in studies with mice showed a tendency to develop into cancer cells following transplantation. Facts about the different categories of stem cells Embryonic stem cells Stem cells from umbilical cord blood Adult stem cells Where are they found? Taken from fertilised eggs (surplus from invitro fertilisation). Taken from the umbilical cord Found in different types of tissue in children and adults Useful information about stem cells Focusing on stem cells from the umbilical cord For what diseases are they used or tested? What are the main characteristics? Until 2011 there have been no treatments with embryonic stem cells as it has been shown that embryonic stem cells are not well controlled and can cause cancer after transplantation into experimental mice Embryonic stem cells are taken from fertilised eggs and are therefore difficult to access. These cells are associated with ethical issues. Donor stem cells from Adult stem cells umbilical cord blood have, since 1960, been are used today as used in bone marrow standard for the treatment of leukaemia tion, adult stem cells transplants. In addi- (blood cancer). are tested in clinical In addition, they are trials for a number tested in clinical of illnesses like heart trials for a variety of disease, arthritis and diseases, such as certain disorders of diabetes, cerebral the immune system. palsy and heart disease Stem cells from the Stem cells taken from umbilical cord are adults have been an easily accessible through a lifetime of source. They have physical and chemical the same therapeutic impact, therefore, potential as adult their therapeutic stem cells and are potential may be better accepted by altered the body s immune system than stem cells from bone marrow 8

11 What are stem cells currently used for? Stem cell treatment is not a new concept. Blood-forming stem cells from bone On the left, a normal vein and on the right an artificial vein made from stem cells. marrow have, for several decades been standard treatment for e.g. leukaemia (blood cancer). Blood-forming stem cells and mesenchymal stem cells from the umbilical cord, peripheral blood 9 and bone marrow are currently used for the treatment of 79 different diseases including aplastic anaemia, Fanconi anaemia, sickle cell anaemia, Thalassaemia and congenital defects in the metabolic system. 10 For the treatment of certain diseases, own stem cells (autologous stem cells) are used, for others, stem cells from a donor (allogenous stem cells) are used. Own (autologous) stem cells can be used for diseases that are not hereditary The majority of all the umbilical cord stem cells are used today for the treatment of leukaemia In most cases umbilical cord stem cells will be used from siblings or from a stranger with a tissue type, suitable for the patient to be treated. 11 A vast number of studies are attempting to determine whether adult mesenchymal stem cells can be used to treat cardiovascular diseases. So far, the results have been promising, and it is expected that the stem cells from umbilical cord blood in these treatments are at least as effective as the adult stem cells. The latest research suggests that stem cells are able to mitigate adverse immune reactions in the body. If an organ or part of an organ is damaged due to disease, wear and tear or accidents, the stem cells can thus be recruited to the damaged areas and restore normal function. It is this property that is exploited in so-called regenerative medicine, and it is at least, in this area that researchers expect stem cells to have great therapeutic potential. 9

12 In recent years, several milestones have been reached in the field of regenerative medicine. For example, in the fall of 2008, a 30-year-old Colombian woman had a windpipe surgically implanted, that had been built using her own stem cells. 12 In February 2010, a 36-year-old Danish sclerosis patient in Costa Rica received stem cell treatment with own and donated stem cells and in 2010 at Rigshospitalet (Copenhagen University Hospital), consultant Jens Kastrup launched a clinical trial with stem cells from fatty tissue for the treatment of heart conditions. In Denmark, at Rigshospitalet, a number of clinical trials have been conducted, in which stem cells are tested for the treatment of various types of heart disease. These first trials have produced positive results, and further trials are currently underway. 13 See examples of milestones in research and stem cell therapy on page 16. Værd at vide om stamceller Med fokus på stamceller fra navlesnoren 10

