Journal
BLOOD
Volume 128, Issue 14, Pages 1829-1833Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-10-676452
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Funding
- Hanne-Liebermann research fellowship
- University of Zurich clinical research priority program Human Hemato-Lymphatic Diseases
- Bill and Melinda Gates Foundation
- National Cancer Institute, National Institutes of Health [CA156689]
- US Department of Defense [CA120128]
- State of Connecticut Department of Public Health [RFP 2014-0135]
- Grants-in-Aid for Scientific Research [15K08532] Funding Source: KAKEN
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Human CD34(+) hematopoietic stem and progenitor cells (HSPCs) can reconstitute a human hemato-lymphoid system when transplanted into immunocompromised mice. Although fetal liver-derived 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 humanized mice on a Rag2(-/-) Il2rg(-/-) background carrying a transgene for human signal regulatory protein alpha (SIRP alpha) and human homologs of the cytokine macrophage colony-stimulating factor, thrombopoietin, with or without interleukin-3 and granulocyte-macrophage colony-stimulating factor under murine promoters. Here we transplanted mobilized peripheral blood (PB) CD34(+) cells in sublethally irradiated newborn and adult recipients. Human hematopoietic engraftment levels were significantly higher in bone marrow (BM), spleen, and PB in newborn transplanted MSTRG/MISTRG as compared with nonobese diabetic/severe combined immunodeficient Il2rg(-/-) or human SIRP alpha-transgenic Rag2(-/-) Il2rg(-/-) recipients. Furthermore, newborn transplanted MSTRG/MISTRG mice supported higher engraftment levels of human phenotypically defined HSPCs in BM, T cells in the thymus, and myeloid cells in nonhematopoietic 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 pathophysiology of the hematopoietic and immune system in vivo.
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