STEM CELLS: THE FUTURE OF REGENERATIVE MEDICINE

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1 STEM CELLS: THE FUTURE OF REGENERATIVE MEDICINE BY SHIVAM KOLHE Grade awarded: Pass RESEARCH PAPER BASED ON PATHOLOGY LECTURES AT MEDLINK and VET-MEDLINK 2014

2 Abstract Within the UK, around 1000 people sustain spinal cord injury every year. With no effective treatment as of yet, it still costs the nation 1 billion per annum. Around 850,000 people suffer from dementia in the UK, with numbers set to rise to over 1 million by 2025 and up to 2 million by Alzheimer s disease, the leading cause of dementia, has no cure yet and costs the UK 26 billion per annum. These costs have a huge impact on the country s economy. In this paper, I have used underlying scientific principles of stem cells, up-to-date research and evidence from clinical trials to propose that stem cells, in the form of stem cell transplants, can be used to successfully treat the above neurological and orthopaedic disorders, and potentially cure them in the near future. In this paper, I also discuss in depth how traditional knee-replacement surgery could be revolutionised using stem cells, and evolved into simple stem cell injections thereby reducing the total cost from 850 million per year, as it currently stands for joint-replacement surgery, to much lower costs for the NHS and reduced recovery times for patients. 2

3 INTRODUCTION Ever since the term stem cell was first coined in 1900s, scores of advances have been made in stem cell research, which have rightly led scientists to believe that a deeper understanding of the mechanisms of stem cells will lead to the potential cure of countless medical conditions in the future that are caused by abnormal cell division, differentiation and cell degeneration. 1 In order to be able to discuss the potential of stem cells in the approaching future of medicine, one must first understand the scientific theories and the ethical ideologies, which may support or oppose the potential clinical use of stem cells within the National Health Service (NHS) as well as internationally, for example within the US Food & Drug Administration (FDA). SO WHAT ARE STEM CELLS? Stem cells are highly distinguished from the other types of cells by few unique properties (Figure 1) Figure 1: Simplistic view of the properties of stem cells 3

4 They have the ability to (1) Self-renew, dividing mitotically to produce two identical daughter cells and (2) Differentiate (under certain conditions) to give rise to more mature and specialised cells with distinct functions including, for example: cardiac cells (cardiomyocytes), liver cells (hepatocytes) and blood cells (haematocytes). The differential element of stem cells is called its potency, and stem cells are classified according to the number of different kinds of cells it has the potential to become, thus stem cells can either be totipotent, pluripotent, multipotent or unipotent: Totipotent stem cells have the ability to give rise to all cell types in the body, including both embryonic and extraembryonic (e.g. placenta) tissue. Pluripotent stem cells have the capability to produce all cells of embryonic tissue (cells of the body) including the cells of all three germ layers however unlike totipotent cells, they can t give rise to extra-embryonic tissue. Multipotent cells (Progenitor cells) only have the ability to produce cells of a single germ layer - the ectoderm, mesoderm or endoderm. Multipotent stem cells from a mesodermal tissue like the blood can make all blood cells, but cannot make cells of a different germ layer such as neural cells (ectoderm) or liver cells (endoderm). (Figure 2) Figure 2: Three germ layers in a 16-day old embryo (dorsal surface view) 2 4

5 CONCEPTS AND PRINCIPLES OF STEM CELL RESEARCH and THE RELEVANCE TO MEDICINE Stem cells can be obtained from the human embryo or from somatic tissue - hence stem cells are called embryonic stem cells or adult/somatic stem cells respectively. Embryonic stem cells (ESCs) are typically derived from the inner cell mass of four to five day old human blastocyst (post-fertilisation). 3 The isolation and derivation of ESCs from human blastocysts was first accomplished by Thomson (1998) and is demonstrated in his published studies. 4 These stem cells are theoretically immortal and extremely valuable due to serious which their pluripotency; however pose ethical issues due to the method in these ESCs are derived from the blastocyst (Figure 3). 5 Figure 3: Process of culturing human embryonic stem cells 6 5

