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Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
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3
RESEARCH

As the full potential for of cord blood is as yet unknown, there is a great deal of research currently being undertaken to discover its capabilities. This chapter summarizes the current state of that research and discusses the potential future applications of cord blood both for research and for the treatment of different diseases and conditions. In addition, because researchers have cord blood unit selection needs that differ from those of transplant physicians, the committee proposes an approach to prioritizing use.

IMPROVING CURRENT TRANSPLANT TECHNOLOGY

As discussed in Chapter 2, cord blood transplantation as a treatment for children with hematological, immunological, metabolic, and neoplastic diseases has been highly successful. The advantage of cord blood transplants is the relatively low rate of graft-versus-host disease (GVHD) compared with the rates of GVHD that occur as a result of bone marrow or peripheral blood transplants. This low rate of GVHD related to cord blood transplantation allows for the use of partially human leukocyte antigen (HLA)-mismatched cord blood units. However, because of the comparatively low number of hematopoietic progenitor cells (HPCs) in a single cord blood unit, transplantation of cord blood into larger and heavier adult patients presents a unique set of complications. The primary problem for larger patients has been prolonged time to hematopoeitic recovery and immune reconstitution related to the low progenitor cell dose per kilogram

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
×

of patient weight. This delayed recovery is associated with a high rate of treatment-related morbidity and mortality.

Research related to the improved clinical use of cord blood is being conducted in four general areas: (1) enhancement of cord blood engraftment, (2) improvements in immune reconstitution, (3) reduction in the rates of treatment-related mortality, and (4) augmentation of immune recognition of infectious agents and tumors. Further research is needed to better understand how cord blood may be used as a source of effector cells (i.e., performing a specific function in the immune system in response to a stimulus) outside the transplant setting. This includes the development of immune regulatory cells that might be useful in solid-organ transplant or for the treatment of autoimmune diseases. Cord blood could also be a source of pluripotent stem cells. Research suggests that these pluripotent stem cells, which are capable of differentiation into, for example, hepatocytes and neural progenitor cells, might be present in cord blood.

Research that may improve the effectiveness of cord blood transplantation for the treatment of a variety of conditions is ongoing, including: nonmyeloblative regimens; the use of ex vivo expansion to increase the numbers of HPCs and the development of new approaches to the acceleration of immune recovery; the use of multiple units in transplantation; the coinfusion of mesenchymal stem cells (MSC); and facilitation of the upregulation of homing receptors.

Cord Blood Transplantation After Nonmyeloablative Therapy

While cord blood as an alternative HPC source has several advantages, including rapid availability and lower risk of GVHD despite HLA-disparity, many older patients, or those with extensive prior therapy or serious co-morbidities, are unable to tolerate conventional myeloablative conditioning. In myeloblative conditioning, the patient’s healthy cells are destroyed along with the cancer cells during chemotherapy and total body irradiation. Therefore, reduced intensity or nonmyeloablative regimens are being investigated using either related or unrelated volunteer donors. However, given that many patients will not have a suitable adult donor, use of unrelated donor cord blood in combination with nonmyeloablative conditioning is being investigated in adults to further extend access to allogeneic transplant.

Several studies have been reported thus far. McSweeney et al. (2001) observed engraftment in 2 of 3 evaluable patients receiving fludarabine and total body irradiation 200 cGy. Chao et al. (2002) observed engraftment in 3 of 5 in patients receiving fludarabine cyclophosphamide and antithymocyte globulin. Barker et al. (2003) observed an incidence of sustained donor

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
×

engraftment in 90 percent (of 51 patients) at a median of 8 days (range 5–32) with complete chimerism1 in all. Importantly, in a patient population whose median age was 50 years (range 19–60), the incidences of grade II-IV and III-IV acute GVHD were 61 percent and 27 percent, respectively. Despite this risk of acute GVHD, the 6-month treatment related mortality was low at 18 percent. Factors influencing treatment-related mortality at 6 months were age and poor fitness. Notably, patients older than 45 years of age had a treatment-related mortality of 11 percent. Together, the results indicate that cord blood transplantation after a nonmyeloablative therapy can be associated with a high probability of chimerism, indicating that the alloreactive response of cord blood lymphocytes is sufficient for engraftment and a low incidence of treatment-related mortality despite older age.

Ex Vivo Expansion of Cord Blood Derived Hematopoietic Progenitor Cells

Due to the relatively low volumes of cord blood typically collected, researchers have been interested in developing approaches to increase the volume ex vivo prior to transplant. Ex vivo expansion involves the use of a growth factor to culture a portion of the cord blood unit to increase the numbers of progenitor cells available for transplantation. Cairo and Wagner (1997) have found that 14-day expansion cultures stimulated with interleukin-2 (IL-2) and granulocyte colony-stimulating factor achieved an 80-fold increase in the number of CD34+ cells as compared with the increase in the number of CD34+ cells achieved with similar bone marrow cultures. The cord blood units are generally divided. One part is cultured, and the remainder is frozen so that the expanded portion of the cell culture can be enriched before transplantation (Cairo and Wagner, 1997; Timeus et al., 2003). The cells for culture are purified and then plated in liquid culture for several days.

There are, however, several challenges with regard to ex vivo expansion of cord blood. Notably:

  • there is a time delay in increasing the cell dose based on the number of immature progenitor cells available within the sample (Kogler et al., 1998),

  • cord blood is generally frozen as a single product; however, clinical trials involve ex vivo expanding a fraction of the unit and then recombining it with the remainder to increase cell dose (McNiece, 2004), and

  • some of the companies that produce clinical grade reagents for laboratory trials have begun limiting availability to academic centers.

1  

The presence of more than one genetically distinct set of cells in an individual.

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
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One primary concern is that expansion may induce commitment of and differentiation in HPCs and exhaust their capacity to self renew (Jaroscak et al., 2003). At this point, there has been no late graft failure from ex vivo expanded units in humans, but the follow-up period post-transplant ranges only from 8–51 months (Kogler et al., 1999; Pecora et al., 2000; Fernandez et al., 2001; Shpall et al., 2002; Jaroscak et al., 2003). Clearly, more research is needed to determine if long-term engraftment is successful and whether expanded units maintain functional hematopoietic repopulating cells. In addition, some argue that the cost and resources required to perform expansion far outweigh the minimal clinical benefit demonstrated to date (McNiece, 2004).

