Human Stem Cell Therapy

Human Stem Cell Therapy: History, Current Use, Limitations and Future Prospects

Must look through referencing first to see where there are too may brackets etc!

This paper concentrates of HSCs because they were the first major breakthrough and have progressed the furthest and are now a genuine clinical therapy…

Stem cells are a special set of cells found in the body, defined by their ability to self-renew and (depending on potency) ultimately differentiate into every cell type in the human body. These specific committed cells, produced by differentiation of stem cells, can be used to replace diseased/damaged tissue or generally maintain the body(http://stemcells.nih.gov/info/basics/). This is achieved without triggering an immune response, causing bodily rejection. Stem cells can be categorised by their potency, this is the number of different committed cells that can be formed by a stem cell. There are many different types of pluripotent stem cells (able to differentiate into more than one type of specialised cell) in the human body, often kept in separate locations according to their function. For example a Haematopoietic stem cell (HSC), located in the bone marrow, can differentiate to form all the cells that constitute the blood (lectures give by Dr Bunce). Neural stem cells, which are located in the brain, give rise to new neural cells, which replace damaged or dying specialised brain cells (http://stemcells.nih.gov/info/basics/). In essence stem cells are the reservoir of cells from which the body can replace damaged tissue and fight the onset of age, disease or trauma related degradation at a cellular level.

What is stem cell therapy?

Stem cell therapy is a rapidly changing field of research into the clinical application of stem cells, involving the introduction of new cells into damaged tissue for the therapeutic purpose of treating a disease, injury or illness from which the current tissue is unable to heal(John Wiley & Sons, Ltd 2001a). Stem cell therapies can initially be split into two groups, ex vivo and in vivo depending on the culturability of the stem cells being used.

Ex vivo stem cell therapy is the process by which a transgene is inserted into a specific cell (or population of cells) whilst they are cultured outside of the body(John Wiley & Sons, Ltd 2001b). This transgene is usually transferred along with a selectable gene, allowing selection for stem cells that have taken up the transgene. Once the desired gene has been incorporated into the stem cells, and is being correctly expressed, the stem cells are introduced into the body to function therapeutically(Gurtner et al. 2007). This type of therapy predominantly involves the use of viruses as vectors to transfer the desired gene to the target cell. The viruses currently being studied for use in this field include Retroviruses (e.g. Moloney Murine Leukaemia Virus), Lentiviruses, Adenoviruses, Adeno-associated viruses (AAV), Vaccina virus and Herpes simplex type 1 virus (HSV1)(John Wiley & Sons, Ltd 2001b). Currently only stem cell therapy using HSCs are being applied using ex vivo techniques, but many other therapies are under investigation(John Wiley & Sons, Ltd 2001a).

In vivo stem cell therapy is used when no suitable cells exist for ex vivo gene therapy, so direct injection of the therapeutic gene into the stem cell population is necessary(Naldini et al. 1996). The future of in vivo research gives a very positive outlook on the possible treatment of diseases such as cancer, diabetes, Parkinson's, Huntington's, Celiac disease, cardiac failure, muscle damage and neurological disorders(Gurtner et al. 2007).

Development of Haematopoietic stem cell therapies.

One of the earliest developments of gene therapy using stem cells was that of murine models to help diagnose and treat β-thalassaemia and sickle cell disease (SCD)(John Wiley & Sons, Ltd 2001c). In 1983 Mann et al. (Mann et al. 1983) completed the stable transfer of genes into the chromosomal DNA of mouse HSCs using recombinant murine leukaemia retroviruses. The stable expression of these genes (encoding viral replication and production proteins) in the mouse fibroblast cell line enabled these cells to produce the recombinant gene product. This was the first major advance in the gene therapy field, and raised the possibilities of genetic therapy for the treatment of many disorders involving the haematopoietic system. The next major breakthrough came in 1985 when Bernstein and Armstrong both reported that it was possible to alter the genome of mouse HSCs permanently using a recombinant oncoretroviral vector containing a reporter gene (Eglitis et al. 1985; Dick et al. 1985).

