title: Advances in umbilical cord blood stem cell expansion and clinical translation.
abstract: Umbilical cord blood (CB) is a rich source of hematopoietic stem cells (HSCs) with important applications in allogeneic stem cell transplantation. However, the low numbers of hematopoietic stem and progenitor cells (HSPCs) in banked units remain a major limitation. Protocols developed for HSPC expansion ex vivo or to improve HSPC homing to the marrow represent solutions to overcome this shortcoming. In recent decades, wide arrays of functionally divergent approaches were developed for the amplification of HSPCs. These include optimization of cytokine cocktails, coculture systems, small molecules, and delivery systems for HSPC-expansion genes. Herein, we review past and current strategies, focusing on studies that characterize the contribution of expanded CB HSPC to short- and long-term engraftment in transplantation models or in clinical trials. Also discussed are homing effectors used to promote engraftment. In summary, these studies underscore that early-acting cytokines alone can expand HSPC with short-term engraftment activity, but that robust expansion of HSPCs with long-term engraftment necessitates the synergistic action of multiple HSC-expansion agonists. In support of this, early clinical trials based on cytokine-driven HSPC-expansion protocols delivered disappointing results, whereas recent trials based on the synergistic action of cytokines and HSPC-expansion agonists reported significant improvements in engraftment and therapeutic outcomes. Conversely, molecules that enhance homing of HSPC may represent a complementary approach to improve and perhaps accelerate engraftment. Optimization of the next generation of HSPC-expansion and priming strategies should support a paradigm shift in CB transplantation in which smaller, better matched units may preferentially be used.
authors.affiliation: Canadian Blood Services Center for Innovation, Ottawa, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada. Electronic address: nicolas.pineault@blood.ca.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pineault
authors.affiliation: Canadian Blood Services Center for Innovation, Ottawa, Canada.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Abu-Khader
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques / Q000379:methods*; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement; D002478:Cells, Cultured / Q000637:transplantation; D002986:Clinical Trials as Topic; D018920:Coculture Techniques; D036101:Cord Blood Stem Cell Transplantation / Q000379:methods*; D016207:Cytokines / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005312:Fetal Blood / Q000166:cytology; D056726:Genetic Association Studies; D006085:Graft Survival / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D016130:Immunophenotyping / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015398:Signal Transduction / Q000235:genetics; D054852:Small Molecule Libraries; D017154:Stromal Cells / Q000166:cytology; D057170:Translational Research, Biomedical; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D054852:Small Molecule Libraries