Multiple genetically engineered humanized microenvironments in a single mouse

Abstract

Background Immunodeficient mouse models that accept human cell and tissue grafts can contribute greater knowledge to human stem cell research. In this technical report, we used biomaterial implants seeded with genetically engineered stromal cells to create several unique microenvironments in a single mouse. The scope of study was focused on human CD34 hematopoietic stem/progenitor cell (HSPC) engraftment and differentiation within the engineered microenvironment. Results A mouse model system was created using subdermal implant sites that overexpressed a specific human cytokines (Vascular Endothelial Growth Factor A (hVEGFa), Stromal Derived Factor 1 Alpha (hSDF1a), or Tumor Necrosis Factor Alpha (hTNFa)) by stromal cells in a three-dimensional biomaterial matrix. The systemic exposure of locally overexpressed cytokines was minimized by controlling the growth of stromal cells, which led to autonomous local, concentrated sites in a single mouse for study. This biomaterial implant approach allowed for the local analysis of each cytokine on hematopoietic stem cell recruitment, engraftment and differentiation in four different tissue microenvironments in the same host. The engineered factors were validated to have bioactive effects on human CD34+ hematopoietic progenitor cell differentiation. Conclusions This model system can serve as a new platform for the study of multiple human proteins and their local effects on hematopoietic cell biology for in vivo validation studies