Introduction to special issue
Placing fresh new cells into old organs to cure disease is the theme of the current special issue of Annals of Medicine. A number of experts address the possibilities, benefits and risks of using stem cells for therapy. A need for such an approach originates from the lack of possibilities to cure many diseases, where losses of tissue or cells with important functions occur. These include myocardial infarction, stroke, Alzheimer's disease, spinal cord injury and many severe disorders for which no treatment exists today. Current availability of tissues for transplantation is not sufficient to supply the need, and immune rejection still often poses problems.
The hopes are that we could cure type 1 diabetes by recovering insulin production with differentiated stem cells, Parkinson's disease with dopamine producing cells, myocardial infarction with new cardiomyocytes, bone loss with osteoblasts, get bone cells from fat tissue etc. There is great potential in the use of stem cells in clinical therapy, but careful studies are still needed to transplant them effectively and safely.
As will become apparent from the following seven articles, stem cell therapy is not as simple as just injecting cells into the damaged tissue areas. The cells need to have the right growth potential and functional activities. The right types, amounts and timing of growth and differentiation signals are needed. The cells will need the right environment and scaffold to grow in and on, and to stop growth when needed. Uncontrolled growth might result in malignancy. The cells also need to be protected against immune rejection.
What is clear now is that both tissue‐derived and embryonic stem cells are needed in different treatments. Our knowledge regarding these cells is accumulating faster now, when several countries have made large investments in promoting this important new area in medicine.
There are studies going on regarding the safety issues. To guarantee the safety of transplantable cells, the European Union has a directive which came into effect in April 2005. According to this, all transplantable cells which are not used for the same patient during the same operation have to be cultured in Good Manufacturing Practice (GMP) laboratories. This directive has been harmonized by the Food and Drug Authority (FDA) in the United States. The risk of infection and human errors can hence be minimized.
In the first article of the special issue, Kalervo Väänänen discusses mesenchymal stem cells that refer to multipotent stromal cells originating from the bone marrow. These cells are different from the hematopoietic stem cells, and as multipotent cells they can differentiate into many cell types that are found in mesenchymal tissues, such as cartilage and bone. These are cells which could be used for the therapy of problems in joints, bones and connective tissues. The scope of potential medical indications is wide: reconstructive repair operations, injuries, malformations, genetic diseases of the bone or cartilage, arthrosis, consequences of rheumatoid arthritis and even autoimmune diseases. Mesenchymal stem cells could offer a very promising use as ‘living implants’. Fetal mesencymal stem cells have been successfully used already in intrauterine cell transplantation in the treatment of osteogenesis imperfecta. What is the history of this type of therapy, how realistic it is and which types of molecular mechanisms have been and need to be worked out have been nicely addressed in the paper by Väänänen.
In the second article, Anna Falk and Jonas Frisén continue the theme with the amazing realization that, after all, our brains contain new neurons. These cells are capable of renewing and provide hope for regenerating lost activities at least in some parts of the central nervous system. This is real encouragement against the depressing thought that our brain is what it is without regenerative capacity. As an example of how the ages of neuronal cells can be determined Frisén et al. themselves have elegantly used nuclear bomb‐derived 14carbon (14C) isotope accumulation in genomic DNA as a date marker for long‐lived cells. This is possible because, luckily, since 1963 no new seeding of 14C into the atmosphere has occurred. The recent new observations provide prospects for stimulating the growth of endogenous neural stem cells, and for the allogeneic transplantation of cultured cells to patients suffering from neuronal cell loss. To what extent do neuronal stem cells have multipotency and self‐renewal capacity? Can we look forward to having our brain cells replaced if we get stroke or Alzheimer's disease? To find out, please, turn a few pages and have a look. In the other articles the reader will find information how neural stem cells differentiated from embryonic stem cells offer an excellent source of cells for neural cell transplantation.
Our third article by Correia, Anisimov, Li and Brundin addresses more specifically stem cell therapy for Parkinson's disease. As these authors have summarized, allogeneic (as well as xenogeneic) nerve cell transplantation has already been tried in vivo in patients, providing first hand experience of the applicability and risks of a this kind of approach. In Parkinson's disease the patients have lost dopamine producing neuronal cells in substantia nigra, and the therapies aim at correcting this deficit. The utilization of neuronal cell transplantation in vivo has brought into light problems related to this type of therapies. The patients develop graft‐related dyskinesias. This raises the question how could one control the activities of the grafted cells? Another major problem was the shortage of donor tissues, because for each single patient the cells had to be obtained from several embryos. The solution could be to use embryonic stem cells, grow them in quantity and differentiate them into dopaminergic neurons. How could this be done? How to make sure that the cells become differentiated into neuronal cells and not into muscle cells, or bone? In their article Correia et al. will tell us whether this is possible and how to proceed.