13 Several treatments with stem cells from umbilical cord blood The first successful transplant of stem cells from umbilical cord blood took place in France in 1988, when a boy was cured of a serious blood disease (Fanconi anaemia) through his sister s umbilical cord stem cells. 14,15 Stem cells from umbilical cord blood are tested for treatment of a variety of diseases in addition to blood diseases. So far, e.g. own mesenchymal umbilical cord stem cells have been used for (autologous) treatment of children with type 1 diabetes, with promising results 16. Furthermore, researchers have been using own (also called autologout) mesenchymal umbilical cord stem cells to treat children with neurological disorders including at least 124 children with cerebral palsy (spastic paralysis). 17 The University of Texas Health Science Center in Houston, Texas, has also started using autologous umbilical stem cell treatment of children, who have suffered severe brain damage at birth or in early childhood. 18 Recent research also points out that stem cells from umbilical cord blood can be used in the treatment of certain brain injuries. 19 By the end of 2012, there were more than 30,000 umbilical cord stem cell transplants on sick children and adults. 20 According to researchers, we have only seen the tip of the iceberg, and the future potential in the use of stem cells will probably be in the area of regenerative treatment, such as the treatment of cardiovascular diseases, osteoarthritis and type 1 diabetes and neurological diseases. It is precisely this potential that has been investigated during these years in major clinical studies in which stem cells from several sources have been tested on a number of trial subjects. The number of treatments with stem cells from umbilical cord blood is increasing exponentially 21, and during the first half of 2009, the number of treatments with umbilical cord stem cells exceeded the number of treatments with bone marrow stem cells in the USA for the first time. 22 Many researchers agree that in future, different sources of stem cells will be used depending on the disease to be treated. Bone marrow transplants Bone marrow transplants are the oldest and best-known form of stem cell treatment The first bone marrow transplant was performed between identical twins and carried out by Dr E Donnall Thomas in Cooperstown, New York, towards the end of the 1950s. 11

14 6.000 Number of bone marrow transplants broken down by cell type Number of transplants broken down by stem cell source during the period Bone marrow Peripheral blood cells Umbilical cord blood Useful information about stem cells Focusing on stem cells from the umbilical cord 12 In the 1960s researchers developed techniques for determining tissue types. The tissue type testing, often referred to as HLA (Human Leukocyte Antigen) testing, determines whether there is genetic identity, a close genetic identity or non-genetic identity (non matching identity) between individual s white blood cells. The possibility of determining tissue typing resulted in unrelated bone marrow donors cells now being used for the treatment of severe e.g. serious blood disorders. In a bone marrow transplant, a healthy person (donor) donates his or her bone marrow to a person with a serious blood disease such as leukaemia. The infusion of the bone marrow cells is a relatively simple procedure, which in practice is carried out like any blood transfusion. Today, blood-forming stem cells from both bone marrow and umbilical cord blood, are used for the treatment of several different types of leukaemia and lymphoma types (blood cancer types). Stem cells from umbilical cord blood are therefore now used as standard treatment in line with bone marrow transplants for leukaemia. 23 The two sources of stem cells complement each other. Stem cells from umbilical cord blood have some advantages as mentioned earlier. However, more stem cells can be harvested from the bone marrow of an adult.

15 How do stem cells work? The precise mechanism behind the healing effect of stem cells (regardless of the source of the stem cells) is currently unknown, but studies show that stem cells have the ability to repair damaged tissue, replace dead cells, regenerate muscle tissue, and even improve the function of entire organs. In addition, it has been shown that certain stem cells called TREG cells in some cases are immunosuppressive and reduce the risk of GVHD (graft-versus -host disease). 24 Stem cells are programmed and influenced by a number of complex systems, which means that they can identify the areas where they are needed and for which they are predestined to work. This is called homing. For example, haematopoietic ( blood stem cells ) cell s fate depends entirely on the homing process working as it should, so that the stem cells can find their way or rebuild a bone marrow. When the stem cells have reached their destination in the body (homing), transforming themselves by coding of the types of blood cells, there is a need for the development and progression of a mechanism, which cannot yet be explained. Mesenchymal stem cells are also passed on to the areas in the organism which, depending on their pre-programming, can adapt to. These cells transform into cartilage cells, muscle cells, bone cells, nerve cells, depending upon where they are needed. Often, mesenchymal cells need to be helped on their way to areas where there is a special need for them to undertake homing. This can be done either by the action of hormones or cytokines, which could change or influence the encoding of the cell and thereby direct the cell to the right place Stem cells therefore have a unique ability to adapt when the cells have first found their homing. But before this homing, a complicated process of encoding the cells is undertaken, so that they accept the new surroundings and understand the mission they have to complete and how they have to adapt in relation to the neighbouring cells they are brought together with. 13

16 The need for tissue compatibility For a stem cell transplant to be successful there must be some degree of tissue compatibility between the stem cells from the donor and the transplant patient. Donor and recipient have some proteins on the cell surfaces, which should be similar to each other they must be tissue compatible. If they are different, the recipient will reject, i.e. kill the transplanted cells (Host versus graft rejection). Even more serious is the fact that the transplanted donor cells can attack the recipient body (called Graft versus Host Rejection, GVHR). However, there are cases where a weak GVHR is produced in order to kill the patient s leukaemia cells. Tissue compatibility is determined by carrying out tissue typing of donor and patient respectively (HLA-typing). A match of 6 out of 6 or 8 out of 8 HLAantigens is aimed for in transplants with umbilical cord blood and bone marrow respectively. Rejection is one of the riskiest side effects of non-compatible tissue types, and even less or almost negligible variations between bone marrow donor and patient can cause rejection, which could mean a risky situation for the patient. When it is the person s own umbilical cord blood, which is used later in life, to form new cartilage in a knee, there is of course no incompatibility and therefore never a rejection issue. There is a 25 % chance that siblings with the same biological parents match each other 100% who thus can make use of each other s stem cells. Stem cells from umbilical cord blood can be used in % tissue type matches corresponding to an HLA match of 4/6 6/6. 25 Of course, the highest possible match is aimed for in each individual treatment 14

