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

Yasuyuki Saito, Jana M. Ellegast, Anahita Rafiei, Yuanbin Song, Daniel Kull, Mathias Heikenwalder, Anthony Rongvaux, Stephanie Halene, Richard A. Flavell and Markus G. Manz

Key points

  • Human cytokine knock-in mice are improved in vivo models for multi-lineage engraftment of mobilized peripheral blood CD34+ cells.

  • Humanized mouse models might open new avenues for personalized studies of human (patho)physiology of the hematopoietic and immune system.

Abstract

Human CD34+ hematopoietic stem and progenitor cells (HSPCs) can reconstitute a human hemato-lymphoid system when transplanted into immunocompromised mice. While fetal liver- 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 hu-manized mice on a Rag2-/-Il2rg-/- background carrying a transgene for human SIRPα and human homologues of the cytokines macrophage-colony stimulating factor, thrombopoietin, with or without interleukin-3 and granulocyte-macrophage colony stimulating factor under murine promotors. Here we transplanted mobilized peripheral blood CD34+ cells in sub-lethally irradiated newborn and adult recipients. Human hematopoietic engraftment levels were significantly higher in bone marrow, spleen and peripheral blood in newborn transplanted MSTRG/MISTRG as compared to non-obese diabetic/severe combined immunodeficient Il2rg-/- or human SIRPα-transgenic Rag2-/-Il2rg-/- recipients. Furthermore newborn transplanted MSTRG/MISTRG mice supported higher engraftment levels of human phenotypically defined HSPCs in bone marrow, T-cells in the thymus, and myeloid cells in non-hematopoietic 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 (patho)physiology of the hematopoietic and immune system in vivo.

  • Submitted October 22, 2015.
  • Accepted August 5, 2016.