Mice engrafted with human hematopoietic stem cells support a human myeloid cell inflammatory response in vivo

Abstract

Mice engrafted with human CD34⁺ hematopoietic stem and progenitor cells (CD34⁺ -HSPCs) have been used to study human infection, diabetes, sepsis, and burn, suggesting that they could be highly amenable to characterizing the human inflammatory response to injury. To this end, human leukocytes infiltrating subcutaneous implants of polyvinyl alcohol (PVA) sponges were analyzed in immunodeficient NSG mice reconstituted with CD34⁺ -HSPCs. It was reported that human CD45⁺ (hCD45⁺ ) leukocytes were present in PVA sponges 3 and 7 days postimplantation and could be localized within the sponges by immunohistochemistry. The different CD45⁺ subtypes were characterized by flow cytometry and the profile of human cytokines they secreted into PVA wound fluid was assessed using a human-specific multiplex bead analyses of human IL-12p70, TNFα, IL-10, IL-6, IL1β, and IL-8. This enabled tracking the functional contributions of HLA-DR⁺ , CD33⁺ , CD19⁺ , CD62L⁺ , CD11b⁺ , or CX3CR1⁺ hCD45⁺ infiltrating inflammatory leukocytes. PCR of cDNA prepared from these cells enabled the assessment and differentiation of human, mouse, and uniquely human genes. These findings support the hypothesis that mice engrafted with CD34⁺ -HSPCs can be deployed as precision avatars to study the human inflammatory response to injury.