17 For various reasons bone marrow stem cells are more difficult to reconcile with patients than stem cells from umbilical cord blood, which are generally better tolerated. 26 It is believed that the reason for this better tolerance is that there are differences in Natural Killer Cells and their degree of maturation. The adult Natural Killer cell, along with other immune cells, (HLA differences) in fact helps to increase the risk of the Graft versus Host reaction. In addition, there are physical and biochemical differences in the outer membranes of stem cells from umbilical cord blood and bone marrow, which imply that there is no need for strict HLA compatibility, when the stem cells from umbilical cord blood are used for transplants. Other factors affecting the effect of a stem cell transplant The effect of a transplant depends furthermore, on tissue compatibility of the cell count (TNC, nucleated cells and CD34+ stem cells), CFU (Colony Forming Unit), stage of the disease and to a lesser extent on the blood type (AB0). The most recent treatment results show that the optimally successful transplant is achieved at a minimum nucleated cells and CD34+ cells per kg of body weight. 27 The parameters typically looked for determining whether a treatment has been successful, are engraftment (which is a measure of how well the transplanted cells grow: The more cells, the better engraftment, relapse, survival, DFS (disease-free survival), GVHD (Graft-versus-host-disease) and development of viral infection such as infection with CMV (Cytomegalovirus). It is against these parameters we have estimated that stem cell transplants with umbilical cord blood are often more successful than bone marrow transplants

18 Milestones in research and treatment Stem cell research groups around the world deal typically with pluripotent stem cells (ips and embryonic) and/or adult stem cells (mesenchymal and blood forming stem cells) and to a lesser but increasing degree, with umbilical cord stem cells. In Denmark, the research is primarily focused on adult stem cells. Useful information about stem cells Focusing on stem cells from the umbilical cord In Denmark, there is no significant commercial activity within the area of stem cell therapy, and there are no actual stem cell based products in the pipeline. Of commercial companies in Sweden and the UK there is far greater commercial activity in this area, mainly due to a more liberal approach to research in embryonic stem cells. In Denmark it is estimated that around DKK 220 million is to be allocated from the official Danish side for research including DKK 65 million to the Danish Stem Cell Center (DanStem), which is a new stem cell centre at the University of Copenhagen. Furthermore, EU funds attracted by Danish research groups, as well as US funds are primarily given to the Hagedorn Research Institute (Novo Nordisk). The vast majority of funds in Denmark are used for projects that have focused on adult stem cells. 16

19 Number of treatments with umbilical cord blood rises to over 30,000. The Nobel Prize in Physiology and Medicine 2012 Professor Shinya Yamanaka for the discovery of ips technology The number of transplants with umbilical cord blood exceeds the number of bone marrow transplants in the USA First danish private umbilical cord blood bank is established President Georg Bush forbids research into embryonic stem cells In the USA the first official umbilical cord stem cell bank (New York Blood Center). The 1960s Stem cells in bone marrow used in the form of bone marrow transplants for treatment of blood cancer First patient with blood cancer succesfully treated with amplified stemcells from the cord blood. New statement from Rigshospitalet shows that until now 32 patients have been treated with stem cells from umbilical cord blood The Health Minister, Astrid Kragh, gives the green light for the establishment of a public stem cell bank in Denmark The number of transplants with umbilical cord blood exceeds 21,000. Rigshospitalet treats two blood cancer patients with stem cells from umbilical cord blood. Danish National Stem Cell Centre (Danstem) established. Around 2002 Stem cells to treat heart conditions show positive results Embryonic stem cells discovered First treatment with stem cells from umbilical cord blood (Dr Gluckman). 17

