On the "controversial" side we got Embryos, Aborted Tissue & cells derived from SCNT.
On the ASC side, we got blood, hypocampus & bone marrow. What about Cadeavers?
I'm sure I'm missing a ton of them. Perhaps it would be good to organize these into some kind of order based on ease of extraction & efficacy or also by some kind of political/controversial order?
What about isolating Spinal Cord Cells from Cadeavers & then growing these in huge quantities in a dish? Could this be a good source of cells that are predisposed to producing neurons, axons, etc?
Abstract
Since its first use more than 30 years ago, bone marrow transplantation has been a curative treatment for leukemias, malignant and nonmalignant disorders of the hematopoietic system, metabolic disorders, and inherited immune system deficiencies. Treatment involves using marrow-derived hematopoietic stem cells to restore hematopoiesis in patients who have received myeloablative chemotherapy and/or radiation therapy. Because such treatment now also includes peripheral blood stem cells (PBSC) or stem cells harvested from the umbilical cords of neonates, stem cell transplantation is now the preferred term for this procedure. The National Marrow Donor Program (NMDP) coordinates unrelated donor stem cell transplants using all three sources of stem cells. This article reviews the clinical aspects of stem cell transplantation using marrow, PBSC, and umbilical cord blood units (CBU), with an emphasis on the procedures used in allogeneic stem cell transplants facilitated by the NMDP.
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Bone Marrow Stem Cells
As of December 2001, the NMDP had coordinated more than 13,000 unrelated donor marrow transplants, and more than 80,000 total autologous and allogeneic transplants have been performed worldwide through 1998 (IBMTR data [1]). Thus, marrow collection is an established medical procedure with extensive donor safety and recipient survival data. However, there are clinical issues for both the donor and recipient that a transplant physician must take into consideration when evaluating transplant treatment options.
Donor Issues
Marrow is harvested from the iliac crest of the donor's pelvis bones while the donor is under general or regional anesthesia. Overall, 77% of NMDP marrow donors receive general anesthesia, 16% receive epidural anesthesia and 7% receive spinal anesthesia. A marrow harvest involves several small incisions in the skin to accommodate a marrow aspirate needle. By inserting the needle at slightly different angles, a single incision in the skin can be used to make multiple punctures into the iliac crest.
On average, one liter of marrow is removed. The exact amount is determined by the needs of the transplant recipient -- larger recipients require more marrow. NMDP regulations prohibit collections greater than 1.5 L. The harvested marrow is placed into standard blood bags containing an anticoagulant such as Heparin and transported to the patient who has undergone myeloablative chemotherapy and/or radiation therapy.
Figure 1. Stem cells can develop into specialized cells.
Marrow harvests are usually very well tolerated by donors, but some mild to moderate side effects can occur, including localized pain (i.e., tenderness at the incision sites) (67%), slight lower back ache (51%), mild fatigue (74%) and occasional nausea (55%). [2] Complications requiring additional medical attention (such as infections at the incision sites) are rare, and serious complications such as cardiac infarctions and sepsis are very rare. [3]
Recipient Issues
Clinical experience with recipients of marrow-derived stem cells is extensive. Opportunistic infections and graft-versus-host disease (GVHD) are the two most frequent causes of transplant-related morbidity and mortality. As in all sources of allogeneic stem cells, marrow recipients may experience GVHD, an immunological response of the graft against the recipient. GVHD is categorized into acute and chronic types; GVHD is classified as chronic if it first appears 100 days or more post-transplant. Most often, GVHD presents as a skin rash, but bloody diarrhea, cramping and nausea are symptomatic of GVHD in the gut, and jaundice can indicate that GVHD is affecting the liver. Acute GVHD is treated prophylactically with cyclosporine, methotrexate and/or corticosteroids.
T-cells in the donor graft are thought to produce acute GVHD, so partial or complete T-cell purging is sometimes performed on the graft prior to infusion into the recipient. Unfortunately, while this procedure reduces the incidence of acute GVHD, it also raises the risk of graft failure. T-cells are also responsible for a graft-versus-tumor effect that can help eliminate any malignant cells remaining in the recipient after pre-transplant conditioning, which is not thought to be completely myeloablative.
Chronic GVHD occurs in approximately 60-80% of long-term survivors of allogeneic bone marrow transplant. [4] Treatment with prednisone, thalidomide, and/or cyclosporine has improved the long-term outlook for recipients with chronic GVHD.
