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Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells

Abstract

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-α 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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Figure 1: The NOD background supports human hematopoiesis in vivo and in vitro.
Figure 2: Strain-specific differences at the Idd13 locus affect the support of human hematopoietic engraftment in vitro and in vivo.
Figure 3: Identification of the critical region of Idd13 associated with the support of human hematopoiesis.
Figure 4: Analysis of mouse SIRP-α.
Figure 5: Sequence alignment of the mouse and human SIRP-α IgV domains.
Figure 6: SIRP-α modulates mouse macrophage–mediated suppression of human hematopoiesis.
Figure 7: SIRP-α from NOD mice confers enhanced cross-species reactivity with human CD47.

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Acknowledgements

We thank Y. Slessarev for cord blood processing; A. Wong for assistance with flow cytometry; O. Gulban for assistance with human HapMap data and sequence analysis; E. Brown and T. Chen (University of California, San Francisco) for the CD47-Fc plasmid; J. Yuan and C.J. Guidos (Hospital for Sick Children) for human IgG-Fc control protein; the Kirin Brewery for MS-5 cells; M. Huang (GenPharm) for Rag and derivative mice; and N. Crispe for experimental advice. Supported by the Juvenile Diabetes Research Foundation (J.S.D.), Genome Canada with funding through the Ontario Genomics Institute (J.S.D. and J.E.D.), the Leukemia and Lymphoma Society Specialized Center of Research (J.S.D. and J.E.D.), the Ontario Ministry of Research and Innovation (J.S.D.), the Canadian Institute of Health Research (J.E.D.), a Canada Research Chair (J.E.D.), the Ontario Institute for Cancer Research with funds from the Province of Ontario (J.E.D.), and National Cancer Institute of Canada with funds from the Canadian Cancer Society and Terry Fox Foundation (J.E.D.).

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K.T. and T.K.P. designed and did experiments, analyzed data and wrote the manuscript; J.C.Y.W. did experiments, analyzed data and wrote the manuscript; S.M.M-T. did experiments and reviewed the manuscript; S.K. did sequencing experiments and bioinformatics analysis; O.I.G. did experiments, analyzed data and reviewed the manuscript; and J.E.D. and J.S.D. designed experiments, analyzed data and wrote the manuscript.

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Correspondence to Jayne S Danska.

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Takenaka, K., Prasolava, T., Wang, J. et al. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nat Immunol 8, 1313–1323 (2007). https://doi.org/10.1038/ni1527

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