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


Saito, Y; Ellegast, J M; Rafiei, A; Song, Y; Kull, D; Heikenwalder, M; Rongvaux, A; Halene, S; Flavell, R A; Manz, M G (2016). Peripheral blood CD34$^+$ cells efficiently engraft human cytokine knock-in mice. Blood, 128(14):1829-1833.

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.

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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Hematology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:August 2016
Deposited On:30 Jan 2017 16:22
Last Modified:31 Jan 2017 02:04
Publisher:American Society of Hematology
ISSN:0006-4971
Publisher DOI:https://doi.org/10.1182/blood-2015-10-676452
PubMed ID:27543436

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