20 Facts and figures on stem cells from the umbilical cord Useful information about stem cells Focusing on stem cells from the umbilical cord 18 How many are treated with stem cells from the umbilical cord? The possibility of storing umbilical cord stem cells from newborn children has existed in the USA since 1992 and in Denmark since 2002 By the end of 2012 there were more than 30,000 umbilical cord stem celltransplants on both children and adults. 29 According to researchers, we have only seen the tip of the iceberg, and the potential in the use of stem cells lies mainly in the regenerative treatment area, where it is the mesenchymal stem cells that apply. In the first half of 2010 in the USA, the number of treatments with umbilical cord stem cells exceeded the number of treatments with bone marrow stem cells for the first time. 30 The increase is linked to the fact that stem cells from umbilical cord blood can change to several more types of cells than adult stem cells, that stem cells from umbilical cord blood are more readily accepted by the body s immune system than stem cells from bone marrow, and that globally, more and more umbilical cord portions are available in public and private stem cell banks. How many stem cell portions are stored in public and private stem cell banks? The 158 private and public umbilical cord banks registered worldwide, today store around 646,000 umbilical cord portions, and the number is rising. Of these, 30,000 umbilical cord portions have been released for transplant purposes as of December

21 What is the probability of needing stem cell treatment? According to US researchers, in future there will be an urgent need for stem cells to treat disease. The American doctor and researcher Marcelo C Pasquini has estimated the probability of requiring stem cell treatment in the future. 32 The calculation is based on the likelihood of a child suffering from a disease that already in 2005 could be treated with stem cells from the umbilical cord. Since then, several more treatments have come about, and this trend will continue. Even today, the likelihood that you will need stem cell treatment is thus greater than these figures indicate. The need for transplants with own stem cells The need for transplants with own or a relative s stem cells Within 20 years 1 in 5,000 1 in 1,700 Within 50 years 1 in 1,100 1 in 450 Within 70 years 1 in in 220 Lifetime 1 in in

22 Useful information about stem cells Focusing on stem cells from the umbilical cord

23 How do you get access to stem cells? Adult stem cells Should the need occur to use stem cells from e.g. siblings to treat a sick brother or sister, these can be provided by minor surgical intervention into the bone marrow, if you don t have your children s umbilical cord stem cells available. Children as young as one-year of age are used today on donors for treatment of a sibling s leukaemia. Current practice is criticised, however, by the Ethical Council and the Council for Children, because a donor must always be able to understand and agree with and give personal consent to donation, as even a minor intervention will always be associated with some risk of complications for the donor. If you have no siblings, or your stem tissue is not compatible with your sibling s, doctors will instead try to find a tissue compatible stem cell donor in international public registers. Collection of stem cells from the umbilical cord Collection of stem cells from the umbilical cord always requires the consent of the newborn child s mother and should the collected stem cells be required for the newborn child s possible own use or use within the family, an agreement should be reached prior to the birth with a private stem cell bank. As soon as the child is born and the umbilical cord cut, the umbilical cord blood from the newborn child is collected. The collection involves no risk to mother or child and is completely painless. 21

24 Useful information about stem cells Focusing on stem cells from the umbilical cord Subsequently, the collected umbilical cord blood will be laboratory processed so that the umbilical cord stem cells can be isolated, analysed and checked. It is then frozen to minus 196 degrees. There is a maximum of 48 hours from the time of birth, to the freezing being a reality. This ensures the maintenance of stem cell characteristics and quality. 22

25 Future prospects It is generally agreed among researchers that the various sources of stem cells could, in the future, may be used for regenerative treatment of diseases such as e.g. spastic paralysis (cerebral palsy), traumatic brain injury, multiple sclerosis, Parkinson s disease, Alzheimer s, Lou Gehrig s disease (amyotrophic lateral sclerosis (ALS)), cardiovascular disease, osteoporosis, diabetes etc. There are currently many clinical trials underway with mesenchymal stem cells,where patients with heart conditions, diabetes, arthritis and nerve disorders are treated. The results from these studies will be of great importance for the future use of mesenchymal stem cells from both bone marrow and umbilical cord blood. The results of many of these trials are currently very promising. 33 Examples: Clinical trials with injection of autologous (i.e. the patient s own) umbilical cord stem cells in young people with type 1 diabetes, where the first results were published in Clinical trials with umbilical stem cells for the treatment of children with neurological disorders including at least 124 children with spastic paralysis (cerebral palsy). 35 Clinical trial at e.g. Rigshospitalet with stem cells from fatty tissue for the treatment of heart conditions. Experimental studies, with positive results through the use of mesenchymal stem cells for the regeneration of a damaged heart muscle following a heart attack

26 Researchers e.g. from the University of Wisconsin - Madison have found evidence that stem cells could replace vital nerve cells in connection with brain damage, and animal studies have shown that treatment with own stem cells can repair seriously damaged brain tissue after a stroke or brain haemorrhage. As a whole, there is evidence that brain diseases could be treated with stem cells, and especially with the patient s own stem cells. 37 Furthermore, stem cells will continue to be used for transplants, e.g. in connection with the treatment of blood disorders such as leukaemia. There are diseases where the supply of stem cells can be lifesaving. In regards to whether stem cells may also have an effect on the body s normal ageing is not know, but it is one of the exciting new prospects under investigation Useful information about stem cells Focusing on stem cells from the umbilical cord 24

