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

Transcription

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

2

3 Useful information about stem cells Focusing on stem cells from the umbilical cord Stem cells - an important component in the future treatment of disorders... 2 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 storage? How is the area regulated? Glossary Notes and references Find out more

4 Stem cells - an important component in the future treatment of disorders Useful information about stem cells Focusing on stem cells from the umbilical cord 2 Many disorders are linked to damaged or defective cells, tissue and organs, which stem cells have the potential to cure. Stem cells are, therefore, one of the largest development areas in medicine. Each month publications appear with results of new research and treatment. We are continuously following the many clinical trials and the results achieved. Many of these trials are conducted at university hospitals throughout the world. Several different sources of stem cells are being researched. One such research subject is umbilical cord blood, which is the blood that remains in the placenta and umbilical cord after the umbilical cord has been cut immediately after birth. Persons expecting a child have particular reason to be interested in the subject, because they must decide, during pregnancy, whether they wish to store stem cells from their baby s umbilical cord. If stem cell therapy is required, matching stem cells can, in many cases, be found in the international stem cell banks, if you do not have access to your own stem cells (or matching stem cells from siblings). This also applies in the event of a disorder that cannot be treated with your own stem cells. The world s first public health umbilical cord stem cell bank, the New York Blood Center, was established in the USA in 1992.

5 Sweden established its own national umbilical cord stem cell bank in 2006, and in 2011 elected to expand it in order to harvest cells in both Gothenburg and Stockholm. Denmark does not yet have a national umbilical cord stem cell bank, despite several attempts to establish one. It has been possible to store stem cells from umbilical cord blood privately since 1992 in the USA, since 1997 in Europe, 2002 in Denmark and 2013 in Sweden. In the USA alone, 1,36 million parents have chosen to store their children s umbilical cord stem cells in private and public stem cell banks. It is required by law in 24 US states to inform pregnant women of the options for freezing umbilical cord stem cells. 1 In Denmark and most places in Sweden, it is still up to individual parents to familiarize themselves with the subject. Magnification of human mesenchymal stem cells that express GFP (Green Fluorescent Protein). 3

6 What is a stem cell? Bone cells Heart cells Muscle 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 of forming new bone tissue, whilst the heart has 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 mainly two types: Blood-forming stem cells (haematopoietic 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.

7 Categories of stem cells 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 are found in: 1. Umbilical cord blood (umbilical cord stem cells) 2. Fully developed organs in children and adults (adult stem cells) 3. The early embryo (embryonic stem cells) Stem cells from umbilical cord blood Blood from the umbilical cord and placenta contains stem cells, which are readily available. These stem cells are harvested after birth, as soon as the umbilical cord is cut. Research shows that stem cells from umbilical cord blood can develop into more cell types 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 2, 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 adult stem cells 3. It is important, if a patient is to be treated with stem cells from a donor, who is 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 so, if they are collected at birth and frozen for long-term storage. 4 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. All adult stem cells must be obtained by surgical procedure. Even children are used as donors, which can be ethically problematic, as even a small intervention will always be associated with the risk of complications for the donor. The donor should therefore always understand, and personally consent to the donation. 6

9 pluripotent stem cells 8 days after fertilisation The inner cell mass is isolated in the laboratory 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 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. Haematopoietic and mesenchymal stem cells Stem cells can be divided into haematopoietic and mesenchymal stem cells. Haematopoietic stem cells can develop into all types of blood cells and are used in the treatment of blood disorder; e.g. leukaemia (blood cancer). Mesenchymal stem cells can be used for regenerative therapies, as they can be developed into a variety of specialized cell types, such as cardiac cells, bone cells, nerve cells and blood vessel cells. It is expected that mesenchymal stem cells (from whatever source) will, within a few years, be used for the treatment of a number of common disorders, such as arthritic disorders, bone formation, cardiac and cerebral disorders. 5 7

