Article abstract


Nature Immunology 8, 1313 - 1323 (2007)
Published online: 4 November 2007 | doi:10.1038/ni1527

Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells

Katsuto Takenaka1,6, Tatiana K Prasolava2,6, Jean C Y Wang1,3, Steven M Mortin-Toth2, Sam Khalouei2, Olga I Gan1, John E Dick1,4 & Jayne S Danska2,5


Graft failure in the transplantation of hematopoietic stem cells occurs despite donor-host genetic identity of human leukocyte antigens, suggesting that additional factors modulate engraftment. With the nobese diabetic (NOD)–severe combined immunodeficiency (SCID) xenotransplantation model, we found that the NOD background allowed better hematopoietic engraftment than did other strains with equivalent immunodeficiency-related mutations. We used positional genetics to characterize the molecular basis for this strain specificity and found that the NOD Sirpa allele conferred support for human hematopoiesis. NOD SIRP-alpha showed enhanced binding to the human CD47 ligand, and its expression on mouse macrophages was required for support of human hematopoiesis. Thus, we have identified Sirpa polymorphism as a potent genetic determinant of the engraftment of human hematopoietic stem cells.

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  1. Division of Cellular and Molecular Biology, University Health Network, Toronto, Ontario M5G2M9, Canada.
  2. Program in Genetics and Genomic Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario M5G1X8, Canada.
  3. Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, and Department of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada.
  4. Department of Molecular Genetics and Microbiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada.
  5. Departments of Immunology and Medical Biophysics and Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada.
  6. These authors contributed equally to this work.

Correspondence to: Jayne S Danska2,5 e-mail: jayne.danska@sickkids.ca



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