27 Challenges Although research has come a long way, and stem cells are already currently being used for the treatment of various diseases, there is still some distance before stem cell treatments will be included as standard in the future routine treatment of serious illnesses. Firstly, there are still too few cells stored to make it possible, publicly, to provide stem cell treatment in general. In order to be able to use stem cells for the treatment of a patient, it must be possible to have sufficient knowledge to the cell tissue with the patient who is to be treated. There are many different tissue types. Some tissue types are more frequent than others, and researchers estimate that a public umbilical cord stem cell bank in Denmark over 3-5 years should be able to collect and store stem cell portions, which should be linked to the international stem cell register NMDP 38 and Netcord. 39 This would ensure that part of the population could be treated with partial matching stem cells for the treatment of e.g. blood disorders, such as acute leukaemia. Theoretically, the stem cell bank will need at its disposal, over 50,000 different stem cell portions to guarantee 80 % of the population at least one tissue compatible donor portion 40, because in relation to international registers there is more likelihood of finding a tissue compatible donor in a 25

28 Useful information about stem cells Focusing on stem cells from the umbilical cord national bank. This is because the tissue types are more closely compatible at national than at international level, where there are major differences in tissue types between the peoples of e.g. the Nordic region, Central Europe, Eastern Europe, the Mediterranean area, Russia, Asia etc. Therefore, if there is a need to find tissue compatible stem cell donors among the more than 500,000 umbilical cord stem cell portions that are registered in international official stem cell banks, a period of 12 monthsit would be possibly used to identify a tissue compatible stem cells for 80 % of the people needing a bone marrow donor. Secondly, there are still relatively few doctors who are able to utilize stem cells for therapeutic use, and finally, there remains the task of targeting each stem cell s individual coding, in order to be able to treat diseases that affect the entire body, e.g. diabetes and arthritis and brain disorders. Considerable research is being undertaken as to what rendering a stem cell development into a specialised cell type, and many of these mechanisms have already been identified Researchers are also working on finding the optimal stem cell sources for specific treatment of diseases, and there is every indication that in the future, different stem cell sources may be used depending on the disease being treated. 26

29 Molecules Blood stem cell Propagation of own stem cells from the umbilical cord If you have saved your own umbilical cord stem cells, you and in many cases also your siblings are ensured access to tissue compatible stem cells, if you suffer from an illness that cannot be treated with foreign non-allogeneic stem cells. The best results are achieved through treatments with many stem cells. The number of stem cells found in a single umbilical cord portion is, however, limited and in addition, the percentage of mesenchymal stem cells (MSC) with respect to haematopoietic stem cells (HSC) is relatively low There are several ways to try to increase the amount of stem cells for treatment, including the culturing methodology to expand a cell culture, which is under way, the use of two umbilical cord portions and propagation of certain stem cells, the methods which is researched thoroughly. Approved methods used for the propagation of mesenchymal stem cells, umbilical cord already currently being used, and it is therefore relatively straightforward to treat a patient s own mesenchymal stem cells with a sufficient number. 41 Propagation of haematopoietic stem cells is a lot more challenging but researchers around the world working in stem cell research these years are trying to find the most suitable methods for laboratory propagation of bloodforming stem cells. 42 Propagation of stem cells is achieved by adding molecules, which bind to specific growth receptors on the cell surface. 27

30 Private versus public? Useful information about stem cells Focusing on stem cells from the umbilical cord 28 In Denmark, in contrast to the USA, the UK and Germany, there is not yet a public stem cell bank for the storage of umbilical cord cells. When there is a need for stem cells for treatment in this country, the hospital therefore tries to find them in a public stem cell bank abroad unless one has access to his/her own stem cells, which can be used for the treatment. After 12 months, in 80 % of cases a matching stem cell donor will be found in the international, public stem cell banks. 43 Time is typically a critical factor, and therefore it may be problematic to wait for months before maybe finding matching donor stem cells Tissue compatibility is partly linked to ethnicity, so the challenge of finding a matching sample in official registers is bigger for children of parents with different ethnic background. Of course, there will also be people who fall outside the tissue type norm, even though the family may have always lived in Denmark. When Denmark gets a public stem cell bank, pregnant women will be faced with having to choose between keeping their own stem cells privately or donating to a public international stem cell register The crucial difference is that by donating umbilical cord blood to a public stem cell bank, you lose the ownership and thus right of disposal over the donated stem cells. Umbilical cord stem cells, held in a public register, are available to all with the same or suitably acceptable tissue type. A donor cannot expect that there will be umbilical cord stem cells with the right tissue type available if he or she should subsequently need them. If one can find tissue compatible donor stem cells in public registers, they will, in turn, be free of charge to the patient, since

