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Stroke is a disease which leads to irreversible neurological damage. Stroke is sudden deficit of oxygen to brain caused by disruption in blood flow. Stroke resulting from disruption in blood flow can result from a blood clot in the artery, called an ischemic stroke or by a rupturing blood vessel, called a haemorrhagic stroke. Ischemic stroke accounts for most of the stroke cases. Ischemic stroke occurs as a result of fatty deposits lining the blood vessels which can lead to thrombosis. Ruptured blood vessel in haemorrhagic stroke results in internal bleeding within the brain. The severity of stroke depends on location and size of the effected brain region .i.e. if the stroke occurs in the cerebellum, the motor control of the body will be affected. Unlike many other neurodegenerative diseases, stroke does not only effect homogenous neuronal population but it can affect any region of the brain consequently affecting the body's function controlled by that region of the brain (Savitz et al.2004). Risk of stroke is increased by several factors like hypertension, high cholesterol levels and coronary heart disease. Therefore, it is vital to primarily prevent stroke by managing these risk factors.
It was previously understood that there was no treatment to reverse the neurological damage caused by stroke. However, many studies have now emphasised the use of stem cell transplantation as successful therapeutic technique to promote functional recovery in stroke (Bliss et al.2007). Stem cell therapy can be applied to understand modelling, neuroprotection and regeneration involved in stroke. Stem cell therapy can be broadly divided into 2 types; Exogenous stem cell therapy where embryonic stem cells, adult stem cells and induced pluripotent stem cells are transplanted into the body and endogenous stem cell therapy where neural stem cells are endogenously stimulated to undergo differentiation (Bliss et a.2007).
Stroke induced brain damage can be functionally improved by promoting endogenous neurogenesis. Brain like other tissues in the body has adult stem cells (neural progenitor cells that act like stem cells) that can be manipulated exogenously or stimulated endogenously to regenerate the neurones and connection pathways. Endogenous neurogenesis is natural process when brain is struck with stroke. The extent of endogenous neurogenesis is limited and doesn't fully restore neuronal functions lost as a result of stroke, though endogenous neurogenesis can be promoted to greater extent. Neural stem cells in brain can be directly affected by growth factors or stem cells can be transplanted in brain to increase endogenous neurogenesis. Endogenous neurogenesis can be promoted by transplanting manipulated stem cells that secrete pharmaceutical compounds to encourage stem cell proliferation and migration however, it is difficult to control secretion of these pharmaceutical compounds. Transplantation of exogenous stem cells lead to migration of neural stem cells in brain to site of lesion leading to increased neurogenesis. In addition to increased proliferation of neural stem cells, occurrence of stroke also promotes recruitment and migration of stem cells from other tissues of the body (Bone marrow). (Komitova 2005, cited in Liu et al 2005, p.469-480) .Stimulation of neural stem cells endogenously is proven to be relatively successful as low risk of contamination or rejection because of in vivo procedure however the the cells originate form limited source.
Stroke induced damage to large extent can be repaired by transplantation of stem cells. The most frequently used stem cells are embryonic stem cells, adult stem cells and neuronal progenitor ( neuronal stem cells) isolated from rodents and humans (Liu et al.2009). Stem cells are able to restore lost neurological functions by mechanism whereby they integrate into host cells, reduce cell death, increase in migration and proliferation of endogenous stem cells. Stem cells have self-renewal capability which allows them to undergo cell division. Stem cells have potential to differentiate into almost all cell types so therefore classed as undifferentiated cells. Their capability to replace damaged tissues allows their therapeutic use in treatment of many neurodegenerative diseases.
Embryonic stem cells are derived from inner mass of blastocyst of a foetus. Isolation of embryo blast from embryo leads to death of the foetus raising ethical issues. Frozen embryos are collected from IVF or abortion clinics and cultured to grow in vitro until blastocyst stage. At this stage, inner cells of blastocyst are extracted and cultured in multi-step procedure to grow producing ESCs (National Institute of Health.2001). These cells can then be administered to stroke sufferer intravenously or grafted to the effected brain region. ESCs have self-renewal properties and they can replicate indefinitely to regenerate damaged neural tissue. ESCs can develop into neurons replacing the damaged neurons restoring lost functions controlled by those neurons. ESCs are specifically of great interest due to their increased pluripotency in comparison to other stem cells and they can be manipulated in vitro prior to transplantation but cells must survive transplantation procedure . ESCs can be genetically altered to increase their survival rate and successful differentiation to promote functional recovery in stroke (Xia et al 2006, cited in Liu et al 2009, p.469-482). Furthermore production of tumor due to contamination at the site of implant can be a huge safety concern despite regeneration of the tissue. However, the risk of tumor can be reduced by using neural stem cells derived from ESCs. When these neural stem cells were transplanted in mouse with ischemic stroke, they integrated and expressed into neurons without causing tumor. (Takagi et al (2007) cited in Liu et al (2005)).
