Combined liver–cytokine humanization comes to the rescue of circulating human red blood cells

Song, Yuanbin; Shan, Liang; Gbyli, Rana; Liu, Wei; Strowig, Till; Patel, Amisha; Fu, Xiaoying; Xu, Mina L.; Gao, Yimeng; Qin, Ashley; Bruscia, Emanuela M.; Tebaldi, Toma; Biancon, Giulia; Mamillapalli, Padmavathi; Urbonas, David; Eynon, Elizabeth E.; Gonzalez, David G.; Chen, Jie; Krause, Diane S.; Alderman, Jonathan; Halene, Stephanie

doi:10.1126/science.abe2485

Cited by 22 publications

(18 citation statements)

References 39 publications

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“…In addition to these two requirements, strong elimination of mouse macrophages is essential. It would be supportive that a paper by Song demonstrated that simultaneous transplantation of human liver and HSC achieved the development of hRBC from human HSC in MISTRG mice with the additive genetic deficiency in the fumarylacetoacetate hydrolase gene (Fah -/-) (23). This model strongly enhances human hematopoiesis by human M-CSF, IL-3, GM-CSF, and thrombopoietin (9).…”

Section: Discussionmentioning

confidence: 86%

“…The absence of mature hRBCs in the peripheral blood (PB) was also reported in the novel NSG-W41 model, which has an enhanced ability for human hematopoiesis (7,22). Although the success of induction of hRBCs was reported in a dual humanized mouse model with human liver and hematopoietic systems during the submission of this manuscript, the frequency in total RBCs remained not more than 5% (23).…”

Section: Introductionmentioning

confidence: 77%

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Generation of Novel Human Red Blood Cell-Bearing Humanized Mouse Models Based on C3-Deficient NOG Mice

et al. 2021

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Despite recent advances in immunodeficient mouse models bearing human red blood cells (hRBCs), the elimination of circulating hRBCs by residual innate immune systems remains a significant challenge. In this study, we evaluated the role of mouse complement C3 in the elimination of circulating hRBCs by developing a novel NOG substrain harboring a truncated version of the murine C3 gene (NOG-C3ΔMG2-3). Genetic C3 deletion prolonged the survival of transfused hRBCs in the circulation. Chemical depletion and functional impairment of mouse macrophages, using clodronate liposomes (Clo-lip) or gadolinium chloride (GdCl3), respectively, further extended the survival of hRBCs in NOG-C3ΔMG2-3 mice. Low GdCl3 toxicity allowed the establishment of hRBC-bearing mice, in which hRBCs survived for more than 4 weeks with transfusion once a week. In addition, erythropoiesis of human hematopoietic stem cells (hHSCs) was possible in NOG-C3ΔMG2-3/human GM-CSF-IL-3 transgenic mice with Clo-lip treatment. These findings indicate that mouse models harboring hRBCs can be achieved using NOG-C3ΔMG2-3 mice, which could facilitate studies of human diseases associated with RBCs.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 77%

Generation of Novel Human Red Blood Cell-Bearing Humanized Mouse Models Based on C3-Deficient NOG Mice

et al. 2021

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“…Human IL-15 knock-in HIS mice support the development and functional maturation of circulating and tissue-resident human NK cells that elicit antitumor responses [ [265] , [266] , [267] ]. Recently, the Flavell group has introduced a model based on the MISTRG background, in which combined human liver and cytokine humanization confer enhanced human erythropoiesis and RBC survival in the circulation [ 268 ].…”

Section: Limitations Of Humanized Mouse Models and Recent Improvementsmentioning

confidence: 99%

Modeling human T1D-associated autoimmune processes

Khosravi‐Maharlooei

Madley

Borsotti

et al. 2022

Molecular Metabolism

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Background Type 1 diabetes (T1D) is an autoimmune disease characterized by impaired immune tolerance to β-cell antigens and progressive destruction of insulin-producing β-cells. Animal models have provided valuable insights for understanding the etiology and pathogenesis of this disease, but they fall short of reflecting the extensive heterogeneity of the disease in humans, which is contributed by various combinations of risk gene alleles and unique environmental factors. Collectively, these factors have been used to define subgroups of patients, termed endotypes, with distinct predominating disease characteristics. Scope of review Here, we review the gaps filled by these models in understanding the intricate involvement and regulation of the immune system in human T1D pathogenesis. We describe the various models developed so far and the scientific questions that have been addressed using them. Finally, we discuss the limitations of these models, primarily ascribed to hosting a human immune system (HIS) in a xenogeneic recipient, and what remains to be done to improve their physiological relevance. Major conclusions To understand the role of genetic and environmental factors or evaluate immune-modifying therapies in humans, it is critical to develop and apply models in which human cells can be manipulated and their functions studied under conditions that recapitulate as closely as possible the physiological conditions of the human body. While microphysiological systems and living tissue slices provide some of these conditions, HIS mice enable more extensive analyses using in vivo systems.

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“…Included Included [7,20,27] Included [8,28] Included [10] Off target problem* PSCs [43] PSCs/differentiated cells [44] Progenitor cells [7,20,27] PSCs [8,28] N/A Application of iPS technology + [43] + [36] + [44] + [21] + [8,28] N/A…”

Section: Not Includedmentioning

confidence: 99%

Generation of chimeric kidneys using progenitor cell replacement: Oshima Award Address 2021

Yamanaka

2022

Clin Exp Nephrol

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It is believed that the development of new renal replacement therapy (RRT) will increase treatment options for end-stage kidney disease and help reduce the mismatch between supply and demand. Technological advancement in the development of kidney organoids derived from pluripotent stem cells and xenotransplantation using porcine kidneys has been accelerated by a convergence of technological innovations, including the discovery of induced pluripotent stem cells and genome editing, and improvement of analysis techniques such as single-cell ribonucleic acid sequencing. Given the difficulty associated with kidney regeneration, hybrid kidneys are studied as an innovative approach that involves the use of stem cells to generate kidneys, with animal fetal kidneys used as a scaffold. Hybrid kidney technology entails the application of local chimerism for the generation of chimeric kidneys from exogenous renal progenitor cells by borrowing complex nephrogenesis programs from the developmental environment of heterologous animals. Hybrid kidneys can also utilize the urinary tract and bladder tissue of animal fetuses for urine excretion. Generating nephrons from syngeneic stem cells to increase self-cell ratio in xeno-tissues can reduce the risk of xeno-rejection. We showed that nephrons can be generated by ablation of host nephron progenitor cells (NPCs) in the nephron development region of animals and replacing them with exogenous NPCs. This progenitor cell replacement is the basis of hybrid kidney regeneration from progenitor cells using chimera technology. The goal of xeno-regenerative medicine using hybrid kidneys is to overcome serious organ shortage.

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Combined liver–cytokine humanization comes to the rescue of circulating human red blood cells

Cited by 22 publications

References 39 publications

Generation of Novel Human Red Blood Cell-Bearing Humanized Mouse Models Based on C3-Deficient NOG Mice

Generation of Novel Human Red Blood Cell-Bearing Humanized Mouse Models Based on C3-Deficient NOG Mice

Modeling human T1D-associated autoimmune processes

Generation of chimeric kidneys using progenitor cell replacement: Oshima Award Address 2021

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