6 Scientists have tried to address this issue by dedicating time and research to trial different methods of deriving ESCs for example the work of Klimanskaya I (2006 & 2007) that demonstrated the derivation of human ESCs (hescs) from single blastomeres isolated from earlier stages in the development of the embryo, that doesn t result in the destruction of the embryo. 7 In Japan that same year, a ground-breaking discovery was made by Shinya Yamanaka, who found a way to reprogramme mature cells by the addition four specific transcription factors which happened to convert adult cells into pluripotent stem cells. This was first demonstrated using mouse cells, but by late 2007, the first human induced pluripotent stem cells (ipscs) were reported. 8 A deeper understanding of how the reprogramming works and how it can be controlled is required before ips cells can take to the clinical front. Ethical issues surrounding ESCs and their derivation has also prompted scientists to research further into other sources of stem cells, including adult stem cells (ASCs), to find 6

7 potential clinical uses in the future, that could be valuable to prolonging and saving human lives. Adult stem cells (ASCs) are classed as being multipotent, therefore they re not as versatile as ESCs; however they still have the potency to differentiate into most of the major specialised cell types. These stem cells pose very few ethical issues compared to ESCs, and are found amongst already differentiated cells in the body. The main role of adult stem cells in humans is to maintain and repair the tissue in which they re found in, e.g. haematopoietic stem cells maintain sufficient numbers of red blood cells in the blood. This ability of stem cells to self-renew is essential within the human body with regard to self-healing wounds and replacing damaged cells therefore establishes a huge potential for use in medicine. However, the possible applications of stem cells in medicine stretches beyond the concept that stem cells can simply only be used as replacement cells. The role of stem cells continues to advance in clinical medicine and research under three major categories: Stem cells as therapy, in order to replace cells that have died or are absent within the body. Stem cells as targets of drug therapy Stem cells to generate differentiated tissue for in vitro study of diseases for drug development Research on adult stem cells has been on-going for the past 60 years, and has had several major impacts on some of the medical treatments used today. The first major breakthrough within adult stem cell research was the discovery of two types of stem cells within the bone 7

8 marrow: Haematopoietic stem cells (blood forming cells) and mesenchymal stem cells (multipotent cells capable of differentiating into cartilage, bone, muscle, tendon, ligament and fat) (Figure 4). 9 Figure 4: Type of cells that MSC can further differentiate into. 9 These two types of stem cells are the two primary types of adult stem cells, along with neural stem cells (found in the brain), which have some of the greatest potential for future clinical use. Haematopoietic stem cells in fact have been used in bone marrow transplants and for treating individuals with haematological malignancies for the past 40 years leukaemia, multiple myeloma and lymphoma are some of the conditions, which can now be treated as a result of stem cell research. 10, 11 Mesenchymal stem cell (MSCs) and neural stem cell research has been more current, thus only a select few treatments using either of these stem cells exist as of now; and many clinical trials have been registered. 12 In recent years, the number of trials using MSCs have increased considerably. (Figure 5) 8

9 Figure 5: Number of registered clinical trials of MSC-based therapy Clinical trials have shown that the potential for MSCs as treatment offers great promise, especially in treating orthopaedic conditions such as: bone and cartilage repair in osteoarthritis, as well as autoimmune diseases (e.g. rheumatoid arthritis). 13 Figure 6: Potential use of stem cells as treatment in the human body: In this paper, I look at the various possibilities of stem cell treatment in some acute musculoskeletal (orthopaedic) and neurological disorders, mainly on their potential for use in treatment of spinal cord injury (paralysis) and dementia (Alzheimer s disease) - but also focusing on how stem cells could possibly revolutionise the traditional joint replacement therapy in future. 9