10 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 in-vitro 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? Since 2011 there have been no treatments with embryonic stem cells, as it has been shown that embryonic stem cells can cause cancer after transplantation into experimental mice. Embryonic stem cells are taken from fertilised eggs and are therefore associated with ethical issues. Today, donor stem cells from umbilical cord blood are used as standard for the treatment of leukaemia (blood cancer). In addition, they are tested in clinical trials for a variety of dis eases, such as diabetes, cerebral palsy and heart disease. Stem cells from the umbilical cord are an easily accessible source. They have the same therapeutic potential as adult stem cells and are better accepted by the body s immune system than stem cells from bone marrow. Since 1960, adult stem cells have been used in bone marrow transplants. In addition, adult stem cells are tested in clinical trials for a number of diseases like heart disease, arthritis and certain disorders of the immune system. Stem cells taken from adults have been through a lifetime of physical and chemical impact. Therefore, their therapeutic potential may be altered. 8

11 What are stem cells currently used for? On the left, a normal vein and on the right an artificial vein made from stem cells. 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. For decades, haematopoietic stem cells from bone marrow have been the standard treatment for disorders such as leukaemia (blood cancer), and haematopoietic stem cells and mesenchymal stem cells from the umbilical cord, peripheral blood 6 and bone marrow are currently used to treat approximately 80 different diseases. 7 Today the majority of all the umbilical cord stem cells are used for the treatment of leukaemia. In most cases umbilical cord stem cells will be used from siblings or from an unknown donor with a tissue type, suitable for the patient to be treated. 8 If an organ or a part thereof is damaged by disease, wear and tear or an accident, stem cells can be recruited to the damaged areas to restore normal function. It is this property that is utilized in regenerative medicine, and this area in particular that scientists predict stemcells to have the potential to provide great treatment options. 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. In recent years, several milestones have been reached in regenerative medicine. In 2010 for example, a 36-year-old Danish sclerosis patient received stem cell treatment in Costa Rica using his own and donated stem cells. And in 2008, a 30-year-old Colombian woman had a windpipe implanted, which was 9

12 constructed from her own stem cells 9. In 2014, a follow-up article in the international journal, The Lancet, reported that the Colombian woman s windpipe was still functioning after 5 years of observation. 10 Recent research also suggests that stem cells are capable of curbing inexpedient immune reactions in the body. Good experience has been gradually gained in the use of stem cell therapy on patients with so-called autoimmune diseases (i.e. the patient reacting to his/her own tissues in joints, intestines, kidneys, etc.). In 2011, a research team from the University Hospital of Basel in Switzerland reported that more than 1,500 patients with serious autoimmune diseases had been transplanted with haematopoietic stem cells worldwide. The majority of whom received their own, i.e. autologous, stem cells. The disorders included 345 cases of multiple sclerosis, 175 cases of systemic sclerosis, 85 cases of serious autoimmune disease, systemic lupus erythematosus, which attacks the skin and organs, 65 children and young adults with debilitating arthritis (juvenile idiopathic arthritis) and 89 patients with rheumatoid arthritis (RA). According to the Swiss scientists, the treatment results show increasing improvements in the autoimmune patients disorders - in line with transplan- Værd at vide om stamceller Med fokus på stamceller fra navlesnoren 10

13 tation specialists growing experience with regard to the organization of treatment strategies. 11 See examples of milestones in research and stem cell therapy on page 16. More and more treatment options 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. 12 Stem cells from umbilical cord blood are tested for the treatment of a variety of diseases in addition to blood diseases and at the beginning of 2015, in the USA alone, 987 clinical trials of umbilical cord stem cells were registered. 13 So far, e.g. own mesenchymal umbilical cord stem cells have been used for experimental treatment of children with type 1 diabetes. 14 Furthermore, in clinical trials scientists have been using own (also called autologous) mesenchymal umbilical cord stem cells to treat children with neurological disorders including at least 124 children with cerebral palsy (spastic paralysis).15 The University of Texas Health Science Center in Houston, Texas, has ongoing clinical trials using autologous umbilical stem cell treatment of children, who have suffered severe brain damage at birth or in early childhood. 16 Recent research also points out that stem cells from umbilical cord blood can be used in the treatment of certain brain injuries. 17 By 2013, more than 30,000 umbilical cord stem cell transplants on sick children and adults had taken place. 18 According to scientists, we have only seen the tip of the iceberg, and the future potential in the use of stem cells will in particular be in the area of regenerative treatment, such as the treatment of cardiovascular diseases, sclerosis, cerebral palsy and osteoarthritis. It is precisely this potential that during these years has been investigated 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 19, and during the first half of 2010, 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. 20 Many scientists agree that, in the future, different sources of stem cells will be used depending on the disease to be treated. 11

