Umbilical cord blood (CB) can serve as an alternative graft for patients lacking a matched related donor, yet intrinsically low cell doses leading to delayed engraftment and graft failure severely restrict wider use of this valuable resource. Hence, the central hypothesis of Project 1 is that CB progenitors expanded ex vivo on mesenchymal stem cells (MSCs) will provide more rapid hematopoietic reconstitution, as well as less engraftment failure, than unmanipulated CB cells. Indeed, the CB mononuclear cell/MSC co-culture system we have developed should avoid the significant CD34+ cell losses we experienced in earlier liquid suspension culture studies and, because it provides a surrogate niche for the propagation of CB progenitors, should yield improved CB cell expansion overall. This prediction will be tested in a phase 1 clinical trial in patients undergoing CB transplantation for hematologic malignancies (Aim 1.1), coupled with mechanistic studies to determine if optimal expansion is inhibited by specific CB "accessory" cells in the coculture system (Aim 1.2). Although a low cell dose is clearly the chief limitation of CB transplantation, a number of investigators have reported a defect in the homing of CB cells to the bone marrow. Thus, even with improved CB expansion. Inadequate homing may limit the rapidity of engraftment ~ the focus of this research project. The homing defect has been attributed to low levels of fucosylation of cell surface molecules responsible for binding to P- and/or E-selections, a key component of the mechanism by which circulating blood progenitors are recruited to the marrow microvasculature. We hypothesize that increasing the level of CB cell surface fucosylation will improve interactions with selectins, thereby improving homing and then engraftment. Thus, to assess the modification of unmanipulated and expanded CB progenitors with fucosyltransferase, as means to facilitate their recruitment to the marrow, we have planned both a clinical trial (Aim 2) and mechanistic studies in mice (Aim 3) that will model the CB transplant setting. Success in this project will help to circumvent two of the remaining barriers to effective CB transplantation, thereby broadening the use of this procedure in patients who otherwise lack practical therapeutic options.
Slow recovery of white blood cells to fight infection, platelets to prevent bleeding and red cells to carry oxygen represent major obstacles to wider use of cord blood transplantation. Project 1 seeks to overcome these barriers by improving the expansion of cord blood cells, and by directing their migration to the bone marrow, before their transplantation into patients. If successful, this strategy will improve the survival of cord blood transplant patients.
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