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Stem cells have been a source of cells for therapeutic applications in metabolic, degenerative and inflammatory disease, for the repair and regeneration of damaged or lost tissues as well as in the treatment of cancer. They can be defined as undifferentiated cells with self-renewing capacity which are capable of proliferation, selfmaintenance, the production of a large number of differentiated functional progeny, regenerating the tissue after injury and flexibility in the use of these options. Various stem cell types can be isolated from different tissues of the human body, expanded and/or differentiated in vitro, and subsequently administered to patients (1,2).
Hematopoeitic stem cells (HSCs) are one of stem cell types which have the unique capacity generating some daughter cells to keep stem-cell properties (3). They can give rise to differentiated cells of all haematopoetic lineages, myeloid and lymphoid, either in the haemopoeitic bone marrow or in the thymus. They can be found in the placental and cord blood at birth in concentratios similar to levels found in adult bone marrow. HSCs have lower frequency in the peripheral blood which are localized in the red bone marror in adult bone marrow. They are mobilized to the blood compartment after treaments with intensive chemotheraphy and/or growth factors (2).
Hematopoeitic stem cell transplantation (HSCT) was established more than 50 years ago to treat either the injury of irradiation or cancer. It is used primarily not only for hematologic and lympoid cancers but also other disorders such as aplastic anemia, thalessemia major etc. Table 1 shows diseases which can be treated with hematopoetic stem-cell transplantation. There are 2 kinds of transplantation in hematopoetic cells. They are autologous and allogenic transplantation. The autologous transplantation is genetically identical to that of the recipient resulted in an immunologic reaction while the allogeneic is not (3). Allogeneic hematopoetic stem cell transplantation is a procedure to treat hematopoetic malignancies, marrow failure syndromes and hereditary immunodeficiency disorder (4). The most common indication of allogeneic HSCT is for relapsed or refractory acute leukemia which is the most common childhood malignancy.
Table 1 : diseases commonly treated with HSCT
Acute myeloid leukemia
acute myeloid leukemia
acute lymphoblastic leukemia
Chronic lymphocytic leukemia
Juvenile chronic myeloid leukemia
Paroxysmal nocturna hemoglubinuria
Black-fan diamond anemia
Sickel cell anemia
Severe combined immunodeficiency
Inborn errors of metabolism
There are 3 HSCs sources today, they are bone marrow (BM), peripheral blood progenitor cells (PBPC), and umbilical cord blood (UBC).
Bone marrow is the first source of HSCs sources. It is obtained by repeated aspiration of the posterior iliac crests whereas the donor is under general or local anesthesia. Discomfort feeling of harvesting procedure will be disaappeared after 2 weeks. It can detach continuosly, enter te circulation and return to the marrow (3). Matched unrelated donor bone marrow was succefully generated in 1979 which did not have graft-versus-host-disease (GVHD) (5).
Procurement of Graft and Donor Safety
All HSCT donors must undergo donor screening using testing and screening questionare within 30 days of their donation with compliance of the applicable laws of their country. They must meet the following requirements:
They must no have any infectious disease which can be transmitted through the blood such as human imunodeciency virus (HIV) 1 and 2, human T-lymphotro (CMV), west nile virus, syphilis, chagas diease, hepatitis B and C, herpes simplex virus, varicella zoster virus, toxoplasmosis and epstein barr virus (EBV).
They must have a screening physical examination.
They must give written informed consent for donation.
For children, their parents or legal guardians provide consent.
For cord blood donors, the mother of the baby provides consent.
Bone marrow harvest from minors.
BM harvest from sibling donors is the most common method to get hematopoeitic progenitor and stem cells. There are some techniques of this method:
Insertion of large bore needles into the posterior illiac crests.
It is not suitable for young children due to smaller size of their bones, post procedure inflammation, chronic scarring and post operative discomfort. The number of bone entry sites could be limited by repositioning the harvest needle within the bone. all donors have to take iron supplementation few weeks before and 2-3 months after a BM harvest. The circulating blood volume of a pediatric donor, transfusion of irradiated, ABO-compatible red cells must be concerned during and after the BM collection.