14 Number of bone marrow transplants broken down by cell type source 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 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. In the 1960s scientists 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 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. 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)

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. 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 predestined to work. This is called homing. For example, haematopoietic ( blood stem cells ) cells 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. Once the stem cells have reached their destination in the body, they transform into the types of cells required. Mesenchymal stem cells are also passed on to the areas in the organism which, depending on their pre-programming, they can adapt to. These cells transform into e.g. cartilage cells, muscle cells, bone cells, nerve cells, depending on where they are needed. 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. 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. 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. When it is the person s own umbilical cord blood, which is used, there is of course no incompatibility and therefore never a rejection issue. Tissue compatibility is determined by 14

17 carrying out tissue typing of donor and patient respectively (HLA-typing). Stem cells from umbilical cord blood can be used for % tissue match, which corresponds to a HLA match of 4/6-6/6. 22 For bone marrow, a match of 8 out of 8 HLA antigens is required for transplantations. Thus, stem cells from umbilical cords can be used despite a lower match, as they are generally more readily tolerated than bone marrow stem cells. 23 One of the advantages of storing stem cells is that they can be used to help others. If for example a brother or a sister gets leukaemia, there is a 25 % chance of a perfect match, even though less can work, depending on the disease. In other words, you as a family have the opportunity to avoid a potential critical waiting time in search of a donor and thus initiate a treatment sooner. Other factors affecting the effect of a stem cell transplant Apart from tissue compatibility the effect of a transplant depends of the cell count (TNC, nucleated cells and CD34+ stem cells), CFU (Colony Forming Unit) and stage of the disease. The most recent treatment results show that the optimally successful transplant is achieved at a minimum nucleated cells and CD34+ cells per kg body weight. 24 The parameters typically looked for in order to determine 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, it has been estimated that stem cell transplants with umbilical cord blood are often more successful than bone marrow transplants

18 Milestones in research and treatment Useful information about stem cells Focusing on stem cells from the umbilical cord How many people are treated with stem cells from umbilical cords? The world s first public health umbilical cord stem cell bank, the New York Blood Center, was established in the USA in The option for private storage of umbilical cord stem cells from newborn children has been available in the USA since 1992, in Denmark since 2002 and in Sweden since Up to 2013 more than 30,000 umbilical cord stem cell transplantations had been carried out on children and adults. 26 In the first half of 2010, the number of treatments using umbilical cord stem cells exceeded, for the first time, the number of treatments using bone marrow stem cells in the United States. 27 The reason for this development is that stem cells from umbilical cord blood can develop into more cell types than adult stem cells, stem cells from umbilical cord blood are more readily accepted by the body s immune system than stem cells from bone marrow and more and more umbilical cord portions are available in public and private stem cell banks around the world. 16

19 clinical trials with umbilical cord stem cells have been registered in the USA alone StemCare is established on the Swedish market, thus making it possible for Swedish parents to privately store their child s umbilical cord blood. First patient with blood cancer succesfully treated with amplified stemcells from the cord blood. Number of treatments with umbilical cord blood rises to over 30, The number of transplants with umbilical cord blood exceeds 21, First Danish private umbilical cord blood bank is established The Nobel Prize in Physiology and Medicine: 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 Around 2002 Stem cells to treat heart conditions show positive results In the USA, the first official umbilical cord stem cell bank (New York Blood Center) is established. 1960s Stem cells in bone marrow used in the form of bone marrow transplants for treatment of blood cancer Embryonic stem cells discovered The first treatment using stem cells from umbilical cord blood takes place in France. A boy was cured of a serious blood disorder using his sister s stem cells. 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 How many stem cell portions are stored in public and private stem cell banks? At least 158 private and public umbilical cord stem cell banks have been registered around the world. According to the Parents Guide to Cord Blood Foundation, approximately 1,360,000 umbilical cord portions are stored in the USA alone 28, and the number is growing. What is the probability of needing a stem cell treatment? According to the scientists, there will be a widespread need for stem cells to treat disorders. Since this area is developing so rapidly, it is difficult to calculate the actual probability that persons will need a stem cell treatment later in life. This is clearly illustrated by the following two examples: One example is presented by the American physician and scientist Marcelo C. Pasquini who, back in 2005, evaluated the likelihood of a person needing stem cell therapy in the future. 29 The calculation was based on the probability 18

