Monocytes derived from humanized neonatal NOD/SCID/IL2Rγnull mice are phenotypically immature and exhibit functional impairments

Gille, Christian; Orlikowsky, Thorsten; Spring, Baerbel; Hartwig, Udo F.; Wilhelm, Ayline; Wirth, Andreas; Goecke, Barbara; Handgretinger, Rupert; Poets, Christian F.; André, Maya C.

doi:10.1016/j.humimm.2012.01.006

Cited by 46 publications

(54 citation statements)

References 44 publications

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“…Multilineage engraftment was durable, lasting for at least 25 weeks after transplant, and human stem and progenitor cells capable of engraftment of secondary recipients were present in the bone marrow of the primary recipients for at least 16 weeks, confirming the presence of primitive hematopoietic stem cells in the primary grafts. These results are similar to previous studies in which adult growth factor-mobilized peripheral blood was used to transplant NSG mice and further support the use of this model system for investigating human disease (Herrera et al, 2001;Shultz et al, 2005;Andre et al, 2010;Gille et al, 2012;Hakki et al, 2014). However, unlike transplantation of neonatal mice with cord blood HSPC, no human cell engraftment of lymph nodes or thymus and minimal engraftment of cells in the circulation of these mice were observed.…”

Section: Discussionsupporting

confidence: 90%

Engraftment and Lineage Potential of Adult Hematopoietic Stem and Progenitor Cells Is Compromised Following Short-Term Culture in the Presence of an Aryl Hydrocarbon Receptor Antagonist

Torres-Coronado

Tran

et al. 2014

Human Gene Therapy Methods

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Hematopoietic stem cell gene therapy for HIV/AIDS is a promising alternative to lifelong antiretroviral therapy. One of the limitations of this approach is the number and quality of stem cells available for transplant following in vitro manipulations associated with stem cell isolation and genetic modification. The development of methods to increase the number of autologous, gene-modified stem cells available for transplantation would overcome this barrier. Hematopoietic stem and progenitor cells (HSPC) from adult growth factor-mobilized peripheral blood were cultured in the presence of an aryl hydrocarbon receptor antagonist (AhRA) previously shown to expand HSPC from umbilical cord blood. Qualitative and quantitative assessment of the hematopoietic potential of minimally cultured (MC-HSPC) or expanded HSPC (Exp-HSPC) was performed using an immunodeficient mouse model of transplantation. Our results demonstrate robust, multilineage engraftment of both MC-HSPC and Exp-HSPC although estimates of expansion based on stem cell phenotype were not supported by a corresponding increase in in vivo engrafting units. Bone marrow of animals transplanted with either MC-HSPC or Exp-HSPC contained secondary engrafting cells verifying the presence of primitive stem cells in both populations. However, the frequency of in vivo engrafting units among the more primitive CD34 + / CD90 + HSPC population was significantly lower in Exp-HSPC compared with MC-HSPC. Exp-HSPC also produced fewer lymphoid progeny and more myeloid progeny than MC-HSPC. These results reveal that in vitro culture of adult HSPC in AhRA maintains but does not increase the number of in vivo engrafting cells and that HSPC expanded in vitro contain defects in lymphopoiesis as assessed in this model system. Further investigation is required before implementation of this approach in the clinical setting.

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Section: Discussionsupporting

confidence: 90%

Engraftment and Lineage Potential of Adult Hematopoietic Stem and Progenitor Cells Is Compromised Following Short-Term Culture in the Presence of an Aryl Hydrocarbon Receptor Antagonist

Torres-Coronado

Tran

et al. 2014

Human Gene Therapy Methods

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“…However, the development and function of several human immune cell types, such as monocytes/macrophages and NK cells, is largely defective in currently available models of humanized mice 2 . More specifically, human monocytes/macrophages are present in low frequency 4,5 and while a report showed that these cells are functional 4 , another report identified functional impairments and an immature phenotype of human monocytes 6 . The maturation, function and homeostasis of human NK cells are also defective in existing humanized mice 7,8 .…”

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confidence: 99%

Development and function of human innate immune cells in a humanized mouse model

et al. 2014

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Mice repopulated with human hematopoietic cells are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, existing humanized mouse models are unable to support development of human innate immune cells, including myeloid cells and NK cells. Here we describe a mouse strain, called MI(S)TRG, in which human versions of four genes encoding cytokines important for innate immune cell development are knocked in to their respective mouse loci. The human cytokines support the development and function of monocytes/macrophages and natural killer cells derived from human fetal liver or adult CD34+ progenitor cells injected into the mice. Human macrophages infiltrated a human tumor xenograft in MI(S)TRG mice in a manner resembling that observed in tumors obtained from human patients. This humanized mouse model may be used to model the human immune system in scenarios of health and pathology, and may enable evaluation of therapeutic candidates in an in vivo setting relevant to human physiology.

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“…Likewise, monocytes from humanized NSG mice and human cord blood-derived neonatal monocytes displayed a similar phenotype concerning their phagocytic activity and expression of costimulatory molecules (14).…”

Section: Il2rgmentioning

confidence: 91%

Humanized Mice, a New Model To Study the Influence of Drug Treatment on Neonatal Sepsis

et al. 2013

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cBacterial infection with group B Streptococcus (GBS) represents a prominent threat to neonates and fetuses in the Western world, causing severe organ damage and even death. To improve current therapeutic strategies and to investigate new approaches, an appropriate in vivo model to study the immune response of a human immune system is needed. Therefore, we introduced humanized mice as a new model for GBS-induced sepsis. Humanized mice feature deficiencies similar to those found in neonates, such as lower immunoglobulin levels and myeloid cell dysfunction. Due to the husbandry in specific-pathogen-free (SPF) facilities, the human immune cells in these mice also exhibit a naive phenotype which mimics the conditions in fetuses/ neonates. Following infection, cytokine release and leukocyte trafficking from the bone marrow to the lymphoid organ (spleen) and into the peritoneum (site of infection) as well as bacterial spreading and clearance were traceable in the humanized mice. Furthermore, we investigated the effects of betamethasone and indomethacin treatment using this novel sepsis model. Although both drugs are commonly used in perinatal care, little is known about their effects on the neonatal immune system. Treatment of infected humanized mice not only induced the reduction of human leukocytes in the spleen but also increased the bacterial load in all analyzed organs, including the brain, which did not show infiltration of live GBS in untreated controls. These studies demonstrate the utility of the humanized mice as a new model to study an immature human immune response during bacterial infection and allow the investigation of side effects induced by various treatments.

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Monocytes derived from humanized neonatal NOD/SCID/IL2Rγnull mice are phenotypically immature and exhibit functional impairments

Cited by 46 publications

References 44 publications

Engraftment and Lineage Potential of Adult Hematopoietic Stem and Progenitor Cells Is Compromised Following Short-Term Culture in the Presence of an Aryl Hydrocarbon Receptor Antagonist

Engraftment and Lineage Potential of Adult Hematopoietic Stem and Progenitor Cells Is Compromised Following Short-Term Culture in the Presence of an Aryl Hydrocarbon Receptor Antagonist

Development and function of human innate immune cells in a humanized mouse model

Humanized Mice, a New Model To Study the Influence of Drug Treatment on Neonatal Sepsis

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