Approaches to Accelerate Immune Recovery

The success of allogeneic HPC transplantation regardless of graft source (including cord blood) is limited in part by slow immune reconstitution and consequent increased risk of opportunistic infection. After the infusion of marrow, peripheral blood, or cord blood, immune recovery first results from the immune cells already present in the graft and subsequently from immune cells derived from the HPC. The pace of immune recovery is dependent upon a number of host and donor factors including: HLA match, age of the recipient, development of GVHD, and duration of and types of immune suppressive therapy employed.

Considerable research to effect more rapid immune recovery includes: pharmacological approaches to induce tolerance, infusion of immune cells that specifically target the more common lethal infectious agents (e.g., cytomegalovirus [CMV], aspergillus), and infusion of T-regulatory cells. These potential solutions are being explored and are not specific to any one graft source (Godfrey et al., 2005).

Multiple Cord Blood Unit Transplantation

Based on outcomes data and risk factor analysis, it is clear that limited cell dose is an important obstacle for recipients of cord blood. One strategy to overcome the limitation of cell dose is infusion of multiple units of partially HLA-matched cord blood from different donors.

Literature review reveals the prior use of multiple cord blood units in the treatment of malignancy as early as the 1970s (Ende and Ende, 1972; Shen et al., 1994; Weinreb et al., 1998; Barker et al., 2001; De Lima et al., 2002). However, only more recently have chimerism assays by molecular techniques been used to determine the contribution of each unit to hematopoiesis after cord blood transplantation. Barker et al. (2001) and De Lima et al. (2002) were the first to report “double chimerism” after the infusion

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
×

of cord blood from two partially HLA matched units. In contrast, Fanning et al. (2003) observed a high rate of graft failure in a study investigating the safety of multi unit cord blood transplantation to achieve a goal of ≥5 × 107 nucleated cells/kg. Seven adults (median age 56 years) with malignancy received cord blood units containing a median of 5.4 × 107 nucleated cells/kg and 2.2 × 105 CD34/kg. While neutrophil recovery occurred at a median of 11 days in six patients (with one patient dying on day 55 with mixed chimerism but without neutrophil recovery), four failed to have sustained chimerism.

Barker et al. (2001; 2005) reported short-term outcomes in 23 adults (median weight, 73 kg) with high-risk hematological malignancies, using two unrelated cord blood grafts that were 1–2 HLA-mismatched with the patient and each other in 91 percent of the patients. Forty-three percent of the patients received grafts with both units (4/6 matches). Of the 21 evaluable patients, all engrafted at a median of 23 days (ranging from 15 to 41 days), with 24 percent of patients engrafting from both donor units. The remaining patients engrafted from only one donor. In all patients, one unit predominated by day 100. These data demonstrate the safety of double cord blood transplantation in terms of engraftment, thus eliminating the theoretical concern of complete bidirectional immunological rejection. Further, the incidence of grade II-IV was 65 percent and the incidence of III-IV acute GVHD was 17 percent, with 6-month transplant related mortality being 22 percent. With a median follow-up of 10 months (range: 3.5 months–2.5 years), the probability of disease-free survival at 1 year was 57 percent. For those in remission, the disease-free survival rate was 72 percent. The results of these trials indicate that the coinfusion of two partially HLA matched cord blood units is safe as manifested by high incidence of engraftment.

Alternative strategies using two stem cell sources are also being explored. For example, Fernandez et al. (2001) have demonstrated engraftment of cord blood that has been coinfused with T-cell depleted haplo-identical peripheral blood HPC. This approach may represent another important clinical strategy for obtaining an earlier transient wave of long-term neutrophil recovery with hematopoiesis derived from a single cord blood unit.

Coinfusion of Mesenchymal Stem Cells

MSC are multipotent stem cells capable of self-renewal and differentiation into multiple cell lines (Pittenger et al., 1999; Deans and Moseley, 2000). These cells produce hematopoietic growth factors within the bone marrow environment and as such play an important role in normal hematopoiesis (Dorshkind, 1990; Deans and Moseley, 2000).

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
×

In various laboratory studies, MSCs have demonstrated the ability to: promote engraftment by inducing HPC homing receptors (see below); replace stromal cells damaged by the conditioning regimens; produce hematopoietic growth factor; and suppress T-cell responses to allogeneic stimuli (Blair and Thomas, 1997; Deans and Moseley, 2000; Bartholomew et al., 2002; Noort et al., 2002). This has led to a great deal of interest in MSCs among researchers.

In the mouse, cotransplantation of fetal MSC and low doses of CD34+ cord blood cells increased engraftment in Severe Combined Immunodeficient (SCID) animals by three- to fourfold (Pecora et al., 2000). Similarly, Kim et al. (2004) have recently successfully infused third-party MSC into mice that were receiving a dual-unit cord blood transplant and achieved a higher level of engraftment.

Thus far, one human study of the use of MSCs with cord blood transplantation has been conducted. In that study, eight pediatric patients with high-risk acute leukemia were coinfused with cord blood from unrelated donors and parental MSCs. There were no serious adverse events, and all patients achieved neutrophil engraftment by day 19 (MacMillan et al., 2002). Although this study demonstrates that MSC can be successfully coinfused with HPC, it is still largely untested and will require more research before any conclusions can be drawn about effectiveness.

Upregulation of Homing Receptors

Research has shown that one of the reasons for delayed hematopoietic reconstitution after HPC transplantation may be the disadvantageous transmigratory behavior of HPCs from cord blood. Short-term treatment with recombinant human stem cell factor (rHuSCF) increased levels of homing-related molecules, thereby increasing their ex vivo transmigratory potential as well as their in vivo homing potential. Recent studies have revealed that homing receptors and chemoattractants have an important association with the engraftment mechanism after stem cell transplantation. If the numbers of progenitor cells as well as homing potential could be increased by the ex vivo expansion of cryopreserved and unselected cord blood, it would be beneficial for transplantation into adult patients, and it could also improve the engraftment speed (Lee et al., 2004).

Zheng et al. (2003) suggest that optimal engraftment might be expected from ex vivo manipulation of cord blood progenitor cells to “reverse their disadvantageous transmigratory behavior in the clinical setting.”