21 of suffering from an illness, which, even then, could be treated with umbilical cord stem cells. 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 Within a lifetime 1 in in 120 The second example paints quite a different picture. According to an article published in the scientific journal, Biomedicines, in 2014, nearly 1 in 3 of all US citizens (equivalent to 128 million people) may need regenerative stem cell therapy during their lifetime. 30 The second article does not relate to stem cell sources, but since there is intensive research into several different sources of stem cells, including umbilical cord stem cells, it is realistic to assume that treatment with umbilical cord stem cells will be included in the estimate to a significant extent. 19

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

23 How do you get access to stem cells? Collection of stem cells from the umbilical cord The harvesting of stem cells from the umbilical cord is the easiest possible access to stem cells. Collection of stem cells from the umbilical cord always requires the consent of the newborn child s mother. Should the collected stem cells be accessible for the newborn child s own use or use within the family, an agreement with a private stem cell bank should be reached prior to the birth. Personal rights of disposal are not afforded if the umbilical cord stem cells are stored in a public umbilical cord stem cell bank. As soon as the child is born and the umbilical cord is cut, the umbilical cord blood from the newborn child is collected. As harvesting takes place after birth, there is no risk to neither mother nor child. 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. 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 surgical intervention into the bone marrow, if you don t have your children s umbilical cord stem cells available. If you have no siblings, or your stem tissue is not compatible with your sibling s, doctors will try to find a tissue-compatible stem cell donor in international public registers storing stem cells from umbilical cord blood and bone 21

24 marrow. This will be possible within one year for 80 % of all who so require. However, this may be a time consuming process, and it cannot always be guaranteed that a matching donor will be found. Useful information about stem cells Focusing on stem cells from the umbilical cord 22

25 Future prospects Scientists generally agree that, in the future, the various sources of stem cells 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 e.g. heart conditions, diabetes, arthritis and nerve disorders are treated. The results from these studies will be of great importance to the future utilization of mesenymale stem cells, regardless of their source. Examples: Clinical trials with injection of autologous (i.e. the patient s own) umbilical cord stem cells in young people with type 1 diabetes. 31 Clinical trial using donated (allogeneic) umbilical cord stem cells for the treatment of children with cerebral palsy. 32 Clinical trial with umbilical stem cells for the treatment of children with neurological disorders including at least 124 children with spastic paralysis (cerebral palsy). 33 Clinical trial at e.g. Copenhagen University Hospital, Rigshospitalet, with stem cells from fatty tissue for the treatment of heart conditions. 23

26 Useful information about stem cells Focusing on stem cells from the umbilical cord Experimental studies with positive results through the use of mesenchymal stem cells for the regeneration of a damaged heart muscle following a heart attack. 34 Scientists 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 treat- 24

27 ment 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. 35 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 known, but it is one of the exciting new prospects under investigation. 25

28 Challenges Useful information about stem cells Focusing on stem cells from the umbilical cord 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 until stem cell treatments will be included as standard in the routine treatment of serious illnesses. Due to the need for tissue compatibility, this is very much linked to the fact that there are still too few umbilical cord stem cell portions stored for public sources to offer widescale stem cell treatment. There are many different types of tissue. Some tissue types are more common than others, and international stem cell registries, such as NMDP 36 and NETCORD 37, can often provide the population needing treatment with partially matching stem cells to treat, for example, blood disorders such as acute leukaemia. 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 guaranteed access to tissue compatible stem cells, if you suffer from an illness that can be treated with stem cells. However, the quantity of stem cells found in a single umbilical cord portion may be limited. In such cases it may be necessary to propagate the number of stem cells. This can be achieved in several ways. The option of using two umbilical cord portions and the propagation of the umbilical cord stem cells are the two most researched methods. Approved procedures for the propagation of mesenchymal umbilical cord stem cells are already used today, and the treatment of patients with a sufficient quantity of their own mesenchymal stem cells is relatively straightforward. 38 Propagation of stem cells is achieved by adding molecules, which bind to specific growth receptors on the cell surface. 27