31 the cost of acquiring stem cells from international registers is the government s responsibility. If you have had your own umbilical cord stem cells frozen, you have a guarantee of tissue compatibility and will therefore never have trouble finding a suitable donor should you fall ill and have an acute need for stem cell treatment with your own stem cells. At the same time siblings are often able to use each other s stem cells. Use of sibling stem cells will often be relevant in the treatment of e.g. hereditary diseases or blood disorders. Public Danish stem cell bank within reach Rigshospitalet has on several occasions applied for funding from the Danish Ministry of Health to establish a public health stem cell bank by 2010 at the latest. At the time, the application was rejected on the basis of cost-benefit considerations. Subsequently, both the Danish Health and Medicines Authority and the Ministry of Health changed position regarding the need for the establishment of a public stem cell bank for umbilical cord stem cells in Denmark A change in attitude came alongside Rigshospitalet s publication in January 2012, to introduce transplants with umbilical cord stem cells from strangers as standard treatment for seriously ill leukaemia patients. 29

32 Useful information about stem cells Focusing on stem cells from the umbilical cord 30 This announcement was a quantum leap in the area of treatment in Denmark and an indirect endorsement of umbilical cord stem cells. 44 The therapeutic benefits of transplantation of umbilical cord stem cells had the result in April, that the Health Minister following consultation with the Danish Health and Medicines Authority gave the green light for the establishment of a public stem cell bank in Denmark. The minister stated, however, at the same time, that the government is currently unable to participate in the funding. On the other hand, the regions are now free to establish a public stem cell bank, if funding can take place within the existing financial frameworks. The minister s and the Danish Health and Medicines Authority s position, the current potential and the fact that the scientific community is generally in agreement that leukaemia is only the first in a series of diseases that in the future it will be possible to treat with stem cells from the umbilical cord, indicates that within the foreseeable future Denmark will have a public umbilical cord stem cell bank. Thus, an important step has been taken in the race to close the gap between Denmark and other EU countries in the field.

33 How is the area regulated? In Denmark, private and public companies, institutions or organisations that deal with human tissue and cells for use in human treatment are subject to the Danish Tissue Act from The Danish Tissue Act with associated regulations and guidelines is an implementation of a European directive from Tissue centres - including stem cell banks - are accredited by the Danish Medicines Agency, which together with the Danish Health and Medicines Authority enforces the Danish Tissue Act, issues licenses and attends inspections Biobanks with living biological material, including stem cell banks must also have the Data Protection Agency s permission to record sensitive personal information, and finally, private stem cell banks are governed by the Danish Health and Medicines Authority s regulations and monitoring as regards the collection procedure as well as information and marketing. 31

34 Glossary Adult stem cells. Stem cells obtained from the fully developed body, e.g. bone marrow or fatty tissue. FDA. Stands for Food and Drug Administration and is the USA s federal food and drug regulatory authority. 32 Allogeneic stem cell treatment. Involves the use of stem cells from persons other than the person undergoing treatment. Autologous stem cell treatment. Involves use of own stem cells. Blood-forming stem cells (Hæmatopoietic). Develop into blood cells. Are used primarily in the treatment of leukaemia and genetic diseases that affect blood cells. Donor: A giver (as opposed to a recipient). Clinical use / trial. When something is clinical it means that it is used for treatment purposes. When the research is applied to a patient,and thus the treatment is tested on patients, it is called a clinical trial. If the treatment is tested on animals, it is called a pre-clinical trial. Embryonic stem cells (ESC). Stem cells from embryos, i.e. from fertilised eggs. These stem cells are pluripotent.. GVHR/GVHD (Graf-versus-hostrejection/disease). Is a frequent and serious complication, that occurs primarily as a result of HLA mismatch and the cause of significant mortality following a transplant. Hæmatopoietic stem cells (HSC). See Blood-forming stem cells. HLA. Stands for Human leukocyte antigen, used in connection with the investigation of whether there is a hereditary identity, near hereditary identity or non-hereditary identity between individuals white blood cells. Immunostimulatory potential. When something is able to influence the immune system in a positive manner. Immunosuppression. Immunosuppressivetreatment, inhibition of the immune system s reactions, e.g. such as treatment of autoimmunity and chronic inflammatory diseases or in connection with a transplant to prevent rejection of the transplanted organ Immunosuppression takes