10 DISCUSSION The promise of stem cell treatment has taken the world by storm and current research with its great potential is being voiced by media and scientists year on year. However, the development and translation of any experimental therapy to the clinical practice, must follow a well established route for it to be recognised as being of value. This process can take time and in the case of stem cells with remarkable therapeutic potential it offers, this could theoretically take many more years. Some of the stem cell treatments, which are already currently used in clinical medicine, and some of the future potential treatments have been succinctly discussed in the introduction. Orthopaedics and neurology, two relatively closely related fields within medicine, are commonly talked about when discussing about stem cells therapies - and in my opinion, have the greatest potential for stem cell treatment in the future. POTENTIAL USES OF STEM CELL THERAPY IN NEUROLOGICAL DISORDERS: Within neurology, stem cells potentially play a huge role in the future treatment of currently incurable disorders and diseases, such as paralysis and Alzheimer s. Paralysis is the loss of muscle function for one or more muscles, most often caused by spinal cord injury and affects around 1000 people every year in the UK and Ireland, with currently around 50,000 people living with paralysis. 14 With no cure, and its ability to affect anybody at the most unexpected of situations and times in peoples lives, it s one of the most disastrous conditions that may follow a spinal cord injury. Stem cell research into the potential treatment of paralysis is promising and mainly involves the replacement of the nerve cells that have been damaged as a result of the injury, by more specific bone marrow stromal cells; and also the generation of new supporting cells to reform the myelin sheath 10

11 and help to stimulate the re-growth of damaged axons. (Figure 7) Figure 7: There have been many clinical trials to investigate the variety of ways in which different types stem cells could be used to treat spinal cord injury. Clinical trials using neural stem cells, mesenchymal stem cells and embryonic stem cells have been administered by many private health corporations globally, all of which aim to try and re-establish/bridge some of the injured nerves that used to carry information around the body, and also to protect the spinal cord from spreading damage after the injury. 15 These clinical trials always pose the risk of being discontinued due to the ethical issues surrounding stem cells in general or due to the adverse effects, before they can prove beneficial for example, a Californian based biotechnology corporation, Geron announced it was stopping its stem cell programme mid-way between the clinical trials using embryonic stem cells. This was claimed to be due to financial reasons as well as the controversial nature of the research trial, as creation of the embryonic cells involved the destruction of human embryos. The trial involved injecting nerve cells derived from ESCs 11

12 into people with severe spinal cord injury. Building upon the foundations of Geron s cellular technology, other companies such as Asterias Biotherapeutics (BioTime Inc.) and Stem Cell Inc. have taken the opportunity to contribute to the further development stem cell research in this field and clinical trials continue to be conducted. 16 For example StemCells Inc. a world leader in the research and development of cell-based therapies for the treatment of disorders of the central nervous system, has sponsored a clinical trial (approved by the FDA) that tests neural stem cells derived from an aborted fetus as a treatment for spinal cord injury. 17 This has posed great ethical concerns: for example, were the fetuses destroyed specifically to obtain the stem cells? And if fetal stem cell treatment produces successful, efficacious treatments, which are not available through other means, could that lead to fetal farming, e.g. creating custom made fetuses for use in bioscience and even designer babies? The bottom line each one of us may have to decide: If a treatment becomes legalised that comes from an unethical source, would you take it, or leave it? What if it s a family member e.g. your child? These are the kind of questions that, in the not so distant future, may be all too real. It is likely that the implementation of stem cell treatment using embryonically derived stem cells on a national scale (e.g. on the NHS) will require many more clinical trials to successfully and reliably regenerate damaged neurons restoring functionality - as well take into consideration sound ethical reasoning. Alzheimer s disease is a progressive neurodegenerative disease and the most common cause of dementia, a chronic syndrome associated with the gradual decline of the brain and its abilities - with 62% of dementia sufferers suffering from Alzheimer s. (Figure 8) 18 12

13 Figure 8: Dementia has labelled as the been 21 st Century Plague affecting around 850,000 people in the UK, with the number expected to hit one million in the next decade. On top of these statistics, around another 40 million people worldwide suffer from the disease. Included in these statistics from Alzheimer s Society, 60,000 UK deaths a year are also directly associated to dementia. 18 Aside from the human costs, dementia costs the UK 26 billion per annum and it s been made a global challenge by David Cameron to tackle it and find a cure to "one of the greatest challenges of our lifetime by The prime minister has initiated in depth discussion on dementia, by announcing the expenditure of more than 300 million on research into the disease establishing the importance of tackling it in an increasing elderly population. A Stem Cell Research Centre, launched by Alzheimer s Research UK in between the University of Cambridge and University College London, looks to build upon pioneering stem cell research in order to generate live brain tissue to be able to study the disease in greater detail. 20 In addition to this, other possible approaches to stem cell therapies are being researched such as neural stem cell transplants, to replace the damaged neurons and restore the communication between neurons in the brain. 13