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Peripheral Blood Stem Cells (PBSC)
The first successful autologous transplants using PBSC were performed in 1986. PBSC transplantation therefore has a shorter clinical history than bone marrow transplantation. A PBSC transplant raises significant clinical issues for both donors and recipients, and these are discussed here.
Donor Issues
Peripheral blood does not normally contain sufficient hematopoietic stem cells for a transplant. PBSC donors must first receive a granulocyte-colony stimulating factor (G-CSF) to stimulate hematopoietic stem cells to migrate from marrow cavities into the peripheral blood. Donors receive daily injections over 5-6 days of G-CSF (generic name: filgrastim), typically either 5 µg/kg/d or 10 µg/kg/d (NMDP donors receive 10 µg/kg/d). Harvest, by apheresis, usually starts on day 5 with a second harvest on day 6 if the first collection is insufficient for transplantation.
Donor side effects are mild to moderate and may include bone pain (up to 85% of donors), headache (40-70%), nausea and vomiting (10%), fatigue (15%), and myalgia (20%). [3] Donor discomfort can be reduced through administration of analgesics such as acetaminophen or an NSAID. Pain almost always resolves rapidly upon cessation of filgrastim, and a dose reduction may be necessary to allow donors to continue in the donation process. It is rare (1%-3%) that donor pain is so severe that filgrastim must be discontinued completely.
Other complications, though rare, are possible. These include stroke, anaphylaxis, arterial thrombosis, iritis, ITP, and splenic rupture. [3] While donors are receiving filgrastim, the white blood cell count, especially the absolute neutrophil count, will increase significantly. A dose reduction is recommended if the WBC count exceeds 70-75 x 109/L. [5]
Inadequate venous access may be present in as many as 10% of donors, requiring the insertion of a central line to accomplish apheresis. Central venous catheters are placed in the femoral vein, the internal jugular, or the subclavian vein. Complications from central line placement are uncommon, but include infection, hemorrhage, and pneumothorax.
Recipient Issues
The number of PBSC transplants facilitated by the NMDP is steadily growing, and PBSC donation is now the preferred donation method among related stem cell donors, primarily due to donor aversion to the risks associated with a marrow harvest, e.g., anesthesia and infection at the needle insertion sites. However, there are also several reasons why transplant physicians may prefer PBSC grafts for their patients.
Several studies have shown that patients receiving PBSC grafts achieve neutrophil engraftment and platelet engraftment significantly faster than marrow graft recipients. [6] In a study of NMDP transplants, patients receiving PBSC grafts (n=111) achieved platelet engraftment a median of 6 days faster than a matched cohort group of bone marrow recipients (n=118).
Despite the higher numbers of T-cells in a PBSC graft (10- to 20-fold higher than in marrow), several studies show that there is no significant difference in the incidence and severity of acute GVHD in PBSC recipients as compared to marrow recipients. [7, 8] However, some preliminary studies indicate that the incidence of chronic GVHD may be higher in PBSC recipients. [9, 10] Physicians must consider these clinical factors when deciding which source of stem cells is appropriate for their patients.
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Umbilical Cord Blood
In 1988, physicians transplanted human umbilical cord blood into a 5-year-old boy with Fanconi's anemia. [11] The success of this procedure led to the establishment of cord blood banks that collect, process, tissue type and cryopreserve cord blood units (CBUs) for use in stem cell transplantation. Using cord blood-derived stem cells for a transplant has both advantages and disadvantages, and a physician must weigh these factors carefully when deciding whether a cord blood transplant is appropriate for a particular patient.
Cord Blood and Matching
Typically, an allogeneic stem cell transplant is only performed if there is a 6-of-6 HLA-matched donor available (matching is done at each of the three pairs of HLA-A, -B and -DR antigens). Some Transplant Centers will perform a stem cell transplant with a one-antigen mismatched donor (5 of 6 match). Because of the immunological immaturity of the T-cells in a CBU, however, cord blood transplants with 4 of 6 HLA-matched donors have been successful. [12] A cord blood transplant may therefore be the best option for a patient who is unable to locate a fully matched or a one-antigen-mismatched donor.
