Humanization with CD34-positive hematopoietic stem cells in NOG-EXL mice results in improved long-term survival and less severe myeloid cell hyperactivation phenotype relative to NSG-SGM3 mice

NSG-SGM3 and NOG-EXL mice combine severe immunodeficiency with transgenic expression of human myeloid stimulatory cytokines, resulting in marked expansion of myeloid populations upon humanization with CD34+ hematopoietic stem cells (HSCs). Humanized NSG-SGM3 mice typically develop a lethal macrophag...

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Bibliographic Details
Published in:Veterinary pathology Vol. 61; no. 4; p. 664
Main Authors: Willis, Elinor, Verrelle, Jillian, Banerjee, Esha, Assenmacher, Charles-Antoine, Tarrant, James C, Skuli, Nicholas, Jacobson, Moriah L, O'Rouke, Donald M, Binder, Zev A, Radaelli, Enrico
Format: Journal Article
Language:English
Published: United States 01.07.2024
Subjects:
Animals
Antigens, CD34 - metabolism
Disease Models, Animal
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells - pathology
Humans
Mice
Mice, Transgenic
Myeloid Cells - pathology
Phenotype
NOG-EXL
mouse
humanization
macrophage activation syndrome
hemophagocytic lymphohistiocytosis
mast cell hyperplasia
NSG-SGM3
human hematopoietic stem cells
ISSN:1544-2217, 1544-2217
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Summary:NSG-SGM3 and NOG-EXL mice combine severe immunodeficiency with transgenic expression of human myeloid stimulatory cytokines, resulting in marked expansion of myeloid populations upon humanization with CD34+ hematopoietic stem cells (HSCs). Humanized NSG-SGM3 mice typically develop a lethal macrophage activation syndrome and mast cell hyperplasia that limit their use in long-term studies (e.g., humanization followed by tumor xenotransplantation). It is currently unclear to what extent humanized NOG-EXL mice suffer from the same condition observed in humanized NSG-SGM3 mice. We compared the effects of human CD34+ HSC engraftment in these two strains in an orthotopic patient-derived glioblastoma model. NSG-SGM3 mice humanized in-house were compared to NOG-EXL mice humanized in-house and commercially available humanized NOG-EXL mice. Mice were euthanized at humane or study endpoints, and complete pathological assessments were performed. A semiquantitative multiparametric clinicopathological scoring system was developed to characterize chimeric myeloid cell hyperactivation (MCH) syndrome. NSG-SGM3 mice were euthanized at 16 weeks after humanization because of severe deterioration of clinical conditions. Humanized NOG-EXL mice survived to the study endpoint at 22 weeks after humanization and showed less-severe MCH phenotypes than NSG-SGM3 mice. Major differences included the lack of mast cell expansion and limited tissue/organ involvement in NOG-EXL mice compared to NSG-SGM3 mice. Engraftment of human lymphocytes, assessed by immunohistochemistry, was similar in the two strains. The longer survival and decreased MCH phenotype severity in NOG-EXL mice enabled their use in a tumor xenotransplantation study. The NOG-EXL model is better suited than the NSG-SGM3 model for immuno-oncology studies requiring long-term survival after humanization.
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ISSN:1544-2217
1544-2217
DOI:10.1177/03009858231222216