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Exp Hematol. 2019 Feb;70:31-41.e1. doi: 10.1016/j.exphem.2018.12.003. Epub 2018 Dec 25.

MISTRG mice support engraftment and assessment of nonhuman primate hematopoietic stem and progenitor cells.

Author information

1
Program in Cell and Gene Therapy, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
2
Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
3
Program in Cell and Gene Therapy, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, University of Washington School of Medicine, Seattle, WA; Department of Pathology, University of Washington School of Medicine, Seattle, WA. Electronic address: hkiem@fredhutch.org.
4
Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Immunology, University of Washington School of Medicine, Seattle, WA. Electronic address: rongvaux@fredhutch.org.

Abstract

Preclinical feasibility, safety, and efficacy testing of hematopoietic stem cell (HSC)-mediated gene therapy approaches is commonly performed in large-animal models such as nonhuman primates (NHPs). Here, we wished to determine whether mouse models would allow engraftment of NHP HSPCs, which would enable more facile and less costly evaluation of promising strategies. In this study, we comprehensively tested two mouse strains for the engraftment of NHP CD34+ hematopoietic stem and progenitor cells (HSPCs). No engraftment of NHP HSPCs was observed in NSG mice, whereas the gene-humanized MISTRG model did demonstrate dose-dependent multilineage engraftment of NHP cells in the peripheral blood, bone marrow, spleen, and thymus. Most importantly, and closely mimicking the hematopoietic recovery of autologous stem cell transplantations in the NHP, only HSC-enriched CD34+CD90+CD45RA- cell fractions engrafted and reconstituted the bone marrow stem cell niche in MISTRG mice. In summary, we here report the first "monkeynized" mouse xenograft model that closely recapitulates the autologous hematopoietic reconstitution in the NHP stem and progenitor cell transplantation and gene therapy model. The availability of this model has the potential to pre-evaluate novel HSC-mediated gene therapy approaches, inform studies in the NHP, and improve the overall outcome of large-animal experiments.

PMID:
30590092
DOI:
10.1016/j.exphem.2018.12.003
[Indexed for MEDLINE]

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