Another study showed that although expansion of the cord blood CD34+ cells may affect other cell properties, it can preserve most of the homing-related characteristics and activities of cord blood (Zhai et al., 2004).

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
×

OTHER CLINICAL USES OF CORD BLOOD

In addition to treatment of blood and blood-related diseases, cord blood has the potential to be an effective therapy in certain inherited diseases. The current literature on these uses is summarized in Box 3-1. A comprehensive listing appears in Table 3-1.

BOX 3-1
Examples of Effective Clinical Use of Cord Blood in Treating Inherited Diseases


Fanconi Anemia. First use of cord blood was a sibling with Fanconi anemia. Several subsequent studies have verified that cord blood is an effective alternative to marrow for the treatment of this disease (Gluckman et al., 1990; Auerbach et al., 1990; Kohli-Kumar et al., 1993; Aker et al., 1999; Guardiola et al., 2003, 2004.


Sickle Cell Anemia. Sibling cord blood transplantation has been an effective treatment. Recent research is focused on the use of nonmyeloablative preparatory regimens (Brichard et al., 1996; Vermylen and Cornu, 1997; Vermylen et al., 1998; Miniero et al., 1998; Gore et al., 2000; Locatelli et al., 2003; Barker et al., 2005).


Beta Thalessemia. Sibling cord blood or mixed marrow and cord blood transplantation have been successful. Research on unrelated cord blood transplantation is in the beginning stages (Issaragrisil et al., 1999, 1995; Gedikoglu, 2001; Goussetis et al., 2000; Orofino et al., 2003; Locatelli et al., 2003; Miniero et al., 1998).


Hurler Syndrome. Unrelated transplant trials involving 20 patients at Duke University have been successful. The stage of the disease at time of transplant has been shown to affect outcome. Larger clinical trials are needed to better understand the full range of cord blood’s potential as a treatment (Staba et al., 2004; Muenzer and Fisher, 2004).


Severe Combined Immunodeficiency. Long-term engraftment has been demonstrated in mice. A 2-month-old female was successfully treated with no pretreatment with a transplant from a fully matched donor (Hogan et al., 1997).


Osteopetrosis. Bone marrow transplantation is the only fully proven treatment. However, bone reabsorption has been achieved with cord blood transplantation. Due to the strain of conditioning regimines, this treatment is generally only reserved for the most severe cases (Locatelli et al., 1997; NIH, 2000).


Wiskott-Aldrich Syndrome. In a data set involving 33 patients transplanted with units provided by the New York Blood Center, 90 percent engrafted, and 63 percent achieved 5-year survival (New York Blood Center, unpublished).a

a  

Personal communication between John Wagner and Cladd Stevens of NYBC (3/13/05).

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
×

TABLE 3-1 Genetic Diseases Treatable by Transplantation of Cord Blood

Disease

Immune Deficiency

 

• X-linked SCID

 

• X-linked a-γ-globulinemia

 

• Wiskott-Aldrich syndrome

 

• Chédiak-Higashi syndrome

 

• Chronic granulomatous disease

 

• Adenosine deaminase (ADA) deficiency

 

• Purine nucleotide phosphorylase deficiency

 

• Gaucher disease, type 1

Bone Marrow Failures

 

• Osteopetrosis

 

• Thalassemia

 

• Sickle cell disease

 

• Fanconi anemia

 

• Dyskeratosis

Metabolic Storage Disorders

 

• Adrenoleukodystrophy

 

• Metachromatic leukodystrophy

 

• Adrenoleukodystrophy

 

• Metachromatic leukodystrophy

 

• Mucopolysaccaridoses

 

 

– Hurler syndrome

 

 

– Hunter (X-linked)

 

 

– Sanfillippo

 

 

– Morquio

 

• Maroteaux-Lamy

 

• Lesch-Nyhan syndrome (X-linked)

Umbilical Cord Blood as Effector Cells

More recently, there has been increasing interest in the immune cell populations present in cord blood as a potential source of cells for adaptive immune therapy. For example, cord blood derived natural killer (NK) progenitor and T-cell subpopulations have been isolated and expanded in culture as anti-tumor therapeutic reagents (Miller and McCullar, 2001). Furthermore, CD4+ CD25+ T cells with profound immunoregulatory properties have been expanded in culture to be used as agents to induce tolerance (Miller and McCullar, 2001) Therefore, it is possible that partially matched or mismatched cord blood units may be important as a source of immune cells and not just as an HPC source for transplant medicine.

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
×

UMBILICAL CORD BLOOD IN REGENERATIVE MEDICINE

Although the primary use of cord blood has been to restore hematopoietic function, a number of other potential applications are possible, but these require further research. While there have been limited successes in controlled laboratory settings, it is unlikely that any of these studies will translate into clinical applications in the near future. Rather, they should be considered a guide for future studies using carefully thought-out animal models. Table 3-2 summarizes the present areas of nonclinical research underway with cord blood.

One of the earliest reports that HPC might be capable of generating other tissues was in 1998 (Goodell, 2004). In that study, researchers lethally irradiated rats and damaged their skeletal muscles. After the rats received a bone marrow transplant, donor nuclei were found in the skeletal muscles at very low frequencies. Similar studies found that donor-derived cells could also be found in heart, liver, gastrointestinal, and neural tissues. The prevalence of these transdifferentiation events has varied widely, and some researchers feel the event is actually cell fusion rather than transdifferentiation. However, research has continued.

TABLE 3-2 Summary of Current Research

Type of Research

Reference

Status

Cardiac repair

Perry and Roth (2003)

Capillary-like tubes are grown in culture

 

Vanelli et al. (2004)

Transplants in animals have led to improved cardiac function

Central nervous system disease

Newman et al. (2004)

Mice with amytropic lateral sclerosis improved after transplantation

Spinal cord injury

Saporta et al. (2003)

HPCs engrafted in the area of injury in rats

Stroke

Taguchi et al. (2004)

Vascular activity in damaged area in mice increased post-transplantation

 

Willing et al. (2003)

Motor improvement was noted in mice post-transplantation

Brain damage

Jensen et al. (2003)

Hypoxic mice showed improvement posttransplantation

Liver injury

Di Campli et al. (2004)

Potential for transdifferentiation was first noted in humans posttransplantation

Gastrointestinal

Ishikawa et al. (2004)

Minimal transdifferentiation for intestinal tissue was noted

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
×

Because early research focused on whole bone marrow, the next step was to refine the marrow to ensure that it was the HPCs and not other cells in the bone marrow that served as the source of the observed donor cells. This has been achieved in several cases and the donor cells have been observed at very low frequencies.