35 place either in the form of radiation or most commonly in treatment with immunosuppressive drugs. Regenerative medicine. Building damaged tissue and thereby curing the underlying disease. ips: Induced pluripotent stem cells General adult cells (somatic), that in the laboratory, are genetically programmed to embryonic-like stem cells. Mesenchymal stem cells. Can develop into many types of cells. They are mainly used for regenerative medicine (see below) and also show positive results in the treatment of e.g. diabetes and some neurological diseases. Multipotent stem cells. Can develop into many types of cells. Some multipotent stem cells are responsible e.g. for the formation of skin or other tissue. Rejection. When transplanting cells and organs it is important that the donor has the same tissue type as the recipient. Otherwise, rejection will occur, either by the recipient s immune system rejecting the transplanted stem cells, or by the actual transplanted stem cells causing rejection by the recipient (GVHD, Graf-versus-host-disease). The latter is seen in some cases in the transplanting of bone marrow in patients undergoing treatment for leukaemia (blood cancer) When using own stem cells rejection will never occur. Tissue compatibility. See under rejection. Placenta. Afterbirth. Pluripotent stem cells. Can differentiate into any cell type in the body. Recipient. The receiver (as opposed to donor). 33

36 Notes and references 1. Source: Cord Blood Europe, April Source: Cowan CA, et al New Engl J Med, Kilde: Kim SJ et al : A multi-center, randomized, clinical study to compare the effect and safety of autologous cultured osterblast (Ossron) injection to treat fractures BMC Musculoskelet Disord, 2009;10: Source: Hare JM et al, A randomized, double-blind, placebocontrolled, doseescalation study of intravenous adult human mesenchymal stem cells (Prochymal) after acute myocardial infarction, J AM Coll Cardiol 2009;54: Source: Cowan CA, Klimanskaya I, Mc- Mahon J, Atienza BS, Witmyer J, Zucker J, Wang S, Morton CC, McMahon A, Powers D, Melton DA, Derivation of Embryonic Stem-Cell Lines from Human Blastocysts New Engl J Med 2004, 350: Source: Malgieri A: Bone marrow and umbilical cord blood human mesenchymal stem cells; state of the art Int J Clin Exp Med Source: Verneris MR, Miller JS, The Phenotypic and Functional Characteristics of Umbilical Cord Blood and Peripheral Blood Natural Killer Cells, Br J Haematol 2009 October; 147(2): Source: Hal E. Broxmeyer, Edward F. Srour, Giao Hangoc, Scott Cooper, Stacie A. Anderson and David M. Brodine: Highefficiency recovery of functional hematopoietic progenitor and stem cells from human cord blood cryopreserved for 15 years. PNAS January 21, 2003, vol.100, no.2, In addition to stem cells from umbilical cord blood and bone marrow, which are the two sources most frequently referred to, there is a third source of stem cells, where the injection of growth factors mobilising stem cells from the bone marrow into the bloodstream, after which the blood is collected, and the stem cells are discarded. Stem cells from peripheral blood are the most common source of transplants today, but as the stem cells originate in the bone marrow, for the purposes of this booklet, the differentiation will only be between the umbilical cord and the bone marrow. 10. Source: Parentsguidecordblood.org 11. Source: Presidential Session at ASH 2010 devoted to Cord Blood : Presented by Professor Eliane Gluckman 12. Source: Macchiarini P et al ; Clinical transplantation of a tissue-engineered airway, Lancet 2008 Dec 3;372(9655): Source: Kastrup J et al : Mesenchymal stromal cells for Cardiovascular repair: current status and future challenges, Future Cardiol 2009;5: Source: Gluckman E et al : Hematopoietic reconstitution in a patient with Fanconi s anemia by means of umbilical-cord blood from an HLA-identical sibling N Engl J Med 1989;321: Source: Wagner JE and E Gluckman: Umbilical Cord Blood Transplantation: The first 20 Years, Semin Hematol 47: Source: Diabetes Care 32(11): samt Klinik fur Kinder und Jugend Medizin, Technical University, Munich. 34

