Efficient differentiation of human neutrophils with recapitulation of emergency granulopoiesis in human G-CSF knockin humanized mice

Ito, Ryoji; Katano, Ikumi; Kwok, Immanuel; Ng, Lai Guan; Ida-Tanaka, Miyuki; Ohno, Yusuke; Mu, Yueying; Morita, Hanako; Nishinaka, Eiko; Nishime, Chiyoko; Mochizuki, Misa; Kawai, Kenji; Chien, Tay Hui; Yunqian, Zhao; Fan, Yiping; Hua, Liew Hui; Celhar, Teja; Chan, Jerry Kok Yen; Takahashi, Takeshi; Goto, Motohito; Ogura, Tomoyuki; Takahashi, Riichi; Ito, Mamoru

doi:10.1016/j.celrep.2022.111841

Cited by 4 publications

(3 citation statements)

References 58 publications

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“…Additionally, FL-NOG mice consistently harboured higher numbers of CD16 hi CD66b hi neutrophils across organs. This is likely due to increased development in the bone marrow and warrants further investigation in models that support better neutrophil reconstitution, such as hG-CSF KI NOG (59). FL-NOG spleens, lungs and liver also contained more macrophages and dendritic cells, possibly due to higher myeloid progenitor frequencies.…”

Section: Discussionmentioning

confidence: 96%

Fetal liver CD34+ contain human immune and endothelial progenitors and mediate solid tumor rejection in NOG mice

Celhar,

Li,

Zhao

et al. 2024

Preprint

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Background Transplantation of CD34+ hematopoietic stem and progenitor cells (HSPC) into immunodeficient mice is an established method to generate humanized mice harbouring a human immune system. Different sources and methods for CD34+ isolation have been employed by various research groups, resulting in customized models that are difficult to compare. A more detailed characterization of CD34+ isolates is needed for a better understanding of engraftable hematopoietic and potentially non-hematopoietic cells. Here we have performed a direct comparison of CD34+ isolated from cord blood (CB-CD34+) or fetal liver (FL-CD34+) and their engraftment into immunocompromised NOD/Shi-scid Il2rgnull (NOG) mice. Methods Three separate cohorts of NOG mice were transplanted with either CB-CD34+, FL-CD34+ or FL-CD34+ depleted of CD14+ endothelial cells to generate CB-NOG, FL-NOG and FL-CD14−-NOG, respectively. After 15–20 weeks, the mice were sacrificed and human immune cell reconstitution was assessed in blood, bone marrow, spleen, lungs and liver. Liver sections were pathologically assessed upon Haematoxylin and Eosin staining. To assess the capability of allogenic tumor rejection in CB- vs FL-reconstituted mice, animals were subcutaneously engrafted with an HLA-mismatched melanoma cell line. Tumor growth was assessed by calliper measurements and a Luminex-based assay was used to compare the cytokine/chemokine profiles. Results We show that CB-CD34+ are a uniform population of HSPC that reconstitute NOG mice more rapidly than FL-CD34+. In addition to HSPC, FL-CD34+ isolates contain non-hematopoietic CD14+ endothelial cells that enhance the engraftment of the human immune system in FL-CD34+-transplanted NOG (FL-NOG) mice. We demonstrate that these CD14+CD34+ cells are capable of reconstituting Factor VIII-producing liver sinusoidal endothelial cells (LSEC) in FL-NOG. However, CD14+CD34+ also contribute to hepatic sinusoidal dilatation and immune cell infiltration, which may culminate in a graft-versus-host disease (GVHD) pathology upon long-term engraftment. Finally, using an HLA-A mismatched CDX melanoma model, we show that FL-NOG, but not CB-NOG, can mount a graft-versus-tumor (GVT) response resulting in tumor rejection. Conclusion Our results highlight important phenotypical and functional differences between CB- and FL-NOG and reveal FL-NOG as a potential model to study hepatic sinusoidal dilatation and mechanisms of GVT.