Researchers have observed donor cells in nonhematopoietic tissue among humans who have received sex-mismatched transplants. Most scientists believe, however, that this does not demonstrate transdifferentiation so much as it demonstrates the ability of the donor cells to circulate (Goodell, 2004).

A final open question with regard to cord blood in nonhematopoietic applications is the presence or absence of the more plastic MSCs. MSCs are a rare form of multipotent progenitor cells capable of supporting hematopoiesis and of differentiating into osteogenic, adipogenic, myoblastic, and chondrogenic cell lines. Several investigators (Wexler et al., 2003; Gang et al., 2004; Bieback et al., 2004) have been able to culture MSCs from human bone marrow, but they have been unable to do so with umbilical cord blood. For this reason, these researchers have concluded that given the current level of knowledge, cord blood is unsuitable for cell therapy applications. Similarly, research by Yu et al. (2004) demonstrated the ability to isolate MSCs from cord blood collected after preterm deliveries, but not from blood extracted after full-term pregnancies.

Bieback et al. (2004) have, however, been able to isolate MSC-like cells from cord blood. Their success, however, is relatively isolated (63 percent of 59 units), and they were successful only under optimized isolation and culture conditions. It is also worth noting that they were able to generate only osteogenic and chondrogenic progenitor cell lines but were not able to develop adipogenic-like cells. Gang et al. (2004) were able to grow myogenic precursor cells; however, their ability to do so was limited and growth seemed to peak at day 3 after the initiation of culture, indicating the need for further research.

Some of the more specific research being conducted is summarized in the following sections.

Cardiac Repair

Perry and Roth (2003) have described the present potential for reconstructing human cardiac cells from bone marrow, peripheral blood, and cord blood. They described a study in which cord blood stem cells were treated with vascular endothelial growth factor and basic fibroblast growth factor and noted the formation of capillary-like tubes. Other research discussed by Perry and Roth isolated HPCs from cord blood, cultured them in a pulse duplicator bioreactor on a conduit artery scaffold, and found that

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
×

the constructs were very similar to those of native tissues (Perry and Roth, 2003).

Vanelli et al. (2004) indicated that the study of cardiac stem cell precursors in human cord blood and bone marrow will lead to a better understanding of the biology of human cardiac cell differentiation, in addition to providing practical applications. They write that studies with animal models have shown that transplantation has led to improved cardiac function. They further note, however, that when transplanting large populations of unsorted marrow or unmanipulated cord blood, researchers should take into account the fact that only a small fraction of such cells will reach the desired organ.

Central Nervous System Disease

Newman et al. (2004) have described some of the current research being conducted using HPCs from cord blood to treat diseases of the central nervous system. A study involving the transplantation of HPCs into mice with amyotropic lateral sclerosis found that the mice showed improvements in motor function, lost weight, and lived longer than the mice that did not receive the HPCs. The mice in that study received the transplant before the onset of significant motor deficits. They were then analyzed for evidence of donor cells. Some of the donor cells located in the central nervous system were found to express neural cell phenotypes. These are the first data to suggest that donor HPCs are capable of both in vivo differentiation and migration to the brain and spinal cord in the absence of injury.

Again, however, much more research is needed before these successes can be considered indicative of what might happen in humans.

Spinal Cord Injury

Saporta et al. (2003) noted the ability of cord blood cells to target and migrate to areas of damage and engraft therein after intravenous infusion. Building on this knowledge, they examined the ability of cord to target a zone of compression injury in the spinal cord of adult male Sprague-Dawley2 rats.

The researchers compressed the spinal cords of these rats and infused cord blood at either 1 or 5 days post injury. By prelabeling the cells, the researchers were able to demonstrate that the cord blood engrafted in the areas of the spinal cord injury. They postulate that the cord blood entered the areas of damage through damaged blood vessels at the site of the injury

2  

A widely accepted, dependable, and general-purpose strain of rat used as a research model.

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
×

or through a compromised blood-brain barrier at sites of secondary damage. The harvested cells did not, however, show evidence of differentiation.

In addition to the evidence of engraftment, the rats also showed significant behavioral improvement compared with the behaviors of the rats that had not received the cord blood. The number of cells transplanted, however, was not enough to restore significant motor function.

Recent reports (AFP, 2004) from Korea, however, indicate that cord blood transplantation may have promising applications in humans with spinal cord injury. A 37-year-old woman who had been paralyzed for almost 20 years reportedly regained the ability to walk after she received a cord blood injection directly in the damaged part of the spinal cord. Other researchers (Willenbring et al., 2004) caution against drawing conclusions from this isolated incident and believe that this research needs to be reliably replicated before it can be regarded as a potential therapy.

Brain Injury

Stroke

In individuals with stroke, blockage of the blood vessels leading to certain areas of the brain causes focal ischemia and subsequent degeneration of the tissue (Peterson, 2004). The severity of degeneration depends on the location and the extent of the injury. In most cases, however, recovery from stroke is not a result of the recovery of the tissue but, rather, is a result of the development of new neural pathways in undamaged regions.

Taguchi et al. (2004) modeled stroke in genetically modified SCID mice. Human CD34+ cells from cord blood were administered to the mice via the tail vein within 48 hours after an induced stroke. Mice that received the cells displayed new vascular activity within 24 hours of the transplant and had significantly enhanced cerebral blood flow (Taguchi et al., 2004). These mice also displayed significant improvement on behavioral tests compared with behaviors of control mice and mice that received CD34- cells (Taguchi et al., 2004).

Willing et al. (2003) have found that mononuclear cells in cord blood function similarly to MSCs in bone marrow. These investigators also transplanted cord blood into rats with stroke, and although the number of rats was small, they also noted significant improvements in motor skills and behavior compared with those of the rats that did not receive cord blood.

Non-Stroke-Related Brain Damage

Jensen et al. (2003) researched the potential of cord blood transplantation as a treatment for children who were brain damaged because of hy-

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
×

poxic incidents during birth. They note that the central nervous system, unlike other tissues, has a limited regenerative potential. The transplantation of cord blood, they argue, could be a new therapy.