37 17. Source: A Randomized Umbilical Cord Blood Reinfusion in Children with Cerebral Palsy, June 2010, Duke University Medical Center; Principal Investigator Joanne Kurtzberg. 18. Source: Cox CS Jr Et al : Autologous Bone Marrow Mononuclear Cell Therapy for Severe Traumatic Brain Injury in Children Neurosurgery, 2010 [Epub ahead of print]. 19. Source: Arien-Zakay et al : Human Umbilical Cord Blood Stem Cells: Rational for Use as a Neuroprotectant in Ischemic Brain Disease, Int J Mol Sci Source: Broxmeyer HE Cord blood hematopoetic stem cell transplantation StemBOOK Cambridge, Source: Gluckman et al, Hematopoietic reconstitution in a patient with Fanconi s anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med Oct 26;321(17): Source: Broxmeyer HE Cord blood hematopoetic stem cell transplantation, StemBOOK Cambridge, 2010 and Broxmeyer HE: Cord blood hematopoetic stem cell transplantation StemBOOK Cambridge, Source: Broxmeyer HE Cord blood hematopoetic stem cell transplantation StemBOOK Cambridge, Source: Review in: Stem Cells: Sources, Therapies and the Dental Professional, Jeremy J, Source: Rewied in Wagner JE and E Gluckman, Umbilical Cord Blood Transplantation: The first 20 Years, Semin Hematol 47: Source: Verneris MR, Miller JS, The Phenotypic and Functional Characteristics of Umbilical Cord Blood and Peripheral Blood Natural Killer Cells, Br J Haematol 2009 October; 147(2): Source: World Cord Blood Congress in Marseilles, France, 4 7 November Source: Broxmeyer HE Cord blood hematopoetic stem cell transplantation StemBOOK Cambridge, Source: Broxmeyer HE Cord blood hematopoetic stem cell transplantation StemBOOK Cambridge, Source: C Navarrete in connection with World Cord Blood Congress, in Marseilles, France, 4 7 November Ballen, Gluckman, Broxmeyer. Umbilical cord blood transplantation: The first 25 years and beyond. Blood 2013; 122: Source: Marcelo C Pasquini (Center for International Blood and Marrow Research, USA) et al : The Likelihood of Hematopoietic Cell Transplantation (HCT) in the United States: Implications for Umbilical Cord Blood (UCB) Storage Presented at the 47th Annual Meeting of the American Society of Hematology i Atlanta Source: Diabetes Care 32(11): Source: A Randomized Umbilical Cord Blood Reinfusion inchildren with Cerebral Palsy, June 2010, at Duke University Medical Center; Principal Investigator Joanne Kurtzberg. 35. Source: Eur Heart J (11): Source: Cell Transplant (9): ; J Neurosci Res (16): The National Marrow Donor Program (NMDP) is a non-profit organisation, working to ensure that all patients who need it, get the opportunity to have a transplant with blood from bone marrow or umbilical cord. Source: The International NetCord Foundation is a non-profit collaboration between umbilical 35

38 cord blood banks. Source: netcord.affiniscape.com/index. cfm 39. Source: Querol S, Mufti GJ Marsh SG, Pagliuca A, Little AM, Shaw BE, Jeffery R, Garcia J, Goldman JM, Madrigal JA, Cord blood stem cells for hematopoietic stem cell transplantation in the UK: how big should the bank be? Haematologica, 2009, 94: Source Cytotherapy (6): Sources: Fx (1) Kusadasi N, van Soest PL, Mayen AE, Koevoet JL, Ploemacher RE successful short-term ex vivo expansion of NOD/SCID repopulating ability and CAFC week 6 from umbilical cord blood Leukemia 2000 Nov;14(11): (2) Nakahata T Ex vivo expansion of human hematopoietic stem cells Int J Hematol 2001 Jan;73(1):6-13 (3) Chao NJ, Emerson SG, Weinberg KI Stem cell transplantation (cord blood transplants Hematology Am Soc Hematol Educ Program 2004: Source: Nature Medicin, Januar 2010, Professor Irwin Bernstein. 43. Source: W Aecese (University of Rome): Speaker at the World Cord Blood Congress in Marseilles, France, 4 7 November Source: reddet-af-blod-fra-navlesnor 36

39 Find out more Version 3, 1st edition October Graphic design and production: www mollers dk Illustrations: mollers dk Hans Møller / Magnus Gaarde Photos: Stemcare and Dreamstime (2 and 23)

40 Useful information about stem cells Focusing on stem cells from the umbilical cord is written by: professor, dr.med. peter ebbesen of the Laboratory for Stem Cell Research, Aalborg University and affiliated Research and Innovation Agency. Professor Peter Ebbesen worked for a few years in surgery and as a medical practitioner. Has now worked for many years with cancer and stem cell research, and in this regard led several international projects, he is currently on the staff of the University of Oslo team leader, m.sc.med. christian clausen, the Research Institute Bioneer A/S Bioneer A/S is a wholly owned subsidiary of DTU, Denmark s Technical University. Bioneer s aim is to drive technological service on a non-profit basis within the biomedical, biotechnological and bio-medicotechnical field. As a non-profit company, Bioneer is independent of special interests. laboratory manager, msc. christophe poirel madsen from Stem- Care A/S StemCare is Denmark s only stem cell bank and specialises in the collection and freezing of stem cells from newborn umbilical cord blood for use in connection with any subsequent illness. StemCare was established in 2002 and is a member of the European Association of stem cell banks, Cord Blood Europe. id: UK