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The stem cells that form the myeloid and lymphoid cell lineages are known as the haematopoietic stem cells and are responsible for the constant renewal of blood. Haematopoietic stem cells are found in the bone marrow and are capable to give rise to all blood cell types (multipotency), self-renew, migrate out of the bone marrow into the circulating blood, and can undergo apoptosis which is programmed cell death (Wagers et al., 2002; Weissman et al., 2001).
Haematopoietic stem cells have long been harvested from the bone marrow. This is done by harvesting the marrow out of the bone. This is carried out by puncturing the hipbone or rare cases the sternum with a needle under general or local anaesthetic. However, there are risks involved for the donor which include fatigue, low back pain, stiffness while walking, bleeding at the procedure site and complications from anaesthesia or injury to nerves, muscles, or bone (Burt et al., 2008; Kesselheim et al., 2009).
Therefore, it is now preferred to harvest cells from the peripherally, circulating blood. This is carried out by inducing the cells to migrate from the bone marrow into the blood by pre-treating the donor with cytokines, such as granulocyte colony-stimulating factors, that allows cells to be released from the bone marrow into the blood, then a few days later cells can be harvested from the blood (Sugarman et al., 1997; Cutler and Antin, 2001; Pulsipher et al., 2006). There are risks to donors for taking out peripheral blood stem cells, as they are exposed to the general anaesthesia, exposure to blood products, growth factors to mobilise haematopoietic stem which may cause pain in the bone or headache and there has been concerns about inducing leukemic transformation (Cutler and Antin, 2001; Pulsipher et al., 2006). However, the risk of serious harm is relatively low (Kesselheim et al., 2009).
Peripherally harvested cells are a lot easier on the donor with minimal pain, no anaesthesia, and no hospital stay and it yields better cells for transplantation. Moreover, studies suggest that patients that receive peripherally harvested cells have a better survival rate than bone marrow transplanted patients. This may be due to the peripherally harvested cells containing twice as many haematopoietic stem cells than from bone marrow. Also, it has been shown to engraft more quickly onto the patient (Laughlin, 2001; Leung and Kwong, 2010). This means patients may recover white blood cells, platelets, and their immune and clotting protection several days quicker than they would with a bone marrow graft (Negrin et al., 2000). A major problem is that transplantations can cause graft-versus-host disease, in which the newly transplanted tissue attacks the patientsâ€™ body (Cutler and Antin, 2001; Pulsipher et al., 2006; Laughlin, 2001). Researchers believe that the main cause of failure of haematopoietic stem cells is host-versus-graft disease, and larger grafts permit at least some donor cells to escape initial waves of attack from a patient's residual or suppressed immune system (Beshlawy et al., 2009). Research currently done on mouse models support the idea that purified haematopoietic stem cells, cleansed of mature lymphocytes, engraft readily and avoid graft-versus-host disease (Pulsipher et al., 2006; Verlinden et al., 1998). This may help eliminate that cause graft-versus-host disease.
Increasingly, umbilical cord blood is harvested, frozen, and stored in cord blood banks, as an individual resource or as a general resource (Beshlawy et al., 2009). Since, blood from the placenta and umbilical cord are a rich source of haematopoietic stem cells, and these cells are typically discarded with the afterbirth. Cell populations residing in waste tissues (cord blood, umbilical cord, and placenta) may be collected without any medical or ethical issues concerning the mother or newborn baby (Beshlawy et al., 2009). Cord blood has been successfully used to transplant children. However, less frequently in adults as we are rarely able to extract more than a few million haematopoietic stem cells from a placenta and umbilical cord and transplants for an adult ideally need 7 to 10 million cells per kilogram of body weight (Lickliter et al., 2000). Moreover, umbilical cord blood does also have its limitation such as the delayed immune development leaving patients vulnerable to infections for a longer period of time. However, umbilical cord blood is readily available, easy to harvest, reduced transmission of infection, able to store and the reduced risk of graft-versus-host-disease (Laughlin, 2001; Koh and Chao, 2004). In addition, cord blood haematopoietic stem cells have been noted to have a greater proliferative capacity than adult haematopoietic stem cells (Beshlawy et al., 2009). Several approaches have been tested to overcome the cell dose issue, including, with some success, pooling of cord blood samples (Koh and Chao, 2004).
Moreover, the low cell count of the graft limits the cord blood therapeutic efficacy as it is associated with increased delayed or failed engraftment (Beshlawy et al., 2009). Scientists have shown that a larger number of stem cell grafts have a better chance of surviving in a patient. Therefore, being able to expand the number of human haematopoietic stem cells in vivo or in vitro would be an enormous advantage to all current and future uses of haematopoietic stem cells transplantation (Weissman et al., 2001; Burt et al., 2008).
The use of cord blood has opened a controversial treatment strategy, embryo selection to create a related umbilical cord blood donor has emerged where embryos are conceived by in vitro fertilization, the embryos are tested by pre-implantation genetic diagnosis to select a disease free or human leukocyte antigen matching the affected sibling, which are then implanted into the mother and conceived. Cord blood from the resulting newborn is then used to treat the affected sibling. But raises many ethical questions, such as are the parents willing to love and care the donor child as a family member and purely look at them as a hematopoietic stem cell donor for their sick child? And even if the parents will love and care for the donor child, there are many risks the child is exposed to. For example, if the umbilical cord blood transplant fails, they may be faced with a decision about a bone marrow harvest from the infant in the first months of life, exposing the child to procedure-associated risks. Parents are conflicted in that they must consider the interests of the donor child and the recipient child (Grewal et al., 2004). Is it right to expose healthy children to such treatments at such a young age?