They reproduced the hypoxic injuries in rats and after transplantation noted markedly improved behavior in the rats that received cord blood transplants compared with the behavior of untreated control rats.

Toxic Liver Injury

Di Campli et al. (2004) compared several studies using both animal models and humans and have highlighted the potential of HPCs to transdifferentiate into nonhematopoietic cells. Marrow-derived hepatocytes were first noted in a rat model that showed male cells in female recipients. Those cells not only had the physical characteristics of liver cells, but also demonstrated the appropriate synthetic and metabolic functions.

Di Campli et al. (2004) noted, however, that the time course of the transdifferentiation process has never been fully explored. They also noted that the number of cells present is well below the therapeutic level needed for the effective treatment of some disorders.

Gastrointestinal Disorders

Inflammatory bowel disorders, such as Crohn’s disease and ulcerative colitis, often require novel treatments. Ishikawa et al. (2004) analyzed the capacity of human bone marrow- and cord blood-derived progenitor cells to generate gastrointestinal epithelial cells. To do this, they analyzed gastrointestinal specimens from pediatric and juvenile recipients of allogeneic sex-mismatched progenitor cell transplants and looked for evidence of donor-derived cells (Ishikawa et al., 2004). None of the human patients exhibited any chimerism. However, upon closer inspection under an electron microscope, donor-derived cells could be found at frequencies between 0.4 and 1.9 percent.

The researchers then performed similar experiments with mice and T-cell-depleted human bone marrow and cord blood mononuclear cells. They injected these cells into newborn mice after the mice were subjected to total body irradiation. After determining that the mice exhibited hematological chimerism, the researchers harvested gastrointestinal tissues from the mice. The results of this experiment indicated that xenogenic transplantation can regenerate epithelial cells in intestinal tissue as well as reconstitute lymphocytes.

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
×

Gene Therapy

Newman et al. (2004) postulated that HPCs are promising targets for gene therapy. In theory, the progenitor cells within the mononuclear cell population of cord blood can be used as cell-based gene therapy.

DEVELOPING RESEARCH PRIORITIES

The general consensus is that HPCs can be incorporated into non-hematopoietic tissue, but with very low efficiency. Whether cord blood will be the optimal source for the regeneration of nonhematopoietic tissues is unknown (Goodell, 2004). However, strategies are being developed to improve the efficiency of transdifferentiation with the long-term aim of using HPCs in therapies for nonhematopoietic diseases. Further research, including adequate animal studies, is clearly needed to better understand the nonhematopoietic potential of cord blood. Furthermore, given the limited availability of cord blood for research purposes it is important that non-clinical units not be discarded or destroyed.

Recommendation 3.1: Federally funded umbilical cord blood banks should have a mechanism by which they can make available for research use units not appropriate for clinical use according to the priority standards developed by the National Cord Blood Policy Board proposed by the committee (see Chapter 7).

The committee suggests that the proposed National Cord Blood Policy Board consider that the following types of research be given priority for nonclinical use of cord blood:

  • research funded by the National Institutes of Health,

  • peer-reviewed research receiving other government funding,

  • other peer-reviewed research, and

  • other unfunded but innovative research proposals.

REFERENCES

AFP (l’Agence France-Presse). November 28, 2004. Paralyzed woman walks again after stem cell therapy.

Aker M, Varadi G, Slavin S, Nagler A. 1999. Fludarabine-based protocol for human umbilical cord blood transplantation in children with Fanconi anemia. Journal of Pediatric Hematology/Oncology 21(3):237–239.

Auerbach AD, Liu Q, Ghosh R, Pollack MS, Douglas GW, Broxmeyer HE. 1990. Prenatal identification of potential donors for umbilical cord blood transplantation for Fanconi anemia. Transfusion 30(8):682–687.

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
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Barker JN, Weisdorf DJ, Wagner JE. 2001. Creation of a double chimera after the transplantation of umbilical-cord blood from two partially matched unrelated donors.[comment]. New England Journal of Medicine 344(24):1870–1871.

Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, Miller JS, Wagner JE. 2003. Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood 102(5):1915–1919.

Barker JN, Weisdorf DJ, Defor TE, Blazar BR, McGlave PB, Miller JS, Verfaillie CM, Wagner JE. 2005. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 105(3):1343–1347.

Bartholomew A, Sturgeon C, Siaskas M, Ferrer K, McIntosh K, Patil S, Hardy W, Devine S, Ucker D, Deans R, Moseley A, Hoffman R. 2002. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Experimental Hematology 30(1):42–48.

Bieback K, Kern S, Kluter H, Eichler H. 2004. Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells 22(4):625–634.

Blair A, Thomas DB. 1997. Preferential adhesion of fetal liver derived primitive haemopoietic progenitor cells to bone marrow stroma. British Journal of Haematology 99(4): 726–731.

Brichard B, Vermylen C, Ninane J, Cornu G. 1996. Persistence of fetal hemoglobin production after successful transplantation of cord blood stem cells in a patient with sickle cell anemia. Journal of Pediatrics 128(2):241–243.


Cairo MS, Wagner JE. 1997. Placental and/or umbilical cord blood: An alternative source of hematopoietic stem cells for transplantation. Blood 90(12):4665–4678.

Cant AJ. 1995. Severe combined immunodeficiency clinicopathological features and treatment. Forum 5(1):6–19.

Chao NJ, Liu CX, Rooney B, Chen BJ, Long GD, Vredenburgh JJ, Morris A, Gasparetto C, Rizzieri DA. 2002. Nonmyeloablative regimen preserves “niches” allowing for peripheral expansion of donor T-cells. Biology of Blood and Marrow Transplantation 8(5): 249–256.


De Lima M, St. John LS, Wieder ED, Lee MS, McMannis J, Karandish S, Giralt S, Beran M, Couriel D, Korbling M, Bibawi S, Champlin R, Komanduri KV. 2002. Double-chimaerism after transplantation of two human leucocyte antigen mismatched, unrelated cord blood units. British Journal of Haematology 119(3):773–776.

Deans RJ, Moseley AB. 2000. Mesenchymal stem cells: Biology and potential clinical uses. Experimental Hematology 28(8):875–884.

