title: Hematopoietic stem cell expansion facilitates multilineage engraftment in a nonhuman primate cord blood transplantation model.
abstract: The use of umbilical cord blood for allogeneic transplantation has increased dramatically over the past years. However, the limited number of cells available in a single cord blood unit remains a serious obstacle. Here, we wished to establish a nonhuman primate cord blood transplantation model that would allow us to test various hematopoietic stem cell expansion and gene therapy strategies. We implemented HOXB4-mediated expansion based on our previous experience with HOXB4 in autologous cells. Cord blood units were divided into two equal parts; half of the cells were transduced with a yellow fluorescent protein control vector and cryopreserved, and half were transduced with a HOXB4GFP vector, expanded, and cryopreserved. Both fractions of cells were transplanted into Macaca nemestrina subjects. We found that neutrophil recovery occurred within 19 days in all animals, and both neutrophil and platelet recovery were substantially accelerated compared to human single unit cord blood transplants. In addition, HOXB4-transduced and expanded cells resulted in superior engraftment of all hematopoietic lineages in all animals over nonexpanded controls. In conclusion, we have successfully established a nonhuman primate cord blood transplantation model and demonstrated that HOXB4 stimulates expansion and engraftment of repopulating cells. The availability of such a model has significant implications for developing and testing strategies to improve clinical cord blood transplantation, as it will allow comparison of different stem cell expansion methodologies within a single animal. Furthermore, it can be used in long-term follow-up studies to determine how specific expansion techniques affect engraftment of various hematopoietic lineages.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, Wash., USA.
authors.forename: Korashon L
authors.initials: KL
authors.lastname: Watts
authors.forename: Veronica
authors.initials: V
authors.lastname: Nelson
authors.forename: Brent L
authors.initials: BL
authors.lastname: Wood
authors.forename: Grant D
authors.initials: GD
authors.lastname: Trobridge
authors.forename: Brian C
authors.initials: BC
authors.lastname: Beard
authors.forename: R Keith
authors.initials: RK
authors.lastname: Humphries
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Kiem
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D019070:Cell Lineage; D003114:Colony-Forming Units Assay; D036101:Cord Blood Stem Cell Transplantation; D005260:Female; D005312:Fetal Blood / Q000166:cytology*; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000235:genetics; D006085:Graft Survival; D049452:Green Fluorescent Proteins / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D008164:Luminescent Proteins / Q000235:genetics; D008254:Macaca nemestrina; D008297:Male; D023421:Models, Animal; D038042:Myelopoiesis; D011183:Postoperative Complications; D011247:Pregnancy; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012190:Retroviridae / Q000235:genetics; D034061:Thrombopoiesis; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014161:Transduction, Genetic; D019172:Transplantation Conditioning; D016662:Virus Integration
chemical_list: D001426:Bacterial Proteins; C090460:HOXB4 protein, human; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C054562:yellow fluorescent protein, Bacteria; D049452:Green Fluorescent Proteins