14 Figure 9: Loss of tissue in a demented brain compared to normal brain POTENTIAL USES OF STEM CELL THERAPY IN ORTHOPAEDIC DISORDERS and STEM CELL INJECTIONS: Orthopaedic conditions that could be treated with possible stem cell intervention haven t been in the spotlight as much as the potential treatments for more prevalent conditions in the population, such as: organ failure, cancer, diabetes and neurological disorders.. Musculoskeletal disorders are nonetheless still very much prevalent within the UK, with around 8.75 million seeking effective treatment for osteoarthritis, the most common musculoskeletal condition in Britain. 21 As the prevalence of osteoarthritis in the knees, continues to rise amongst the working age and older people, the importance of an effective treatment with a shorter recovery period is very much in demand. The traditional knee replacement surgery has been proven to be an effective treatment for the last 40 years, and is a procedure that has been improved and refined considerably over the years, however the concept still remains the same

15 Figure 10: The estimated proportion of people in the UK who have sought treatment for osteoarthritis, by gender and age group: But for how long exactly, can this traditional procedure continue to be improved and finespun? Maybe another few years, maybe even a decade pushing it therefore the point remains that: for an increasing retiring age, a growing older population and an increasing consultation for osteoarthritis (Figure 10) - a change to how it s treated, is required. I believe that the answer to this, which will also open the doors to the future of orthopaedic treatments, is the use of stem cells. In the knee, osteoarthritis is used to describe the damage to the coating called the articular cartilage. In a healthy knee it s this tissue, which allows the bones to move smoothly around the joint. Damage to the articular cartilage of the knee, can hinder movement around the joint and make it difficult for a person to carry out everyday tasks, such as walking. Osteoarthritis of the knee is most commonly caused due to the wear and tear of the knee joint over many years, or as a result of injury. It is the inability of the articular cartilage to repair itself that causes its degeneration. Surgical intervention can be used to replace and 15

16 repair the damaged cartilage but with limited success, as the procedure will never be able to restore the damaged cartilage back to its full working potential. In 2010, a team of researchers from the University of Manchester programmed human embryonic stem cells (hescs) to specifically differentiate into chondrocytes (cells which form the cartilage) from a series of controlled cultures in 14 days. 23 This successful research carried out by researchers in Manchester on a molecular level demonstrated the basis for a potential treatment for articular cartilage repair. This is also a big step towards understanding the process of differentiation of hescs to be able to derive, not only chondrocytes, but also other specialised cells from hescs by endorsing similar techniques and principles. Professor Hardingham, of the WTCCMR (Wellcome Trust Centre for Cell Matrix Research) expressed that the use of these hesc-derived chondrocytes could lead to a treatment for cartilage repair that is both easier and cheaper and may be extended to younger osteoarthritic patients. 24 However, with any stem cell intervention there are usually ethical issues surrounding it, especially when embryonic stem cells are involved. One of the major risks from harvesting cells from human embryos and the genetical modification of them in vitro is the subsequent formation of teratomas, which are tumours composed of tissues which resemble more than one germ layer. Unlike embryonic stem cells, mesenchymal stem cells have already differentiated to some extent and are more stable therefore much less inclined to transform into teratomas. The use of MSCs instead of ESCs also sparks less of a debate and controversy; therefore research into articular cartilage repair has tended to follow the mesenchymal stem cell route. MSCs are found in abundance in the bone marrow, and their ability to be induced and differentiate into cartilage cells (chondrocytes) shows great promise to the repair of the 25, 26 16

