Multilineage readout after HSC expansion – erythrocytes matter

Mende, Nicole; Rahmig, Susann; Waskow, Claudia

doi:10.1080/15384101.2016.1156904

Cited by 2 publications

(2 citation statements)

References 7 publications

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“…To date, the ex vivo generation of platelets from donor-independent or autologous sources has been hampered by an incomplete understanding of mechanisms promoting platelet differentiation and maturation ( Karagiannis and Eto, 2015 , Lambert et al., 2013 ). Finally, it is impossible to test for differentiation of these lineages in vivo ( Mende et al., 2016 ), underlining the need for suitable in vivo models to study these processes.…”

Section: Introductionmentioning

confidence: 99%

Improved Human Erythropoiesis and Platelet Formation in Humanized NSGW41 Mice

et al. 2016

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SummaryHuman erythro-megakaryopoiesis does not occur in humanized mouse models, preventing the in vivo analysis of human hematopoietic stem cell (HSC) differentiation into these lineages in a surrogate host. Here we show that stably engrafted KIT-deficient NOD/SCID Il2rg−/−KitW41/W41 (NSGW41) mice support much improved human erythropoiesis and platelet formation compared with irradiated NSG recipients. Considerable numbers of human erythroblasts and mature thrombocytes are present in the bone marrow and blood, respectively. Morphology, composition, and enucleation capacity of de novo generated human erythroblasts in NSGW41 mice are comparable with those in human bone marrow. Overexpression of human erythropoietin showed no further improvement in human erythrocyte output, but depletion of macrophages led to the appearance of human erythrocytes in the blood. Human erythropoiesis up to normoblasts and platelet formation is fully supported in NSGW41 mice, allowing the analysis of human HSC differentiation into these lineages, the exploration of certain pathophysiologies, and the evaluation of gene therapeutic approaches.

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Section: Introductionmentioning

confidence: 99%

Improved Human Erythropoiesis and Platelet Formation in Humanized NSGW41 Mice

et al. 2016

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“…Within the bone marrow of the animals with detectable reconstitution, HES6 knockdown increased the frequency of NK cells and had no consistent impact on myeloid cells, but both NK and myeloid cell numbers were not significantly altered compared to the control (Figure 5C-D). Although this mouse model is not optimal in supporting human erythroid and megakaryocytic development 34 , we did observe, within the mice that showed reconstitution, a reduction in both megakaryocytes and erythroblasts upon HES6 knockdown (Figure 5C-D). In addition, the frequency and total number of B cells were decreased in case of HES6 knockdown (Figure 5C-D).…”

Section: Hes6 Is Needed For In Vivo Precursor Engraftment and Differe...mentioning

confidence: 83%

<i>HES6</i> knockdown in human hematopoietic precursor cells reduces their <i>in vivo</i> engraftment potential and their capacity to differentiate into erythroid cells, B cells, T cells and plasmacytoid dendritic cells

De Vos,

Oatman,

Boehme

et al. 2024

haematol

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Hematopoiesis is driven by molecular mechanisms that induce differentiation and proliferation of hematopoietic stem cells and their progeny. This involves the activity of various transcription factors, such as members of the Hairy/Enhancer of Split (HES) family, and important roles for both HES1 and HES4 have been shown in normal and malignant hematopoiesis. Here, we investigated the role of HES6 in human hematopoiesis using in vitro and in vivo models. Using bulk and scRNA-seq data, we show that HES6 is expressed during erythroid/megakaryocyte and pDC development, as well as in multipotent precursors and at specific stages of T- and B-cell development following preBCR and preTCR signalling, respectively. Consistently, knockdown of HES6 in cord blood-derived hematopoietic precursors in well-defined in vitro differentiation assays resulted in reduced differentiation of human hematopoietic precursors towards megakaryocytes, erythrocytes, pDCs, Band T-cells. In addition, HES6 knockdown HSPCs displayed reduced colony forming unit capacity in vitro and impaired potential to reconstitute hematopoiesis in vivo in a competitive transplantation assay. We demonstrate that loss of HES6 expression impacts cell cycle progression during erythroid differentiation and provide evidence for potential downstream target genes that impact these perturbations. Thus, our study uncovers new insights for a role of HES6 in human hematopoiesis.

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Multilineage readout after HSC expansion – erythrocytes matter

Cited by 2 publications

References 7 publications

Improved Human Erythropoiesis and Platelet Formation in Humanized NSGW41 Mice

Improved Human Erythropoiesis and Platelet Formation in Humanized NSGW41 Mice

<i>HES6</i> knockdown in human hematopoietic precursor cells reduces their <i>in vivo</i> engraftment potential and their capacity to differentiate into erythroid cells, B cells, T cells and plasmacytoid dendritic cells

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