Peripheral blood CD34+ cells efficiently engraft human cytokine knock-in mice

Abstract

Human CD34 hematopoietic stem and progenitor cells (HSPCs) can reconstitute a human hemato-lymphoid system when transplanted into immunocompromised mice. Although fetal liver-derived and cord blood-derived CD34 cells lead to high engraftment levels, engraftment of mobilized, adult donor-derived CD34 cells has remained poor. We generated so-called MSTRG and MISTRG humanized mice on a background carrying a transgene for human signal regulatory protein α (SIRPα) and human homologs of the cytokine macrophage colony-stimulating factor, thrombopoietin, with or without interleukin-3 and granulocyte-macrophage colony-stimulating factor under murine promoters. Here we transplanted mobilized peripheral blood (PB) CD34 cells in sublethally irradiated newborn and adult recipients. Human hematopoietic engraftment levels were significantly higher in bone marrow (BM), spleen, and PB in newborn transplanted MSTRG/MISTRG as compared with nonobese diabetic/severe combined immunodeficient or human SIRPα-transgenic recipients. Furthermore, newborn transplanted MSTRG/MISTRG mice supported higher engraftment levels of human phenotypically defined HSPCs in BM, T cells in the thymus, and myeloid cells in nonhematopoietic organs such as liver, lung, colon, and skin, approximating the levels in the human system. Similar results were obtained in adult recipient mice. Thus, human cytokine knock-in mice might open new avenues for personalized studies of human pathophysiology of the hematopoietic and immune system in vivo.

Engraftment of chronic myelomonocytic leukemia cells in immunocompromised mice supports disease dependency on cytokines

“…The use of single separated knockin mice would provide a more precise answer on the impact of each cytokine on engraftment, as demonstrated previously. [10][11][12] Although primary transplantation was effective for most patient samples, secondary transplantation was observed for a limited number of cases. This low efficacy may be the consequence of the expansion of GM-CSF hypersensitive progenitors while engraftment of leukemic stem cells may remain limited in these conditions.…”

Establishment of a Patient-Derived Tumor Xenograft Model and Application for Precision Cancer Medicine

“…[34][35][36] The human bone marrow microenvironment was also established from mesenchymal stem cells etc.…”

Differential Dynamics of HIV Infection in Humanized MISTRG versus MITRG Mice

“…However, we observed that human peripheral cells waned at ;36 wk of age. Furthermore, MITRG/MISTRG mice also support engraftment with mobilized peripheral blood CD34 + cells from adults (43). Thus, MITRG/MISTRG mice support engraftment of any kind of CD34 + cells, with more prominent engraftment if irradiated prior to transplantation.…”

“…MITRG and MISTRG mice support better human myeloid cell engraftment than the current gold standard NSG mice and closely mirror the human hematopoietic profile (24). In addition to the efficient engraftment of cord blood-derived CD34 + , MISTRG mice show superior engraftment of mobilized peripheral blood CD34 + cells and myeloid lineage development in comparison with other mouse strains (25).…”