Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells

• Published in: Nature immunology Vol. 8; no. 12; pp. 1313 - 1323
• Main Authors: Mortin-Toth, Steven M, Takenaka, Katsuto, Gan, Olga I, Danska, Jayne S, Prasolava, Tatiana K, Dick, John E, Wang, Jean C Y, Khalouei, Sam
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.12.2007
• Subjects: Animals; Antigens, Differentiation - genetics; Antigens, Differentiation - physiology; Genetic aspects; Genetic polymorphisms; Health aspects; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Polymorphism, Genetic; Receptors, Immunologic - genetics; Receptors, Immunologic - physiology; Transplantation; Canada
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni1527

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.