title: NUP98-HOXA10hd-expanded hematopoietic stem cells efficiently reconstitute bone marrow of mismatched recipients and induce tolerance.
abstract: Gene therapy as well as methods capable of returning cells to a pluripotent state (iPS) have enabled the correction of genetic deficiencies in syngenic adult progenitors, reducing the need for immunosuppression in cell therapy approaches. However, in diseases involving mutations that  lead to the complete lack of a protein, such as Duchenne muscular dystrophy, the main immunogens leading to rejection of transplanted cells are the therapeutic proteins themselves. In these cases even iPS cells would not circumvent the need for immunosuppression, and alternative strategies  must be developed. One such potential strategy seeks to induce immune tolerance using hematopoietic stem cells originated from the same donor or iPS line from which the therapeutic progenitors are derived. However, donor hematopoietic stem cells (HSCs) are available in limiting numbers and  embryonic stem (ES) cell-derived HSCs engraft poorly in adults. While these limitations have been circumvented by ectopic expression of HOXB4, overexpression of this protein is associated with inefficient lymphoid reconstitution. Here we show that adult HSCs expanded with a NUP98- HOXA10hd  fusion protein sustain long-term engraftment in immunologically mismatched recipients and generate normal numbers of lymphoid cells. In addition, NUP98-HOXA10hd-expanded cells induce functional immune tolerance to a subsequent transplant of myogenic progenitors immunologically matched with  the transplanted HSCs.
authors.affiliation: Department of Medicine, The Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Even
authors.forename: J L
authors.initials: JL
authors.lastname: Bennett
authors.forename: S
authors.initials: S
authors.lastname: Sekulovic
authors.forename: L
authors.initials: L
authors.lastname: So
authors.forename: L
authors.initials: L
authors.lastname: Yi
authors.forename: K
authors.initials: K
authors.lastname: McNagny
authors.forename: R K
authors.initials: RK
authors.lastname: Humphries
authors.forename: F M V
authors.initials: FM
authors.lastname: Rossi
mesh_terms: D000818:Animals; D015316:Genetic Therapy; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007108:Immune Tolerance; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D028861:Nuclear Pore Complex Proteins; D011993:Recombinant Fusion Proteins; C093350:nuclear pore complex protein 98; C092119:Hoxa10 protein, mouse