30 Private versus public storage? Useful information about stem cells Focusing on stem cells from the umbilical cord 28 Most countries have established national stem cell banks, which, with parental consent, harvest and store the newborn s umbilical cord stem cells for general use. This is the case in Sweden, USA, the UK and Germany. Denmark is one of the only developed countries that does not yet have a national stem cell bank. When stem cells are required for treatment, the hospital will try to source them from international public stem cell banks, unless they have direct access to their own stem cells. Such searches can be time consuming, and there is no guarantee that a suitable match will be found. In the course of a year, only 4 out of 5 of patients will have found a matching donor in the international public stem cell banks. 39 If time is a critical factor in treating the disorder, the risk of waiting so many months may be problematic. 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 lived in the same country for generations. In countries with both public and private stem cell banks (such as Sweden), pregnant women will be faced with having to choose between storing their own stem cells privately or donating them 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 the right of disposal over the donated stem cells. Umbilical cord stem cells held in a public register are available to all with the

31 same or a suitably acceptable tissue type. Thus, 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 you have had your own umbilical cord stem cells stored, 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. In at least 25% of all cases, siblings can make use of 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. 29

32 Useful information about stem cells Focusing on stem cells from the umbilical cord 30

33 How is the area regulated? In Europe, private and public companies, institutions and organizations that handle human tissue and cells (tissue centres) are subject to an EU directive from In Denmark, the Act on Requirements for Quality and Safety when handling Human Tissues and Cells (the Danish Tissue Act) with associated regulations and guidelines apply. In Sweden, the Act (2008:286) on Quality and Safety Standards for handling Human Tissues and Cells (the Swedish Cell and Tissue Act) and associated regulations and edicts applies. Only tissue centres that meet these stringent requirements may be authorized to carry out tissue centre activities. StemCare s licence to operate is issued by the Danish Health and Medicines Authority. 31

34 Glossary 32 Adult stem cells. Stem cells obtained from the fully developed body, e.g. bone marrow or fatty tissue. 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 (Haematopoietic). 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. FDA. Stands for Food and Drug Administration and is the USA s federal food and drug regulatory authority. 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. Haematopoietic 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, nearly 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. Immunosuppressive treatment, inhibition of the immune system s reactions, e.g. such as treatment of autoimmunity and chronic inflammatory

35 diseases or in connection with a transplant to prevent rejection of the transplanted organ. Immunosuppression takes place either in the form of radiation or most commonly in treatment with immunosuppressive drugs. 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. Recipient. The receiver (as opposed to donor). Regenerative medicine. Building damaged tissue and thereby curing the underlying disease. 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 rejection. Placenta. Afterbirth. Pluripotent stem cells. Can differentiate into any cell type in the body. 33

36 Notes and references Source: Cord Blood Europe, April 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, Source: 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, 10:20. Hare JM et al.: A randomized, doubleblind, placebocontrolled, dose- escalation study of intravenous adult human mesenchymal stem cells (Prochymal) after acute myocardial infarction, J AM Coll Cardiol 2009;54: Cowan CA, Klimanskaya I, McMahon 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 Bastocysts. New Engl. J. Med. 2004, 350: 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. 7. Source: Parentsguidecordblood.org. 8. Source: Presidential Session at ASH 2010 devoted to Cord Blood : Presented by Professor Eliane Gluckman. 9. Source: Macchiarini P et al; Clinical transplantation of a tissue-engineered airway, Lancet 2008 Dec 3;372(9655): Source: Gonfiotti A, et al.: Kastrup J et al: The first tissue-engineered airway transplantation: 5-year follow-up results, Lancet, 2014, Jan 18,383(9913): Source: Daikeler T et al: Stem cell treatment of autoimmune disease [Article in German], Dtsch Med Wochenschr Aug;136(33): 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: Wagner JE and E. Gluckman: Umbilical Cord Blood Transplantation: The first 20 Years, Semin Hematol 47: Source: Source: Diabetes Care 32(11): and Klinik fur Kinder und Jugend Medizin, Technical University, Munich.