Research has been carried out using ESCs to improved stroke induced damages in mice. ESCs were transplanted in mice and following 8 days of controlled measurements, a reduction in brain lesion size was noticed suggesting that EMS transplantation can reduce brain damage caused by stroke. Together with reduction in brain lesion size, there was also an increase in the number micro vessels indicating that ''embryonic stem cell transplantation reduced the brain lesion through the acceleration of angiogenesis by endogenous endothelial cells'' (Nobuo, N. 2010).
Currently no clinical trial has completed using ESCs to treat stroke. Using ESCs involve great ethical and safety issues together with the concerns regarding the number of embryonic stem cells needed from limited source which raises a huge economical and practical issue. However, ESCs have been used in animal models where positive results hold great promise for clinical trials.
Existing cell lines of embryonic cells and adult stem cells can be used as an alternative source in stem cell therapy.
Adult stem cells also known as somatic stem cells are undifferentiated cells found in specific regions of several tissues throughout the body. They are undifferentiated cells and they can specialise to form cell types of several different tissues. Adult stem cells have self-renewal properties but unlike embryonic stem cells, they do not divide indefinitely. Adult stem cell can be stimulated endogenously to promote differentiation into specific cell types and promote migration to target site. Adult stem cells can also be extracted, manipulated and transplanted at target site to allow the cells to undergo differentiation.
Adult stem cells promote recovery after stroke by mechanism which releases tropic factors which leads to reduction in cell death. Adult stem cells promote recovery by endogenous repair mechanism which stimulate neurogenesis and angiogenesis (Savitz et al.2004)
The exact mechanism of repair by stem cells is still unclear, however research conducted on mice suggests that the functional repair by adult stem cells facilitate axonal sprouting and remyelination at region damaged by stroke and corpus collasum which leads to functional improvement in neurological functions (Shen et al. 2006).
Type of pluripotent adult cells, marrow stromal cells were cultured exogenously and administered intravenously to twenty five rats who suffered ischemic stroke. Neurological improvements in rats were observed over 14 days. The research concluded that marrow stromal cells migrated to site of stroke and lead to functional improvement without any significant adverse reactions. This research indicates the use of adult stem cells in further clinical trials and potential use of adult stem cells in treatment for stroke (Li et al. 2001)
Mesenchymal stem cells (MSCs) are adult stem cells and they have the ability to migrate to site of damage, differentiate into neurons and improve neurological functions. ''Many studies showed that MSC treatment decreases mortality, infarct volume and neurological deficits after ischemic stroke in rodents'' (Liu et al 2009, pp. 469-480).
MSC have been used in clinical trials using 30 people who suffered from ischemic stroke. Patients who suffered from stroke were randomly chosen for the clinical trial. The group was divided into two, one of which received intravenous administration of autologous mesenchymal stem cells (undifferentiated adult stem cells) and the other was the controlled group. Neurological improvements in both the group were measured using neuroimaging. The result concluded significant neurological improvements in patients who received stem cell treatment (Bang et al. 2005).
MSC can be cultured to form neural stem cells which have greater impact on improvement of neurological functions (Liu et al.2009). MSCs are considered the main source of stem cells for stem cell therapy as they are readily available in bone marrow and bone marrow clinics however the extraction process is relatively painful.
Bone marrow stromal cells (BMSCs) can improve neurological functions damaged by stroke. This improvement is noticed as a result of increased neurogenesis and angiogenesis which primarily occurs as result of differentiation of BMSCs into neural cells upon exposure to growth factors (Savitz et al. 2004). Bone marrow stromal cells can be extracted from the patient's bone marrow however, the procedure is painful and intravenous administration may affect other tissues.
Neural stem cells are adult stem cells found throughout the central nervous system (CNS). Neural stem cells can also be isolated from embryonic human brain. Neural stem cells have the ability to promote neurogenesis after stroke. Intracerebral, intraventricular or intravenous administration of embryonic mouse neuronal stem cells in rats who suffered ischemic stroke showed expression of neuronal marker as a result of migration of stem cells into ischemic striatum (Jen et al 2005, cited Liu et al 2009, p. 469-480). Neural stem cells can also be produced by separation from cell cultures of embryonic human CNS. Neural stem cell lines, retro virally transduced with the v-myc oncogene, were studied in a rat with haemorrhagic stroke (Savitz et al.2005). Haemorrhagic stroke has different pathology compared to ischemic stroke so the results displayed from this study requires in depth analysis before it can generalised. Haemorrhagic stroke damages the neuronal pathway unlike ischemic stroke which affects the neural cell body. Nevertheless, neural stem cells can lead to functional repair in ischemic stroke.
