Improved Human Erythropoiesis and Platelet Formation in Humanized NSGW41 Mice

Rahmig, Susann; Kronstein‐Wiedemann, Romy; Fohgrub, Juliane; Kronstein, Nicole; Nevmerzhitskaya, Aleksandra; Bornhäuser, Martin; Gassmann, Max; Platz, Alexander; Ordemann, Rainer; Tonn, Torsten; Waskow, Claudia

doi:10.1016/j.stemcr.2016.08.005

Cited by 90 publications

(99 citation statements)

References 25 publications

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“…After reconstitution, significant numbers of mature thrombocytes were present in the peripheral blood while human erythroblasts were seen in the BM. In addition, the morphology, composition, and enucleation ability of de novo generated human erythroblasts were similar with those in the human BM (Rahmig et al 2016). However, as this model is relatively new, more studies are needed to further characterise the advances and limitations of this platform.…”

Section: Evolving History Of Humanized Micesupporting

confidence: 55%

Humanized Mice as Unique Tools for Human-Specific Studies

Yong

Her

Chen

2018

Arch. Immunol. Ther. Exp.

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With an increasing human population, medical research is pushed to progress into an era of precision therapy. Humanized mice are at the very heart of this new forefront where it is acutely required to decipher human-specific disease pathogenesis and test an array of novel therapeutics. In this review, “humanized” mice are defined as immunodeficient mouse engrafted with functional human biological systems. Over the past decade, researchers have been conscientiously making improvements on the development of humanized mice as a model to closely recapitulate disease pathogenesis and drug mechanisms in humans. Currently, literature is rife with descriptions of novel and innovative humanized mouse models that hold a significant promise to become a panacea for drug innovations to treat and control conditions such as infectious disease and cancer. This review will focus on the background of humanized mice, diseases, and human-specific therapeutics tested on this platform as well as solutions to improve humanized mice for future clinical use.

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Section: Evolving History Of Humanized Micesupporting

confidence: 55%

Humanized Mice as Unique Tools for Human-Specific Studies

Yong

Her

Chen

2018

Arch. Immunol. Ther. Exp.

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“…Cytokine humanization does not alter the lack of mature human red blood cells (RBC) and the low human platelet percentage in the peripheral blood as also shown previously 14,19 . Administration of human erythropoietin has shown no benefit in this regard 46 as the defect lies in RBC and platelet destruction by the murine innate immune system. Thus modulation of the murine innate immune system will be necessary to promote mature human cell persistence in peripheral blood, transiently achieved by administration of liposomeencapsulated clodronate 41,47 .…”

Section: Discussionmentioning

confidence: 99%

A Highly Efficient and Faithful MDS Patient-Derived Xenotransplantation Model for Pre-Clinical Studies

Song

Rongvaux

Taylor

et al. 2018

Preprint

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key points:1. Cytokine humanized MISTRG mice reliably engraft lower-and higher-risk MDS 2. MISTRG engraft the clonal MDS stem cells and afford propagation of genetically faithful patient-derived xenografts (PDX) in serial transplantation.3. MISTRG uniquely model multi-lineage MDS hematopoiesis, including erythro-and megakaryopoiesis, and replicate myelodysplasia.4. MISTRG MDS PDX are ideally suited to study targeted therapeutics.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/265082 doi: bioRxiv preprint first posted online Feb. 14, 2018;

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“…Normal human HSCs show a predominant B-lymphoid bias upon long-term engraftment in NSG mice 25 . We therefore repeated our xenotransplantation assays using c-kit-deficient NSGW41 recipients, which support enhanced erythropoiesis and megakaryocyte formation 26 . Limiting dilution analysis of CRISPR/Cas9-edited LT-HSCs in NSGW41 mice for 12 weeks revealed a repopulating cell frequency of ~1/175, compared to ~1/100 in the NSG background for 24 weeks ( Supplementary Fig.…”

Section: Limiting Dilution Analysis 24 Of Crispr/cas9 Control-editedmentioning

confidence: 93%

Functional Profiling of Single CRISPR/Cas9-Edited Human Long-Term Hematopoietic Stem Cells

Wagenblast

Azkanaz

Smith

et al. 2019

Preprint

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and Eric R. Lechman (elechman@uhnresearch.ca) regenerative therapies. Thus, LT-HSCs are essential for therapeutic genome editing to correct acquired and genetic hematopoietic disorders 3,4 . Furthermore, the pathogenesis of hematological malignancies like acute myeloid leukemia (AML) is associated with the presence of initiating mutations acquired in LT-HSCs, which lead to their competitive expansion 5,6 . Pre-leukemic LT-HSCs are a source of clonal evolution within blood malignancies and can act as a reservoir of relapse after chemotherapy treatment 7 . Thus, modeling and understanding the genetic complexity and cellular heterogeneity seen in human hematological malignancies requires novel methodologies that allow genome editing in LT-HSCs and their functional read-out 3,4 .Recently several studies have demonstrated efficient gene editing of bulk CD34 + populations that are enriched for human HSPCs [8][9][10][11][12][13][14][15][16] . Highly efficient non-homologous end joining (NHEJ) mediated gene disruption of up to 80-90% efficiency has been reported in CD34 + HSPCs 10,11,14,16 . In addition, homology-directed repair (HDR) mediated knock-ins, with or without selectable fluorescent reporter genes, have been established with an efficiency of up to 20% in CD34 + HSPCs 8,9,11,13,15 . Stable integration of a fluorescent reporter using rAAV6 combined with flow cytometrybased sorting enabled enrichment of CRISPR/Cas9 edited HSPCs 8,9,16 . Because LT-HSCs represent only 0.1 -1% of CD34 + populations, these studies did not address LT-HSC targeting in the most direct manner. Previous studies have reported long term engraftment of up to 16 weeks following xenotransplantation of CRISPR/Cas9 edited human CD34 + HSPCs 8,15,16 , suggesting that rare LT-HSCs within the CD34 +

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Improved Human Erythropoiesis and Platelet Formation in Humanized NSGW41 Mice

Cited by 90 publications

References 25 publications

Humanized Mice as Unique Tools for Human-Specific Studies

Humanized Mice as Unique Tools for Human-Specific Studies

A Highly Efficient and Faithful MDS Patient-Derived Xenotransplantation Model for Pre-Clinical Studies

Functional Profiling of Single CRISPR/Cas9-Edited Human Long-Term Hematopoietic Stem Cells

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