Regardless, the general consensus is that parents are in the best position to decide whether or not a young child should donate bone marrow to a sibling. The process of obtaining parental permission and child assent may include an independent assessment of the child donor's understanding, concerns, and willingness to donate (Pulsipher et al., 2006). However, the institutional review board does not allow these benefits to count as direct research benefits, regardless of their moral relevance (Grewal et al., 2004; Mychaliska et al., 1998). Some researchers therefore may feel that institutional review board should be more flexible about the regulations by approving research that seems ethical even when it does not actually meet regulatory requirements. However, allowing flexibility might ultimately allow approval of research that does not adequately protect human subjects (Mychaliska et al., 1998; Peerzada and Wendler, 2006). Moreover, the fact that ethical analyses of haematopoietic stem cells donation might be different between clinical and research settings is appropriate. Research is guided by the search for knowledge rather than the best interests of the subjects. Even when haematopoietic stem cells donation is ethically acceptable in the clinical setting, requiring it to satisfy research regulations as well ensures adequate human subject protection in the research setting (Mychaliska et al., 1998; Chan et al., 1996; Ross, 1994; Ross, 1993).
Requiring approval for transplant research that do not fit the minimal risk category with respect to the donor seems appropriate, especially given the conflicts of interest that parents might face when deciding whether to allow one child to participate in a transplant protocol in order to benefit another (Peerzada and Wendler, 2006). On the other hand, some may consider it too restricted in light of the lifesaving potential of transplant research and the fact that transplant donation within a research may be considered ethical in many circumstances (Kopelman and Murphy, 2004; Kopelman and Murphy, 2004).
The main application of haematopoietic Stem Cells is transplantation can be autologous or allogeneic. Autologous transplantations uses patients own haematopoietic stem cells and so no host-versus-graft disease. The main disadvantage of an autologous graft in the treatment of cancer is the absence of a graft-versus-leukaemia or graft-versus-tumour response, the specific immunological recognition of host tumour cells by donor-immune effecter cells present in the transplant. Moreover, the possibility exists for contamination with cancerous or pre-cancerous cells (Brown and Boussiotis, 2008; Paulson et al., 2011).
Allogeneic transplantations occur between two individuals who differ in their human leukocyte antigens, proteins which are expressed by their white blood cells. The immune system uses human leukocyte antigens to distinguish between self and non-self. For successful transplantation, allogeneic grafts must match most, if not all, of the six to ten major leukocyte antigens between host and donor (Brown and Boussiotis, 2008; Ferrara et al., 1999). The main advantage of allogeneic grafts is the potential for a graft-versus-leukaemia response, which can be an important contribution to achieving and maintaining complete remission (Brown and Boussiotis, 2008; Paulson et al., 2011).
Among the first clinical uses of haematopoietic stem cells were the treatment of cancers of the blood, leukaemia and lymphoma (Paulson et al., 2011), which result from the uncontrolled proliferation of white blood cells. In these applications, the patient's own cancerous haematopoietic cells were destroyed via radiation or chemotherapy, and then replaced with a bone marrow or with a transplant of haematopoietic stem cells collected from the peripheral circulation of a matched donor (Brown and Boussiotis, 2008). Although there was significant risk of patient death soon after the transplant either from infection or from graft-versus-host disease, for the first time, many patients survived this immediate challenge and had survival times measured in years or even decades, rather than months. A recent strategy is transplantation using umbilical cord blood, allowing us to be able to expand the potential donor pool while reducing the level of graft-versus-host disease. Allogeneic haematopoietic stem cell transplants are also used in the treatment of hereditary blood disorders, such as different types of inherited anaemia, and inborn errors of metabolism. These disorders include sickle-cell anaemia, Hunter's syndrome and osteopetrosis (Brown and Boussiotis, 2008; Paulson et al., 2011).
Another application in cancer therapy, patientsâ€™ haematopoietic stem cells are collected and stored while they undergo chemotherapy or radiotherapy to destroy cancer cells (Brown and Boussiotis, 2008). Once the drugs have washed out of a patient's body, the patient receives a transfusion of their stored haematopoietic stem cells. As patients get their own cells back, there is no chance of graft-versus-host disease. However, one problem with the use of autologous haematopoietic stem cells transplants in cancer therapy has been that cancer cells are sometimes accidentally be collected and re-infused back into the patient along with the stem cells (Saiz and Graus, 2010).
Haematopoietic stem cells have seen widespread clinical use. Yet the study of haematopoietic stem cells remains active and continues to advance very rapidly. Fuelled by new basic research and clinical discoveries, haematopoietic stem cells hold promise for such indications as treating autoimmunity, generating tolerance for solid organ transplants, and directing cancer therapy. However, many challenges remain. The availability of (matched) haematopoietic stem cells for all of the potential applications continues to be a major hurdle. Efficient expansion of haematopoietic stem cells in culture remains one of the major research goals. With the possibility of ex vivo expansion of umbilical cord blood, some of the ethical issues raised currently in this field can be lessened.