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 8 publications

(5 citation statements)

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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

Self Cite

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show abstract

“…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 [ 63 ]. FL-NOG spleens, lungs and liver also contained more macrophages and dendritic cells, possibly due to higher myeloid progenitor frequencies.…”

Section: Discussionmentioning

confidence: 99%

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

Celhar,

Li,

Zhao

et al. 2024

Stem Cell Res Ther

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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 FL-CD34+CD14−) and their engraftment into immunocompromised NOD/Shi-scid Il2rgnull (NOG) mice. Methods NOG mice were transplanted with either CB-CD34+, FL-CD34+ or FL-CD34+CD14− 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 and several organs. 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+ due to faster B cell development. However, upon long-term engraftment, FL-NOG display increased numbers of neutrophils, dendritic cells and macrophages in multiple tissues. In addition to HSPC, FL-CD34+ isolates contain non-hematopoietic CD14+ endothelial cells that enhance the engraftment of the human immune system in 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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“…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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Efficient differentiation of human neutrophils with recapitulation of emergency granulopoiesis in human G-CSF knockin humanized mice

Cited by 8 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

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

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