Abstract
The mouse (Mus musculus) is an extensively used model of human disease and responses to stresses such as ionizing radiation. As part of our work developing gene expression biomarkers of radiation exposure, dose, and injury, we have found many genes are either up-regulated (e.g. CDKN1A, MDM2, BBC3, and CCNG1) or down-regulated (e.g. TCF4 and MYC) in both species after irradiation at ~4 and 8 Gy. However, we have also found genes that are consistently up-regulated in humans and down-regulated in mice (e.g. DDB2, PCNA, GADD45A, SESN1, RRM2B, KCNN4, IFI30, and PTPRO). Here we test a hematopoietically humanized mouse as a potential in vivo model for biodosimetry studies, measuring the response of these 14 genes one day after irradiation at 2 and 4 Gy, and comparing it with that of human blood irradiated ex vivo, and blood from whole body irradiated mice. We found that human blood cells in the hematopoietically humanized mouse in vivo environment recapitulated the gene expression pattern expected from human cells, not the pattern seen from in vivo irradiated normal mice. The results of this study support the use of hematopoietically humanized mice as an in vivo model for screening of radiation response genes relevant to humans.
Highlights
The mouse (Mus musculus) is an extensively used model of human disease and responses to stresses such as ionizing radiation
The ex vivo model has been very useful to determine gene expression responses to radiation in human blood[2,3,4], it is limited by culture times and conditions and lacks an in vivo microenvironment and tissue context
In the field of radiation biology, and in the area of identification of biomarkers of radiation exposure and survival based on gene expression changes in blood, we and others have identified gene panels that have the potential to be used to determine exposure to radiation in humans and model animals[2,3,4,8,17,18,19,20,21,22,23,24,25,26,27,28]
Summary
The mouse (Mus musculus) is an extensively used model of human disease and responses to stresses such as ionizing radiation. The ex vivo model has been very useful to determine gene expression responses to radiation in human blood[2,3,4], it is limited by culture times and conditions and lacks an in vivo microenvironment and tissue context To overcome such limitations in other fields, humanized animals have been proposed to bridge the gap between in vitro/ex vivo models to the more realistic in vivo systems. In the field of radiation biology, and in the area of identification of biomarkers of radiation exposure and survival based on gene expression changes in blood, we and others have identified gene panels that have the potential to be used to determine exposure to radiation in humans and model animals[2,3,4,8,17,18,19,20,21,22,23,24,25,26,27,28]. We chose to test the gene response to radiation of human blood cells that mature in vivo in a humanized mouse model, which provides a healthy in vivo microenvironment
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