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Blood. 2016 Aug 19. pii: blood-2015-10-676452. [Epub ahead of print]

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

Author information

1
Hematology, University Hospital and University of Zurich, Zurich, Switzerland;
2
Department of Immunobiology, Yale University, New Haven, CT, United States;
3
Institute of Virology, Technische Universitaet Muenchen, Helmholtz Zentrum Muenchen, Munich, Germany;
4
Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany;
5
Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, United States;
6
Section of Hematology/Department of Internal Medicine and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, United States;
7
Howard Hughes Medical Institute, Yale University, New Haven, CT, United States.
8
Hematology, University Hospital and University of Zurich, Zurich, Switzerland; markus.manz@usz.ch.

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.

PMID:
27543436
PMCID:
PMC5054696
[Available on 2017-10-06]
DOI:
10.1182/blood-2015-10-676452
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