37 15. Source: A Randomized Umbilical Cord Blood Reinfusion in Children with Cerebral Palsy, June 2010, Duke University Medical Center, Principal Investigator Joanne Kurtzberg. 16. 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]. 17. 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: Ballen, Gluckman, Broxmeyer. Umbilical cord blood transplantation: The first 25 years and beyond. Blood 2013; 122: Source: Gluckman et al., 2010, Hematology. 20. The National Marrow Donor Program (NMDP) is a non-profit organization that works to ensure that all patients who need it, receive a transplantation of blood from bone marrow or umbilical cord. Source: Source: Broxmeyer HE. Cord blood hematopoetic stem cell transplantation, StemBOOK Cambridge, 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 October; 147(2): Source: World Cord Blood Congress in Marseilles, France, November 4th 7th Source: Broxmeyer HE. Cord blood hematopoetic stem cell transplantation, StemBOOK Cambridge, Source: Ballen, Gluckman, Broxmeyer. Umbilical cord blood transplantation: The first 25 years and beyond. Blood 2013; 122: Source: The National Marrow Donor Program (NMDP) is a non-profit organization that works to ensure that all patients who need it, receive a transplantation of blood from bone marrow or umbilical cord. Source: www. nmdp.org. 28. Source: org/press. 29. 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 in Atlanta Source: David T. Harris, Stem Cell Banking for Regenerative and Personalized Medicine, Biomedicines 2014, 2, ; doi: /biomedicines Source: Diabetes Care 32(11): Source: Kyunghoon Min et al.: Umbilical Cord Blood Therapy Potentiated with Erythropoietin for Children with Cerebral Palsy: A Double-blind, Randomized, Placebo-Controlled Trial. STEM CELLS 2013;31:

38 33. Source: A Randomized Umbilical Cord Blood Reinfusion in Children with Cerebral Palsy, June 2010, at Duke University Medical Center; Principal Investigator Joanne Kurtzberg. 34. Source: Eur. Heart J (11): Source: Cell Transplant (9): ; J Neurosci Res (16): Source: The National Marrow Donor Program (NMDP) is a non-profit organization that works to ensure that all patients who need it, receive a transplantation of blood from bone marrow or umbilical cord. Source: www. nmdp.org. 38. Source: Ballen, Gluckman, Broxmeyer. Umbilical cord blood transplantation: The first 25 years and beyond. Blood 2013;122: 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: and Nature Medicin, January 2010, Professor Irwin Bernstein. 37. The International NetCord Foundation is a non-profit partnership of umbilical cord-blood banks. Source: affiniscape.com/index.cfm. 36

39 Find out more Version 4, 1st edition December 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, md. Peter Ebbesen, who has, for many years, been affiliated with the Laboratory for Stem Cell Research, the University of Aalborg, the Danish Agency for Science, Technology and Innovation and the University of Oslo. Professor Peter Ebbesen has worked with cancer, and he has been a visionary pioneer in stem cell research and has led several international projects in the area. He has also been an active advocate for the creation of a public umbilical cord stem cell bank in Denmark. 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 biomedicotechnical field. As a non-profit company, Bioneer is independent of special interests. Medical Director With Stemcare A/S, md Henrik Lawaetz. StemCare protects childrens stem cells and specializes in the harvesting, laboratory processing and storage of stem cells from the umbilical cord blood of newborns for treating possible future illness. StemCare was established in Denmark in 2002 and in Sweden in 2013 and is a member of the European Association of Stem Cell Banks, Cord Blood Europe. In 2015 StemCare was acquired by Vita 34 AG - the largest private umbilical cord blood bank in Europe with more than 127,000 umbilical cord blood portions stored. Vita 34 s main office is located in Leipzig, Germany ENG