Although these papers showed promising signs of development in this field, there were still problems to be overcome. Most importantly the identification of sequences which would enhance the expression of the transgenic genes to the levels required. In the late 1980s a key region was identified for the β-globin gene cluster, known as the locus control region (LCR) The LCR is a series of nuclease hypersensitivity (HS) sites in the 21kb immediately upstream of the β-globin gene (Grosveld et al. 1987). This work was continued to show that the LCR enhanced the activity of the gene greatly. Unfortunately Grosveld et al. found that these HS sites were unusable in a clinical setting, containing many serious problems. (M Sadelain et al. 1995) managed to refine this process and develop a working model based on Grosveld et al.'s work. Following these breakthroughs two papers (Karlsson et al. 1988; Dzierzak et al. 1988) reported the successful transfer of a β-globin gene (including its minimal promoter elements) into mouse HSCs using an oncoretroviral vector.

Much more recently murine models of SCD (Blouin et al. 2000) and β-thalassaemia (Persons et al. 2001) have been the centre of studies on levels of transgenic HSCs required for therapeutic effect. The authors agreed that the expression of the transferred globin gene must reach at least 10-20% of the endogenous globin in the majority of developing erythroblasts for the therapeutic effect to be beneficial. It was understood that the larger the HS fragment that could be transferred, the more potent the treatment would be, and the higher the level of β-globin expression.

The development of a recombinant lentiviral vector systems, derived from components of HIV, allowed major advances in the amount of HS fragments that could be transmitted (Naldini et al. 1996; May et al. 2000). The major impact of the lentiviral vector system is its ability to suppress aberrant RNA processing. In the murine oncoretroviral system this processing led to instability of the blobin vector upon insertion and in some cases genome rearrangement. Therefore a β-globin lentiviral vector could accomplish efficient gene transfer and globin gene expression sufficient to restore the diseased phenotype to a healthy one (Rivella et al. 2003; May et al. 2000). The authors also stated that expression levels are always much higher with higher copy number of the transferred gene.

Current stem cell therapies.

The only stem cell therapy that is widely used is that of bone marrow transplantation. In use for over 30 years, originally it required the extraction of bone marrow tissue directly from the long bones of the body, but more recently, with the use of cytokines, it has been possible to extract the required stem cells (HSCs) from the circulating blood (lectures given by Dr Bunce). Recently there has also been an inclination towards using umbilical cord blood for this same therapy, but as this carries a risk it has not become as prevalent. Patients who undergo chemotherapy or radiotherapy are subjected to the destruction of the majority of their actively growing cells. For example the target leukaemia cells are killed, but so are the HSCs, which are required for normal regeneration in the blood system. Transplantation of HSCs can reverse this and allow the body to continue to replenish the blood as it would normally pre-chemotherapy (lectures give by Dr Bunce).

A recent BBC news article (2005) (http://news.bbc.co.uk/1/hi/england/southern_counties/4495419.stm) reported on the use of adult stem cells to restore the vision of 40 patients with damaged cornea. The Queen Victoria hospital in West Sussex trialed the process of implanting donated stem cells, either from the patient themselves or a donor, into the areas of the cornea that required treatment. The stem cells were obtained from limbal tissue cells and cultured ex vivo to form sheets of cornea tissue pre-implantation. The work was originally pioneered in 1997, it was discovered that corneal progenitor cells are located in the limbus, and these cells can be cultured ex vivo to form corneal sheets, which can be subsequently implanted into a host cornea, to restore the correct function (Pellegrini et al. 1997).

Future prospects for stem cell therapies and their limitations.

There are many studies currently being undertaken to determine whether it is viable to use stem cells therapeutically to combat tissue damage and disease. The relatively large amount of funding made available to this broad area of research underlines the high expectations that funding bodies have for stem cell therapies.

Patients who suffer a stroke or trauma of the brain will experience neural cell death. The neural stem cells actively divide and differentiate to become progenitor cells. These progenitor cells will migrate within the brain to the area of trauma (John Wiley & Sons, Ltd 2001d). This system is regulated by a number of growth factors that increase the rate at which stem cells self-renew and differentiate. There is compelling evidence to state that this system lacks robustness, as post-stroke or serious trauma the system will proceed as usual, but recovery is very rarely to the point of pre-stroke or trauma (John Wiley & Sons, Ltd 2001d).

