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