Overcoming the barriers to umbilical cord blood transplantation
Introduction
Umbilical cord blood (UCB) has become an important source of hematopoietic stem cell (HSC) support following myeloablative and non-myeloablative therapies (1., 2., 3.). UCB is rapidly available and appears to have a lower incidence of graft-versus-host disease (GvHD) despite HLA disparity. This makes it an attractive option for many patients, including patients with non-malignant disease where GvHD should be minimized and proceeding to transplant rapidly may be of prime importance. In addition, because of the allowance for greater HLA disparity than bone marrow (BM) or peripheral blood stem cell grafts, UCB has provided a significantly higher chance of finding a donor, especially for minority populations that are currently underrepresented in donor registries.
While the use of UCB as a stem cell source has seen a significant increase in recent years, especially in children and young adults, it is not without drawbacks. One of the major limitations of UCB as an HSC therapy is the low cell dose available for transplantation. It is now well documented that the total nucleated cell (TNC) dose transplanted per kilogram (kg) of body weight of the recipient correlates with outcomes (4., 5., 6.). As a consequence, UCB transplantation (UCBT) remains significantly more successful in children (5). Also, even in children receiving satisfactory cell doses, there is still often some delay in engraftment of all cell lines compared with traditional stem cell sources (7., 8., 9.) and in immune reconstitution (10,11), suggesting that, even in the optimal patient population, the low progenitor cell dose given with UCBT could have negative effects on outcomes.
In general there have been two approaches to overcome the obstacle of low TNC cell dose seen with UCBT. One has been to utilize more than one UCB unit in order to achieve a higher number of TNC available for infusion (12., 13., 14., 15.). Many trials are currently underway assessing the efficacy and outcomes in both adults and children (Table I). The second approach has been to attempt to expand UCB units ex vivo. Ex vivo expansion can be performed on either a portion of a UCB unit or the unit in its entirety, with the expanded cells infused either at the time of transplant of ‘unmanipulated’ fraction or given at a separate time. The manipulated UCB could be from either the same unit or, potentially, a different UCB unit. The combination of ex vivo-expanded fractions and unmanipulated UCB fractions might prove to be a beneficial strategy (16,17) and clinical trials are currently underway (18., 19., 20., 21., 22.) (Table II).
Section snippets
Double-unit UCBT
In an effort to overcome the issue of low cell dose with a single cord, case reports of combining cord blood units started appearing in the late 1990s (12,14,21., 22., 23., 24., 25., 26., 27., 28.). In early studies, up to 12 cord blood units were used per patient but, because of the cost of the units and resource allocation, two units are generally regarded as the standard in multiple cord blood protocols. To date, hundreds of double-unit UCBT (DUCBT) have been performed (29., 30., 31., 32.).
Ex vivo expansion
The goal of ex vivo expansion of cord blood is at least two-fold. The primary focus of expansion has been to generate sufficient numbers of HSC to optimize the graft available for transplant. Another important goal is to generate higher numbers of lineage-committed progenitor cells that, although transient, will allow rapid recovery from pancyotpenia, thus decreasing early morbidity and mortality. There is a concern that ex vivo-expanded products may possess an inherent reduction in long-term
Summary
Recently, trials have shown improved outcomes for UCBT. In pediatric patients, cord blood may even emerge as the preferred stem cell source. In adult patients more obstacles still exist; however, progress continues to be made. Combining cord blood units has allowed higher cell doses to be achieved, reduced graft failure rates and improved outcomes. Current clinical trials have demonstrated that the use of expanded UCB can be safe and recent results suggest the potential for improved outcomes;
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Endothelium-targeted Delta-like 1 promotes hematopoietic stem cell expansion ex vivo and engraftment in hematopoietic tissues in vivo
2013, Stem Cell ResearchCitation Excerpt :One is to increase the number of infused cells by ex vivo expansion or two UCB grafts, for instances. The other is to modulate HSCs or the microenvironment to enhance homing and engraftment of the infused HSCs (Kelly et al., 2010; Delaney et al., 2010a). Our data reported in the current study revealed that, in addition to enhance ex vivo expansion of HSCs, D1R could directly stimulate hematopoiesis in vivo in normal mice and sublethally irradiated mice.
Regional localization within the bone marrow influences the functional capacity of human HSCs
2013, Cell Stem CellCitation Excerpt :Based on the notion that HSCs operate in a cell-autonomous fashion, isolation and transplantation of greater numbers of human HSCs is thought to be a plausible solution. This approach, however, is constrained both by the inability to expand and maintain these cells ex vivo (Kelly et al., 2010) and by the difficulty in obtaining larger numbers of donor HSCs (Schoemans et al., 2006). This is further complicated by limitations in purifying HSCs due to the significant phenotypic (Doulatov et al., 2012) and functional heterogeneity in cell populations enriched for hematopoietic regenerative capacity (Schoemans et al., 2006; Hope and Bhatia, 2011).
Toll-like receptors 2 and 4 mediate the capacity of mesenchymal stromal cells to support the proliferation and differentiation of CD34<sup>+</sup> cells
2012, Experimental Cell ResearchCitation Excerpt :Umbilical cord blood (UCB) has become an important source of hematopoietic stem cell for stem cell transplantation, especially in the pediatric population. However, graft failure, delayed engraftment and profound delay in immune reconstitution were commonly observed in clinical application, due to low cell dose [37]. To overcome this obstacle, short-term ex vivo expansion was performed on whole CB units prior to transplantation, including liquid culture, stromal coculture and continuous perfusion culture systems.
TNFSF15 facilitates human umbilical cord blood haematopoietic stem cell expansion by activating Notch signal pathway
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