The fourth article by van Laake, van Hoof and Mummery deals with stem cell‐derived cardiomyocytes. This is a most relevant field for potential therapeutic applications because acute myocardial infarction, cardiac insufficiency and cardiac myopathies remain as extremely important and still increasing medical problems. Common to all these disorders is the loss of effective, actively working cells in an organ with continuous energy‐consuming physical activity in our bodies. Van Laake et al. will tell us whether it is feasible to use stem cells to generate new cardiomyocytes. They suggest that the best potential would be in embryonic stem cells or in cardiomyocyte progenitors taken directly from the heart. Stem cells isolated from bone marrow or blood would be unlikely to be of benefit in transplantation, although they could have beneficial effects by other mechanisms. Repair of the heart engine with spare parts from living cells is a real challenge. But, if successful, it could be vital in saving lives and avoiding disability.
The fifth article by Otonkoski, Gao and Lundin provides an update on prospects of using stem cells for the treatment of diabetes. Like Parkinson's disease, type 1 diabetes is a disorder that originates from the loss of one particular, but important, cell type. These cells, the beta cells of pancreatic islets of Langerhans, have one major function, the production of insulin and thereby control of glucose metabolism. The therapy with cells instructed to produce insulin in response to blood glucose levels would be an obvious goal and a test case for any stem cell therapies. Still, it is a great challenge. In their review, Otonkoski et al. indicate that pancreatic and hepatic cells can be differentiated into beta‐like cells. The regulating molecular mechanisms are, however, complex. There seems to be a long way to go until clinically applicable results can be obtained, although the fact that insulin‐producing cells can be successfully transplanted gives some hope. As with the car engine, it is important that the use of fuel is very carefully monitored and dosed. Secure feed‐back mechanisms are needed to guarantee that the glucose levels remain within an acceptable range, reflective of and in balance with tissue responses and body metabolism. In biologically engineered systems it is difficult to create and maintain this kind of fine balance and feed‐back activities. For a touch of realism on stem cell therapy in diabetes the reader is advised to read this focused and balanced review.
In the sixth article, Liew, Moore, Ruban, Shah, Cosgrove, Dunne and Andrews touch the heart of the whole stem cell research field by discussing human embryonic stem cells (ESC) and their potential applications to restore many different types of cell functions. ESCs cells can be grown in vitro. They are pluripotent and have self‐renewal capacity. Thus, they would provide an unlimited source for cell transplantation to heal a variety of diseases. The challenges are to differentiate them into the right directions, to control their growth and make them adapt into the target scaffold structures. Furthermore, the cells need to be kept functionally active and protected from immune rejection. In this comprehensive review Liew et al. demonstrate that ESCs can differentiate into various phenotypes of any of the three germ layers. The clinical use would still be premature, but animal experiments have suggested that the cells can adapt into their new hosts and have therapeutic impact. What preconditions need to be met before ESC therapy can be attempted? How can or should the cells be manipulated biologically or genetically? What are the risks? Some answers are given in this excellent, cross‐sectional and practically oriented review.
Finally, in the seventh article, the last paper of the series, Jantunen and Luosujärvi provide an update of the potential use of autologous stem cells in autoimmune diseases. The ones addressed include systemic lupus (SLE), systemic sclerosis and rheumatoid arthritis. The authors discuss practical aspects of the therapy thus providing useful hints to physicians working with this kind of therapy. The traditional therapy of diseases with immune overactivation has been to give immune suppressants. The therapy is non‐specific and can predispose the patients to side effects or infections. Autologous stem cell therapy, originally used in the therapy of malignancies and loss of endogenous bone marrow, has recently gained ground increasingly as a new experimental therapy in different types of autoimmune diseases, as well. Trials are ongoing, and data is accumulating in international registries. How promising the therapy looks in the treatment trials of multiple sclerosis, systemic sclerosis, rheumatoid arthritis, SLE and other ‘immune’ diseases can now be evaluated from this review.
We hope that the readers of this special issue will get useful and updated information regarding this new area of medicine, and on what still has to be done before clinical applications are possible.