17 articular cartilage in the knee. They are also derived from the patients themselves, therefore there s no risk of rejection. 26 Future developments of this potential treatment could involve MSCs being administered either surgically or via an intra-articular injection into the knee, which then differentiate into chondrocytes and regenerate the damaged articular cartilage. (Figure 11) 27 Figure 11: Osteoarthritis affecting the knee This futuristic idea of a is not at all a myth; it s in has been proved by Dr stem cell injection fact a reality and Christopher Centeno - an international expert and specialist in regenerative medicine and the clinical 17

18 use of mesenchymal stem cells in orthopaedics. One of his patients Patricia Beals, 72, opted for an experimental procedure conducted by Dr Centeno, which involved harvesting mesenchymal stem cells from the bone marrow of her hip, concentrating the cells in a centrifuge and injecting them back into her damaged joints. 28 The procedure was done on an outpatient basis and was proved successful, with the patient being able to move around within 24 hours. 29 With virtually no risks in comparison to traditional joint replacement surgery, and an easier and quicker recovery - stem cell injections could be the way forward into the future for the treatment of osteoarthritis of not only the knee, but also many other joints around the body. Further refinement of this treatment in the next few decades could even outgrow conventional joint replacements and significantly decrease the early onsets of osteoarthritis in the working age population; while also providing a quick recovery period for those who ve suffered acute damage to joints from injury e.g. from sport, allowing them to continue with their lifestyle. CONCLUSION Orthopaedic surgery has the potential to undergo a complete transformation with the intervention of stem cells within particular treatments during the next few decades, or maybe even sooner given the fast paced nature of medical research nowadays. The medical world has already witnessed some major transformations within surgery within the last couple of decades, demonstrated well by the development of cardiovascular surgery over the years. The treatment of heart valve diseases and coronary atherosclerosis, was originally treated by making an 8-inch incision going through the breastbone to open up the chest; whereas now a minimally invasive cardiac surgery (MICS) involving much smaller incisions, fewer risks and a faster recovery time has replaced it. Further advances include 18

19 robot-assisted heart surgery showing the outstanding pace at which modern medicine is changing to set the foundations for the future of medical practice. 30 In the same way as cardiac surgery has evolved; the development of orthopaedic surgery with the use of stem cells is very much a reality! Stem cell injections, to treat osteoarthritis in the knee, are minimally invasive compared to knee replacement surgery. We should all be aware of some practical issues that may arise from this proposed stem cell therapy including costs and storage, as well as regulatory and ethical issues. 31 The FDA and NHS currently do not offer stem cell treatments to treat cartilage repair in the knee, as almost all potential treatments are still undergoing extensive clinical trials, in order to achieve both efficacy (appropriate biological and biomechanical properties) and safety in patients - given that the majority of orthopaedic disorders are not life threatening before they can be viable for government funding in the future. Until that status is achieved, any available stem cell treatments will be expensive through private research corporations/doctors. There are still some issues regarding the effective use of stem cells, including their reduced potentiality for treatment with age and disease, as well as possible stimulation for postinjection tumours in target and non-target tissues. Nevertheless, so far the clinical outcomes of on-going and available trials in patients are encouraging; and demonstrate the potential of stem cell injections for cartilage repair, upon further optimisation in line with the legal requirements and regulatory standards for use within international drug and health regulatory frameworks - particularly the US FDA and the British NHS. Stem cell injections in osteoarthritis would not only prevent joint-replacement surgery, but also reduce recovery time for patients and reduce the treatment costs if the NHS were to fund this simple but effective treatment. 19

20 REFERENCES 1. n/a Derivation of Embryonic Stem Cells Method of harvesting ES cells from human blastocysts Human embryonic stem cell lines derived from single blastomeres ips Discovery by Shinya Yamanaka 9. Potential of Adult Human Mesenchymal Stem Cells figure-title. 20

21 11. Haematopoietic Stem-Cell Transplantation in Patients With Haematologic Malignancies Time period of use of haematopoietic stem cells as treatment Clinical Trials and Applications of MSCs Statistics on Spinal Cord Injury How long have knee replacements been performed? 21

22 24. Scientists turn stem cells into cells for cartilage repair Teratoma formation from hescs Practical Concerns: 22