Semi-automated processing technique to salvage red blood cells from pediateric BM donors.
This technique salvages red blood cells from pediatric BM donors to minimize the severe anemia risk following BM harvest and ABO incompatibility. It can reduce the risk of post-bone marrow harvest anemia, decreased volume infused into the donor. The mononuclear and CD34+ cell population will be increased without affecting reconstitution (5).
The administration of recombinant human erythroprotein (rh-Epo) to normal pediatric BM donors.
There is no longterm safety data in this technique and it is not recommended in routine marrow harvest from healthy pediatric donors.
There is no severe adverse effects in bone marrow harvest. Fatigue, transient anemia, local pain at the harvest site(s) are rare and self-limited. However, the responsible team must be experienced for the information, pre-harvest physical examination, donor clearance, general anesthesia and BM collection. The psychological responses should be given particular attention to the pediatric donors (5).
Bone marrow harvest from adults
The technique is similiar with pediatric donors. Minor adverse effects are transient syncope, headache, local infectious whereas severe adverse effects are rare. Donor safety is highly noted such as careful donor selection and follow up (5).
Peripheral blood progenitor cells (PBPC)
PBPC is estimated with use of the cell-surface molecule CD34 as a surrogate marker. Granulocyte colony-stimulating factor (G-CSF) can increase the number of CD34+ cell in blood and cause the proliferation of neutrophils and the release of proteases. Proteases degrade the proteins that anchor the stem cells to the marrow stroma and together with protease-independent mechanisms (3).
PBPC collection from G-CSF stimulated pediatric sibling donors
PBPC is implemented by G-CSF administration about 4-6 hours per day. The number of collections depends on the number of stem cells collected with each procedure. Pediatric donors have high medical risks and complications of PBSC collection such as low platelet count, anemia, vasovagal complications, hypotension, nausea etc. There is also a high risk of leukemia for the siblings of patients with the cancer after short term exposure to G-CSF. G-CSF-mobilized stem cell or G-CSF primed BM harvest could be implemented for pediatric donors though the safety data is limited (5).
PBPC collection from G-CSF stimulated adult donors
The serious adverse effects of this method are low. The most common side effects are bone pain, headache, fatigue, hypocalcemia and thrombocytopenia. Women and obese donors are not recommended due to the increase of adverse effects (5).
Umbilical cord blood
Umbilical donor cord blood (UCB) is a suitable alternative source of hematopoietic progenitors (CD34+) for allogeneic stem cell transplantation in patients who lack HLA-matched marrow donors (6). UCB transplantation (UCBT) from matched related siblings has been established since 1988 (5). The advent of UCBT has improved allogeneic transplantation as a treatment and more beneficial than donor bone marrow transplantation (UBMT) including rapid availability, low risk of infection transmission, absence of donor and the relatively lower risk of graft-versus-host disease (GVHD). The disadvantage of UCBT are the limited cell dose, delayed engraftment, and lack of additional immune cells if donor lymphocytes are needed (6).
The availability of volunteer Human leukocyte antigen (HLA) matched unrelated donors (MUD) has been established since many children with acute leukemia have an indication for allogeneic HSCT. The unrelated umbilical cord blood transplantation (UUCBT) has overcome the disadvantage of UCBT. The strategies to enhance engraftment of UUCBT are by combining two cord blood units, supplementing cord blood with haploidentical donor cells, third party mesenchymal cells, ex vivo expansion (5).
Procurement, processing, cryopreservation and banking
Cord blood is rich in hematopoeitic stem cells and typically discarded with the placenta at birth. It can be collected without physical risk to the mother or baby and from delivered placenta ror during the hird stage of labor (in utero). Many cord blood banks could perform either ex utero collections away from the delivery room or in utero colllections while waiting for the placenta to deliver. The process is after sterile preparation, the umbilical vein is punctured with a 17-gauge needle attached to a sterile, closed system bag containing citrate phosphate dextrose anticoagulant lower than the placenta. Blood flows from the placenta through the cord approximately 9-10 minutes and harvest an average of 110 ml from a single placenta. The cord blood unit is labeled and sent to the bank for processing, testing, cryopreservation and storage.