If this is the main issue surrounding the ineffectualness of neural stem cells to recover from trauma/stroke then keeping a library of neural stem cells for a patient, which can be reintroduced at anytime to greatly increase the number of available progenitor cells, would be beneficial to the recovery process. By this same method it is arguable that neural stem cells could be used to treat Parkinson's and Alzeihmer's disease, although there are many more problems to be overcome in these potential treatments (Lindvall & Kokaia 2010).

Recent research from the Harvard medical school showed that the injction of human neural stem cells into the intercranial tumours rats could be therapeutic (Emsley et al. 2004). The neural stem cells migrated into the cancerous areas within days of injection and produced cytosine deaminase, which converts a pro-drug (currently non-toxic) into a chemotherapeutic drug (Emsley et al. 2004). This injected substance, upon interaction with the cytosine deaminase reduced the tumour mass by 81% (Emsley et al. 2004). In this study the stem cells were found to neither differentiate or become tumourgenic/harmful in anyway.

In 2003 multipotent adult stem cells from umbilical cord blood were transplanted directly into the spinal cord of a patient suffering from a long term spinal cord injury. The patient had been unable to walk for over 15 years, but is now able to walk freely (Kang et al. 2005). This study implies that blastocyst stem cells may be able to differentiate into neural cells upon reinjection into the neural system. More work needs to be done to confirm this finding. If these treatments prove to be a continuing success then subsequent treatments of muscular dystrophy and other spinal cord injuries may be possible.

A 2009 clinical trial using adult stem cells to treat heart damage due to coronary heart disease and chronic heart failure has now been completed (Strauer et al. 2009). The authors declared the treatment to be safe and effective, and it is now moving into the next phase of trials. This led the U.S. departement of health and human services to further report on possible mechanisms of treatment of heart damage by adult stem cells (http://stemcells.nih.gov/info/basic/basic6.asp).

The theory of healing wounds, which are too severe for the body to fully heal, using cultured stem cells has been discussed for many years. In the foetus wounded tissue is replaced with normal tissue, whereas in adults it is replaced with scar tissue, this is much less desirable. Recently techniques have been described, by which adult stem cells are manipulated to carry out this function. This would reduce the need for ESCs, and make the treatment much less controversial (Gurtner et al. 2007).

Other, less prominent, areas of research currently being undertaken for stem cell therapy are baldness, missing teeth, behavioural birth defects, deafness, diabetes, infertility and orthopaedics. These areas may not be as ground breaking as others, but serve as a reminder of how versatile stem cell therapies can be, and how large a variety of potential treatments are available.

Section about iPS here?

Discussion

Although many stem cell therapies are already a routine part of modern medicine, there is great potential for future clinical use in this field. HSCs have been established as a front line treatment for bone marrow deficiencies, mostly caused by other treatments such as chemotherapy, but they are quickly being caught up by other stem cell based treatments. The trial from the Queen Victoria hospital underlines the faith that the scientific community have in these therapies, and the results support this.

Funding for research into stem cell therapies is ever increasing, as the public and private sector recognise the potential benefit, and potential income, from this field. The more recent trials, which use adult stem cells to treat issues such as heart damage are very important to the development of stem cell therapies. There is an important argument surrounding the use of ESCs, debating at what stage of an embryo's development would it constitute murder when harvesting the ESCs. This limits the amount of ESCs available for study in many countries, and makes it difficult, in some cases, to fully culture the required tissue.

The relatively new technique of creating induced pluripotent stem cells (iPS) attempts to overcome this problem. By understanding the mixture of environmental factors, transcription factors and cell-cell interactions research scientists hope to induce pluripotency in adult stem cells to a point where they are analogous to ESCs, and can carry out the same processes.

Finally there is the potential of stem cells to be used in a non-direct clinical setting. Many diseases in the body are hard to diagnose, let alone experimentally understand. By culturing stem cells ex vivo, to form the diseased tissue, there is a virtually unlimited supply of tissue to work with. This would allow research scientist to carry out as many tests as required to understand the disease process and discover the most effective treatments.

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