Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells.
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.
Takenaka
Katsuto
K
Division of Cellular and Molecular Biology, University Health Network, Toronto, Ontario M5G2M9, Canada.
Prasolava
Tatiana K
TK
Wang
Jean C Y
JC
Mortin-Toth
Steven M
SM
Khalouei
Sam
S
Gan
Olga I
OI
Dick
John E
JE
Danska
Jayne S
JS
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011110:Polymorphism, Genetic; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*
D000943:Antigens, Differentiation; D011971:Receptors, Immunologic; C501920:SIRPA protein, human