Di Campli C, Piscaglia AC, Pierelli L, Rutella S, Bonanno G, Alison MR, Mariotti A, Vecchio FM, Nestola M, Monego G, Michetti F, Mancuso S, Pola P, Leone G, Gasbarrini G, Gasbarrini A. 2004. A human umbilical cord stem cell rescue therapy in a murine model of toxic liver injury. Digestive and Liver Disease 36(9):603–613.

Dorshkind K. 1990. Regulation of hemopoiesis by bone marrow stromal cells and their products. Annual Review of Immunology 8:111–137.


Ende M, Ende N. 1972. Hematopoietic transplantation by means of fetal (cord) blood. A new method. Virgina Medical Monthly (1918) 99(3):276–280.


Fanning L, Hamza N, Tary-Lehmann M, Jaroscak J, Koc O, Lazarus H, Cooper B, Gerson S, Rubinstein P, Stevens C, Laughlin M. 2003. High rate of graft failure after infusion of multiple (3–5) umbilical cord blood (UCB) units in adults with hematologic disorders: Role of HLA disparity and UCB graft T cell-cross immune reactivation. Blood 102(11): 195a.

Fernandez MN, Regidor C, Cabrera R, Garcia-Marco J, Briz M, Fores R, Sanjuan I, McWhinnie A, Querol S, Garcia J, Madrigal A. 2001. Cord blood transplants: Early recovery of neutrophils from co-transplanted sibling haploidentical progenitor cells and lack of engraftment of cultured cord blood cells, as ascertained by analysis of DNA polymorphisms. Bone Marrow Transplantation 28(4):355–363.

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
×

Gang EJ, Jeong JA, Hong SH, Hwang SH, Kim SW, Yang IH, Ahn C, Han H, Kim H. 2004. Skeletal myogenic differentiation of mesenchymal stem cells isolated from human umbilical cord blood. Stem Cells 22(4):617–624.

Gedikoglu G. 2001. Bone marrow transplantation in thalassemia. Bone Marrow Transplantation 28(Suppl. 1):S10.

Gluckman E, Devergie A, Bourdeau-Esperou H, Thierry D, Traineau R, Auerbach A, Broxmeyer HE. 1990. Transplantation of umbilical cord blood in Fanconi’s anemia. Nouvelle Revue Francaise d’Hematologie 32(6):423–425.

Godfrey WR, Spoden DJ, Ge YG, Baker SR, Liu B, Levine BL, June CH, Blazar BR, Porter SB. 2005. Cord Blood CD4+ CD25+-derived T regulatory cell lines express FoxP3 protein and manifest potent suppressor function. Blood 105(2):750–758.

Goodell MA. 2004. Potential non-hematopoietic uses for stem cells in cord blood: An analysis prepared for the Committee on Establishing a National Cord Blood Stem Cell Bank, Institute of Medicine, Washington, DC.

Gore L, Lane PA, Quinones RR, Giller RH. 2000. Successful cord blood transplantation for sickle cell anemia from a sibling who is human leukocyte antigen-identical: Implications for comprehensive care. Journal of Pediatric Hematology/Oncology 22(5):437–440.

Goussetis E, Peristeri J, Kitra V, Kattamis A, Petropoulos D, Papassotiriou I, Graphakos S. 2000. Combined umbilical cord blood and bone marrow transplantation in the treatment of beta-thalassemia major. Pediatric Hematology and Oncology 17(4):307–314.

Guardiola P, Kurre P, Vlad A, Cayuela JM, Esperou H, Devergie A, Ribaud P, Socie G, Richard P, Traineau R, Storb R, Gluckman E. 2003. Effective graft-versus-leukaemia effect after allogeneic stem cell transplantation using reduced-intensity preparative regimens in Fanconi anaemia patients with myelodysplastic syndrome or acute myeloid leukaemia. British Journal of Haematology 122(5):806–809.

Guardiola P, Socie G, Li X, Ribaud P, Devergie A, Esperou H, Richard P, Traineau R, Janin A, Gluckman E. 2004. Acute graft-versus-host disease in patients with Fanconi anemia or acquired aplastic anemia undergoing bone marrow transplantation from HLA-identical sibling donors: Risk factors and influence on outcome. Blood 103(1):73–77.


Hogan CJ, Shpall EJ, McNiece I, Keller G. 1997. Multilineage engraftment in NOD/LtSzscid/scid mice from mobilized human CD34+ peripheral blood progenitor cells. Biology of Blood and Marrow Transplantation 3(5):236–246.


Ishikawa F, Yasukawa M, Yoshida S, Nakamura KI, Nagatoshi Y, Kanemaru T, Shimoda K, Shimoda S, Miyamoto T, Okamura J, Shultz LD, Harada M. 2004. Human cord blood-and bone marrow-derived CD34+ cells regenerate gastrointestinal epithelial cells. FASEB Journal 18(15):1958–1960.

Issaragrisil S, Leaverton PE, Chansung K, Thamprasit T, Porapakham Y, Vannasaeng S, Piankijagum A, Kaufman DW, Anderson TE, Shapiro S, Young NS. 1999. Regional patterns in the incidence of aplastic anemia in Thailand. The Aplastic Anemia Study Group. American Journal of Hematology 61(3):164–168.

Issaragrisil S, Visuthisakchai S, Suvatte V, Tanphaichitr VS, Chandanayingyong D, Schreiner T, Kanokpongsakdi S, Siritanaratkul N, Piankijagum A. 1995. Brief report: Transplantation of cord-blood stem cells into a patient with severe thalassemia. New England Journal of Medicine 332(6):367–369.


Jaroscak J, Goltry K, Smith A, Waters-Pick B, Martin PL, Driscoll TA, Howrey R, Chao N, Douville J, Burhop S, Fu P, Kurtzberg J. 2003. Augmentation of umbilical cord blood (UCB) transplantation with ex vivo-expanded UCB cells: Results of a phase 1 trial using the AastromReplicell System. Blood 101(12):5061–5067.

Jensen A, Vaihinger HM, Meier C. 2003. Perinatal brain damage—from neuroprotection to neuroregeneration using cord blood stem cells. Medizinische Klinik (Munich) 98(Suppl. 2):22–26. (In German.)

