Long-term engraftment of adult hematopoietic progenitors in a novel model of humanized mice

Abstract

Pre-clinical use of humanized mice transplanted with CD34+ hematopoietic progenitor cells (HPCs) is limited by insufficient engraftment with adult HPCs. Here, we developed a novel immunodeficient mice based in NOD-SCID-Il2{gamma}c-/- (NSG) mice to support long-term engraftment with human adult HPCs and tissue colonization with human myeloid cells. As both Flt3L and IL-6 are critical for many aspects of hematopoiesis, we knock-out mouse Flt3 and knock-in human IL6 gene. The resulting mice showed an increase in the availability of mouse Flt3L to human cells, and a dose-dependent production of human IL-6 upon activation. Upon transplantation with low number of human HPCs from adult bone marrow, these humanized mice demonstrated a significantly higher engraftment with multilineage differentiation of human lymphoid and myeloid cells. Furthermore, higher frequencies of human lymphoid and myeloid cells were detected in tissues at one year after adult HPC transplant. Thus, these mice enable studies of human hematopoiesis and tissue colonization over time. SummaryPre-clinical use of humanized mice is limited by insufficient engraftment with adult hematopoietic progenitor cells (HPCs). Here, we developed a novel immunodeficient mice which support long-term engraftment with adult bone marrow HPCs and facilitate building autologous models for immuno-oncology studies.