Mice Description

The use of severely immunodeficient mice engrafted with human hematopoietic stem cells (HSCs) to reconstitute immune system humanized mice has provided researchers with powerful tools for virus research and cellular immunotherapy preclinical evaluation of the human immune system and related primates. However, the maintenance, differentiation and function of human HSCs are not ideal in these hosts. The thrombopoietin (THPO) has been shown to be an important cytokine supporting HSCs maintenance and self-renewal. In addition, the species barrier between human immune cells and the mouse microenvironment limits the development of human innate and acquired immune cells, such as human macrophages. Cytokine CSF1 (colony stimulating factor 1, MCSF) can promote the production, differentiation and function of macrophages.

Biocytogen developed B-NDG hCSF1/hTHPO mice in which the full-length CSF1 and THPO gene sequences of the mice were replaced with the full-length coding sequences of the human CSF1 and THPO genes in B-NDG mice to obtain severely immunodeficient mice expressing both human CSF1 and THPO. The mice could reconstitute the human immune system, especially human macrophages, without irradiation pretreatment.

Background

Genomic organization and expression of theThpogene

Activation of the TPO receptor by TPO or TPO receptor agonists. TPO and romiplostim bind to the distal cytokine receptor homology domain (CRH-2) of the preformed, inactive TPO receptor dimer. Eltrombopag binds to the transmembrane region of the TPO receptor. Multiple signal transduction pathways are thereby activated.

Kuter, D. J. The biology of thrombopoietin and thrombopoietin receptor agonists. International journal of hematology 98, 10-23, doi:10.1007/s12185-013-1382-0 (2013).

CSF-1 regulation of the wandering macrophage

Circulating CSF-1, produced by endothelial cells in blood vessels, together with locally produced CSF-1 regulates the survival, proliferation and differentiation of mononuclear phagocytes and osteoclasts.

CSF-1 regulation of the wandering macrophage: complexity in action Fiona J. Pixley and E. Richard Stanley, 2004

B-NDG hCSF1/hTHPO mice can successfully reconstitute the human immune system without irradiation

B-NDG hCSF1/hTHPO mice engrafted with human CD34+ HSCs promote the reconstitution of human monocytes/macrophages. Human CD34+ HSCs (1.5E5) were intravenously injected into non-irradiated B-NDG hCSF1/hTHPO mice (female, 6-week-old, n = 15). The peripheral blood was taken every 2 weeks to analyze the proportion of reconstituted human immune cells. The results showed that the reconstitution success rate of non-irradiated B-NDG hCSF1/hTHPO mice engrafted with human HSCs for 14 weeks reached 80%, and their survival rate reached 98%, without obvious GvHD symptoms. The proportion of reconstitution was relatively high in human myeloid cells and monocytes/macrophages. The results indicated that B-NDG hCSF1/hTHPO mice were able to successfully reconstitute the human immune system without irradiation, especially monocytes/macrophages.