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
×

Kim DC, Chung YJ, Kim TG, Kim YL, Oh IH. 2004. Cotransplantation of third-party mesenchymal stromal cells can alleviate one-donor predominance and increase engraftment from double cord transplantation. Blood 103(5):1941–1948.

Kogler G, Callejas J, Sorg RV, Fischer J, Migliaccio AR, Wernet P. 1998. The effect of different thawing methods, growth factor combinations and media on the ex vivo expansion of umbilical cord blood primitive and committed progenitors. Bone Marrow Transplantation 21(3):233–241.

Kogler G, Nurnberger W, Fischer J, Niehues T, Somville T, Gobel U, Wernet P. 1999. Simultaneous cord blood transplantation of ex vivo expanded together with non-expanded cells for high risk leukemia. Bone Marrow Transplantation 24(4):397–403.

Kohli-Kumar M, Shahidi NT, Broxmeyer HE, Masterson M, Delaat C, Sambrano J, Morris C, Auerbach AD, Harris RE. 1993. Haemopoietic stem/progenitor cell transplant in Fanconi anaemia using HLA-matched sibling umbilical cord blood cells. British Journal of Haematology 85(2):419–422.


Lee YH, Han JY, Seo SY, Kim KH, Lee YA, Lee YS, Lee HS, Hur WJ, Han H, Kwon HC, Kim JS, Kim HJ. 2004. Stem cells expressing homing receptors could be expanded from cryopreserved and unselected cord blood. Journal of Korean Medical Science 19(5): 635–639.

Locatelli F, Beluffi G, Giorgiani G, Maccario R, Fiori P, Pession A, Bonetti F, Comoli P, Calcaterra V, Rondini G, Severi F. 1997. Transplantation of cord blood progenitor cells can promote bone resorption in autosomal recessive osteopetrosis. Bone Marrow Transplantation 20(8):701–705.

Locatelli F, Rocha V, Reed W, Bernaudin F, Ertem M, Grafakos S, Brichard B, Li X, Nagler A, Giorgiani G, Haut PR, Brochstein JA, Nugent DJ, Blatt J, Woodard P, Kurtzberg J, Rubin CM, Miniero R, Lutz P, Raja T, Roberts I, Will AM, Yaniv I, Vermylen C, Tannoia N, Garnier F, Ionescu I, Walters MC, Lubin BH, Gluckman E. 2003. Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Blood 101(6):2137–2143.


MacMillan ML, Ramsay NKC, Atkinson K, Wagner JE. 2002. Ex-Vivo Culture-Expanded Parental Haploidentical Mesenchymal Stem Cells (MSC) To Promote Engraftment in Recipients of Unrelated Donor Umbilical Cord Blood (UCB): Results of a Phase I-II Clinical Trial (Poster presentation, American Society of Hematology, Philadelphia, PA). Blood 100(11):836a.

McNiece I. 2004. Ex vivo expansion of hematopoietic cells. Experimental Hematology 32(5):409–410.

McSweeney PA, Bearman SI, Jones RB, et al. 2001. Nonmyeloblative hematopoietic cell transplantations using cord blood. Blood 98:666a.

Miller, JS, McCullar V. 2001. Human natural killer cells with polyclonal lectin and immunoglobulinlike receptors develop from single hematopoietic stem cells with preferential expression of NKG2A and KIR2DL2/L3/S2. Blood 98:705–713.

Miniero R, Rocha V, Saracco P, Locatelli F, Brichard B, Nagler A, Roberts I, Yaniv I, Beksac M, Bernaudin F, Gluckman E. 1998. Cord blood transplantation (CBT) in hemoglobinopathies. Bone Marrow Transplantation 22(Suppl. 1):S78–S79.

Muenzer J, Fisher A. 2004. Advances in the treatment of mucopolysaccharidosis type I. New England Journal of Medicine 350(19):1932–1934.


Newman MB, Davis CD, Borlongan CV, Emerich D, Sanberg PR. 2004. Transplantation of human umbilical cord blood cells in the repair of CNS diseases. Expert Opinion on Biological Therapy 4(2):121–130.

NIH (National Institutes of Health). 2000. Information for Patients about Osteopetrosis. [Online] Available: http://www.osteo.org/newfile.asp?doc=p117i&doctitle=Osteopetrosis&doctype=HTML+Fact+Sheet [accessed July 2004].

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
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Noort WA, Kruisselbrink AB, in’t Anker PS, Kruger M, van Bezooijen RL, de Paus RA, Heemskerk MH, Lowik CW, Falkenburg JH, Willemze R, Fibbe WE. 2002. Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34+ cells in NOD/SCID mice. Experimental Hematology 30(8):870–878.


Orofino MG, Argiolu F, Sanna MA, Rosatelli MC, Tuveri T, Scalas MT, Badiali M, Cossu P, Puddu R, Lai ME, Cao A. 2003. Fetal HLA typing in beta thalassaemia: Implications for haemopoietic stem-cell transplantation. Lancet 362(9377):41–42.


Pecora AL, Stiff P, Jennis A, Goldberg S, Rosenbluth R, Price P, Goltry KL, Douville J, Armstrong RD, Smith AK, Preti RA. 2000. Prompt and durable engraftment in two older adult patients with high risk chronic myelogenous leukemia (CML) using ex vivo expanded and unmanipulated unrelated umbilical cord blood. Bone Marrow Transplantation 25(7):797–799.

Perry GS III, Spector BD, Schuman LM, Mandel JS, Anderson VE, McHugh RB, Hanson MR, Fahlstrom SM, Krivit W, Kersey JH. 1980. The Wiskott-Aldrich syndrome in the United States and Canada (1892–1979). Journal or Pediatrics 97(1):72–78.

Perry TE, Roth SJ. 2003. Cardiovascular tissue engineering: Constructing living tissue cardiac valves and blood vessels using bone marrow, umbilical cord blood, and peripheral blood cells. Journal of Cadiovascular Nursing 18(1):30–37.

Peterson DA. 2004. Umbilical cord blood cells and brain stroke injury: Bringing in fresh blood to address an old problem. Journal of Clinical Investigation 114(3):312–314.

Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. 1999. Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147.


Saporta S, Kim JJ, Willing AE, Fu ES, Davis CD, Sanberg PR. 2003. Human umbilical cord blood stem cells infusion in spinal cord injury: Engraftment and beneficial influence on behavior. Journal of Hematotherapy and Stem Cell Research 12(3):271–278.