Use of the immortalized human neural stem cell line NT2N derived from NTera 2/D1 teratocarcinoma cell line is the most promising exogenous stem cell therapy for treatment of stroke. NT2N transplanted in striatum of rats after ischemic stroke lead to functional improvement (Sparota et al 1999, cited in Liu et al 2009, p. 469-480). Neural stem cells are safer and more practicable then other stem cells. Successful trial in animal has lead to first clinical trial in humans.
World's first regulated clinical trial called Pilot investigation of stem cells in stroke using stem cells produced by ReNeurone has been initiated in Glasgow. The purpose of this trial is to establish safety of stem cell therapy for the treatment in ischemic stroke in humans. Animal studies have already suggested that the cells are safe and effective in restoring functions lost due to stroke. In this study, the patient will be closely monitored over two years time to determine the effect of stem cell therapy on neurological functions effected by stroke. The successful completion of this clinical trial may be milestone in treatment of stroken (Sample,I.2010).
Adult stem cells are great candidates for stem cell therapy. However, their self-renewal capability and mobilization rate is low. In vitro procedure of extracting, manipulating and transplanting adult stem cells carry hug risk of contamination. Adult stem cells can be extracted from the patient to be used in stem cell therapy for that same patient therefore there is less like hood of rejection. Induced pluripotent stem cells (IPSCs) can be used as an alternative to adult stem cells.
Induced pluripotent cells are adult 'host' somatic cells that are reverted back to embryonic stem cell state by means of genetic manipulation. They are reprogrammed to express transcription factors essential in maintaining their embryonic stem cell properties. Induced pluripotent cells can differentiate into almost all types of cell have the same morphologies as the embryonic stem cells. IPSCs are derived by transfection of certain stem cell genes into non-pluripotent stem cells. To produce pluripotent stem cells, firstly host cells are extracted. Following extraction, they are cultured and then transfected with viral vector containing embryonic stem cell genes. The cells expressing correct genes (ESCs genes) are identified and sequestered. These cells are then cultured with mitotically inactivated feeder cells. A small population of the cells will form IPS colonies containing embryonic stem like properties. Four genes, Oct-3/4, SOX2, c-Myc, and Klf4 are essential for induced pluripotent stems cells to enable them to exhibit same properties as embryonic stem cells.
The first line of mouse induced pluripotent stem cells was produced in 2006 with DNA methylation errors. Following year in 2007, second generation of induced pluripotent cell lines was produced using mouse adult cells without c-Myc as it is an oncogenic gene and cell can survive without c-Myc gene (Swaminathan, N. 2007). The same year, induced pluripotent cells were obtained from human fibroblast cells (Takahashi et al. 2007). Induced pluripotent cells have been tested to identify its effect on stroke. Injection of induced pluripotent cell into stroke induced damage area of the brain can improve motor functions and reduce lesion size. Induced pluripotent cells mixed with fibrin glue have shown to increase therapeutic effects by promoting neuroprotection after stroke with decrease in lesion size. Mixing IPSC's with fibrin have been reported to reduce the risk of iatrogenic injury to the brain. (Chang et al.2010)
The main drawback for using induced pluripotent cells is formation of tumor. To minimise safety concerns, induced pluripotent cells were produced using recombinant proteins(Chang et al.2010). Although this method was low in efficiency, further in depth analyses of this method can provide more efficient and safer induced pluripotent cells with less risk of tumour.Induced pluripotent cells can be manipulated exogenously in vitro and they provide continuous supply of cells once transplanted in to the brain. However, exogenous manipulation may give rise to contamination.
Successful use of stem cell to treat stroke in animals highlights the use stem cell therapy in future for incurable neurodegenerative disease. Many questions need to be considered to optimize success rates for stem cell therapy. Key points to be considered are the site of implant, location and size of the infarct, route and site of migration, best cell types and severity of stroke. Successful Research on animals have pointed towards more clinical trials and upon successful completion of these clinical trials, generalised findings can be used to treat stroke in human. Many issues need to be overcome before stem cell therapy can be applied amongst patients globally. Most importantly ethical concerns are hugely debatable with questions relating to practical safety of stem cell therapy. Stem cell treatment currently on its initial stage of clinical trials doesn't seem to be cost effective. Furthermore, it is inconclusive whether or not stem cell therapies are sustainable lifelong so more long term research need to be conducted. Evidently, greater in depth understanding of all aspects concerning stem cell therapy need to be further researched before applying it in humans globally.