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Section: Discussionmentioning

confidence: 96%

Fetal liver CD34+ contain human immune and endothelial progenitors and mediate solid tumor rejection in NOG mice

Celhar,

Li,

Zhao

et al. 2024

Preprint

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“…This mouse model could thus be used to test dendritic cell-targeted therapies. In addition, MISTRG-GR [162] and NOG-GCSF mice [163] have been developed, which express human G-CSF and lack mouse G-CSF receptor (G-CSFR), and therefore support human granulocyte development and function.…”

Section: Human Immune System Development and Function In Next-generat...mentioning

confidence: 99%

Modeling the Tumor Microenvironment and Cancer Immunotherapy in Next-Generation Humanized Mice

Chen,

Neuwirth,

Herndler-Brandstetter

2023

Cancers

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Cancer immunotherapy has brought significant clinical benefits to numerous patients with malignant disease. However, only a fraction of patients experiences complete and durable responses to currently available immunotherapies. This highlights the need for more effective immunotherapies, combination treatments and predictive biomarkers. The molecular properties of a tumor, intratumor heterogeneity and the tumor immune microenvironment decisively shape tumor evolution, metastasis and therapy resistance and are therefore key targets for precision cancer medicine. Humanized mice that support the engraftment of patient-derived tumors and recapitulate the human tumor immune microenvironment of patients represent a promising preclinical model to address fundamental questions in precision immuno-oncology and cancer immunotherapy. In this review, we provide an overview of next-generation humanized mouse models suitable for the establishment and study of patient-derived tumors. Furthermore, we discuss the opportunities and challenges of modeling the tumor immune microenvironment and testing a variety of immunotherapeutic approaches using human immune system mouse models.

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“…NOD-scid IL-2rg null (NOG and NSG) mice possess a mutated Prkdc gene (severe combined immunode ciency; scid) and lack the interleukin (IL)-2 receptor subunit gamma (IL-2rg); accordingly, these mice can be useful recipients for transferring CD34 + human hematopoietic stem cells (HSCs) [1,2]. We have previously established NOG-based second-generation humanized mice that systemically express myeloid cell-accelerated cytokines and successfully induce the differentiation of multiple human myeloid lineage cells, such as monocytes/macrophages, basophils, and mast cells [3], eosinophils, [4], and neutrophils [5]. To achieve su cient human hematopoietic cell engraftment in humanized mice, standard methods require a large number of enriched CD34 + HSCs, along with total body irradiation before transplantation.…”

Section: Introductionmentioning

confidence: 99%

Improvement of multilineage hematopoiesis in hematopoietic stem cell-transferred c-kit mutant NOG-EXL humanized mice

Ito,

Ohno,

et al. 2023

Preprint

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Human hematopoietic stem cell (HSC)-transferred humanized mice are valuable for exploring human hematology and immunology. However, sufficient recapitulation of human hematopoiesis in mice requires large quantities of enriched human CD34+ HSCs and total body irradiation for adequate engraftment. Recently, we generated a NOG mouse strain with a point mutation in the c-kit tyrosine kinase domain (W41 mutant; NOGW mice). Herein, we first examined the potential of NOGW mice for reconstituting human hematopoietic cells. Irradiated NOGW mice exhibited a high engraftment level of human CD45+ cells in peripheral blood, even on transferring 5,000–10,000 CD34+ HSCs. The efficient engraftment of human CD45+ cells was also observed in non-irradiated NOGW mice transferred with 20,000–40,000 HSCs. The bone marrow (BM) of NOGW mice exhibited significantly more engrafted human HSCs or progenitor cells (CD34+CD38− or CD34+CD38+ cells) than the BM of NOG mice. Furthermore, we generated a human cytokine (interleukin-3 and granulocyte-macrophage colony-stimulating factor) transgenic NOG-W41 (NOGW-EXL) mouse to achieve multilineage reconstitution with sufficient engraftment of human hematopoietic cells. Non-irradiated NOGW-EXL mice showed significantly higher engraftment levels of human CD45+ and myeloid lineage cells, particularly granulocytes and platelets/megakaryocytes, than non-irradiated NOGW or irradiated NOG-EXL mice after human CD34+ cell transplantation. Serial BM transplantation experiments revealed that NOGW mice exhibited the highest potential for long-term HSC compared with other strains. Consequently, c-kit mutant NOGW-EXL humanized mice represent an advanced model for HSC-transferred humanized mice and hold promise for widespread application owing to their high versatility.

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Efficient differentiation of human neutrophils with recapitulation of emergency granulopoiesis in human G-CSF knockin humanized mice

Cited by 4 publications

References 58 publications

Fetal liver CD34+ contain human immune and endothelial progenitors and mediate solid tumor rejection in NOG mice

Fetal liver CD34+ contain human immune and endothelial progenitors and mediate solid tumor rejection in NOG mice

Modeling the Tumor Microenvironment and Cancer Immunotherapy in Next-Generation Humanized Mice

Improvement of multilineage hematopoiesis in hematopoietic stem cell-transferred c-kit mutant NOG-EXL humanized mice

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