Shen BJ, Hou HS, Zhang HQ, Sui XW (Department of Pediatrics, Affiliated Hospital, Shandong Medical University, People’s Republic of China). 1994. Unrelated, HLA-mismatched multiple human umbilical cord blood transfusion in four cases with advanced solid tumors: initial studies.[see comment]. Blood Cells 20(2–3):285–92.

Shpall EJ, Quinones R, Giller R, Zeng C, Baron AE, Jones RB, Bearman SI, Nieto Y, Freed B, Madinger N, Hogan CJ, Slat-Vasquez V, Russell P, Blunk B, Schissel D, Hild E, Malcolm J, Ward W, McNiece IK. 2002. Transplantation of ex vivo expanded cord blood. Biology of Blood and Marrow Transplantation 8(7):368–376.

Staba SL, Escolar ML, Poe M, Kim Y, Martin PL, Szabolcs P, Allison-Thacker J, Wood S, Wenger DA, Rubinstein P, Hopwood JJ, Krivit W, Kurtzberg J. 2004. Cord-blood transplants from unrelated donors in patients with Hurler’s syndrome. New England Journal of Medicine 350(19):1960–1969.


Taguchi A, Soma T, Tanaka H, Kanda T, Nishimura H, Yoshikawa H, Tsukamoto Y, Iso H, Fujimori Y, Stern DM, Naritomi H, Matsuyama T. 2004. Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. Journal of Clinical Investigation 114(3):330–338.

Timeus F, Crescenzio N, Saracco P, Doria A, Fazio L, Albiani R, Cordero Di Montezemolo L, Perugini L, Incarbone E. 2003. Recovery of cord blood hematopoietic progenitors after successive freezing and thawing procedures. Haematologica 88(1):74–79.


Vanelli P, Beltrami S, Cesana E, Cicero D, Zaza A, Rossi E, Cicirata F, Antona C, Clivio A. 2004. Cardiac precursors in human bone marrow and cord blood: In vitro cell cardiogenesis. Italian Heart Journal 5(5):384–388.

Vermylen C, Cornu G. 1997. Hematopoietic stem cell transplantation for sickle cell anemia. Current Opinion in Hematology 4(6):377–380.

Suggested Citation:"3 Research." Institute of Medicine. 2005. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: The National Academies Press. doi: 10.17226/11269.
×

Vermylen C, Cornu G, Ferster A, Brichard B, Ninane J, Ferrant A, Zenebergh A, Maes P, Dhooge C, Benoit Y, Beguin Y, Dresse MF, Sariban E. 1998. Haematopoietic stem cell transplantation for sickle cell anaemia: The first 50 patients transplanted in Belgium. Bone Marrow Transplantation 22(1):1–6.


Wagner JE, Barker JN, DeFor TE, Baker KS, Blazar BR, Eide C, Goldman A, Kersey J, Krivit W, MacMillan ML, Orchard PJ, Peters C, Weisdorf DJ, Ramsay NKC, Davies SM. 2002. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: Influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood 100(5):1611–1618.

Weinreb S, Delgado JC, Clavijo OP, Yunis EJ, Bayer-Zwirello L, Polansky L, Deluhery L, Cohn G, Yao JT, Stec TC, Higby D, Anderzejewski C. 1998. Transplantation of unrelated cord blood cells. Bone Marrow Transplantation 22(2):193–196.

Wexler SA, Donaldson C, Denning-Kendall P, Rice C, Bradley B, Hows JM. 2003. Adult bone marrow is a rich source of human mesenchymal “stem” cells but umbilical cord and mobilized adult blood are not. British Journal of Haematology 121(2):368–374.

Willenbring H, Bailey AS, Foster M, Akkari Y, Dorrell C, Olson S, Finegold M, Fleming WH, Grompe M. 2004. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nature Medicine 10(7):744–748.

Willing AE, Lixian J, Milliken M, Poulos S, Zigova T, Song S, Hart C, Sanchez-Ramos J, Sanberg PR. 2003. Intravenous versus intrastriatal cord blood administration in a rodent model of stroke. Journal of Neuroscience Research 73(3):296–307.

Winkelstein JA, Winkelstein ML. 2001. The Wiskott-Aldrich syndrome. Winkelstein JA, Winkelstein ML, eds. Patient and Family Handbook for the Primary Immune Deficiency Diseases. Towson, MD: Immune Deficiency Foundation. Pp. 36–39. [Online] Available: http://www.primaryimmune.org/pubs/book_pats/e_ch07.pdf.


Yu M, Xiao Z, Shen L, Li L. 2004. Mid-trimester fetal blood-derived adherent cells share characteristics similar to mesenchymal stem cells but full-term umbilical cord blood does not. British Journal of Haematology 124(5):666–675.


Zhai QL, Qiu LG, Li Q, Meng HX, Han JL, Herzig RH, Han ZC. 2004. Short-term ex vivo expansion sustains the homing-related properties of umbilical cord blood hematopoietic stem and progenitor cells. Haematologica 89(3):265–273.

Zheng Y, Watanabe N, Nagamura-Inoue T, Igura K, Nagayama H, Tojo A, Tanosaki R, Takaue Y, Okamoto S, Takahashi TA. 2003. Ex vivo manipulation of umbilical cord blood-derived hematopoietic stem/progenitor cells with recombinant human stem cell factor can up-regulate levels of homing-essential molecules to increase their transmigratory potential. Experimental Hematology 31(12):1237–1246.

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With the potential for self-renewal and differentiation, the possibilities for stem cells are enormous. One specific type of stem cell, the hematopoietic progenitor cell (HPC), which is derived from umbilical cord blood (as well as adult bone marrow and mobilized peripheral blood), holds particular promise. To make the most of these HPCs, the Institute of Medicine was asked to consider the optimal structure for a national cord blood program and to address pertinent issues related to maximizing the potential of stem cell technology. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program examines:

  • The role of cord blood in stem cell transplantation
  • The current status of blood banks already in existence
  • The optimal structure for the cord blood program
  • The current use and utility of cord blood for stem cell transplants
  • The best way to advance the use of cord blood units and make them available for research

Expert advice from leaders in the fields of economics, public health, medicine, and biostatistics combine to make this very timely and topical book useful to a number of stakeholders.

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