The immunological immaturity of the T-cells in a CBU results in another clinical benefit: a lower incidence and severity of both chronic and acute GVHD. [12] A CBU is also less likely to have acquired viruses or bacteria that can be present in marrow or PBSC harvested from adults. [13]
Patients without a related stem cell donor may also benefit from the relative speed at which a cryopreserved cord blood unit can be located and made available for transplant. For PBSC or marrow transplants, the median time from the initiation of a search of the NMDP Registry to transplantation is approximately 4 months. A CBU can be obtained through one of the NMDP's cord blood banks in a median time of one month, and the wait can be as little as two weeks. Thus, cord blood transplantation may be the best alternative for patients with acute leukemias or other diseases progressing rapidly.
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Cord Blood: Other Factors to Consider
Umbilical cord blood provides limited numbers of stem cells because the typical cord blood unit (CBU) is only approximately 100 mL. Graft failure, especially in adult patients, is always an issue when smaller CBUs are used for transplantation. Although no firm medical consensus has yet developed, a dose equal to or greater than 1.5 x 105 CD34+ cells/kg of donor weight is generally thought to be optimal. Although the availability of banked allogeneic cord blood theoretically benefits all patients, cord blood transplantation may not be a realistic option for adult patients. However, cord blood transplantation for adult patients is a viable treatment provided an HLA-matched CBU with an adequate cell dose is obtained. [12]
Another factor to consider is that a second donation of umbilical cord blood is not available if the first infusion of stem cell fails to engraft or the recipient relapses. With marrow or PBSC donors, there is the possibility of obtaining a second stem cell or leukocyte donation in these situations, but this is extremely rare with a cord blood transplant.
Finally, the genetic history of a CBU is relatively unknown. With adult marrow or PBSC donors, one can prevent the transmission of a genetic disease to the recipient by excluding donors who have developed recognizable genetic disorders. Although this risk is reduced by acquiring a thorough maternal health history, the probability that a CBU will transmit a genetic disease can never be reduced to zero. [13]
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References
International Bone Marrow Transplant Registry (IBMTR) data. http://www.ibmtr.org/infoserv/info_sums.html
Stroncek DF, Holland PV, Bartch G, et al. Experiences of the first 493 unrelated marrow donors in the National Marrow Donor Program. Blood, 1993; 81(7): 1940-6.
Confer DL, Stroncek DF. Bone marrow and peripheral blood stem cell donors. In Thomas ED, Blume KG, Forman SJ, editors: Hematopoietic Stem Cell Transplantation, second edition. Oxford, England: Blackwell, 1999: 421-430.
Ratanatharathorn V, Ayash L, Lazarus HM, Fu J, Uberti JP. Chronic graft-versus-host disease: clinical manifestation and therapy. Bone Marrow Transplant, 2001; 28(2): 121-9.
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Bernstein SH, Nademanee AP, Vose JM, et al. A multicenter study of platelet recovery and utilization in patients after myeloablative therapy and hematopoietic stem cell transplantation. Blood, 1998; 91(9): 3509-17.
Bensinger WI, Weaver CH, Appelbaum FR, et al. Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony-stimulating factor. Blood, 1995; 85(6): 1655-8.
Urbano-Ispizua A, Solano C, Brunet S, et al. Allogeneic peripheral blood progenitor cell transplantation: analysis of short-term engraftment and acute GVHD incidence in 33 cases. Bone Marrow Transplant, 1996; 18: 35-40.
Majolino I, Saglio g, Scime R, et al. High incidence of chronic GVHD after primary allogeneic peripheral blood stem cell transplantation in patients with hematologic malignancies. Bone Marrow Transplant, 1996; 17(4): 555-60.
Urbano-Ispizua A, Garcia-Conde J, Brunet S, et al. High incidence of chronic graft versus host disease after allogeneic peripheral blood progenitor cell transplantation. Haematologica, 1997; 82(6): 683-9.
Gluckman E, Broxmeyer HE, Auerbach AD, et al. Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical cord blood from an HLA-identical sibling. N Engl J Med, 1989; 321: 1174-78.
Laughlin MJ, Barker J, Bambach B, et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med, 2001; 344(24): 1815-22.
Rubinstein P, Rosenfield RE, Adamson JW, Stevens CE. Stored placental blood for unrelated bone marrow reconstitution. Blood, 1993; 81(7): 1679-90.
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