Experimental Hematology

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Experimental Hematology Human iPSC-based model of severe congenital neutropenia reveals elevated UPR and DNA damage in CD34+ cells preceding leukemic transformation  Benjamin Dannenmann, Azadeh Zahabi, Perihan Mir, Benedikt Oswald, Regine Bernhard, Maksim Klimiankou, Tatsuya Morishima, Klaus Schulze-Osthoff, Cornelia Zeidler, Lothar Kanz, Nico Lachmann, Thomas Moritz, Karl Welte, Julia Skokowa  Experimental Hematology  Volume 71, Pages 51-60 (March 2019) DOI: 10.1016/j.exphem.2018.12.006 Copyright © 2019 ISEH -- Society for Hematology and Stem Cells Terms and Conditions

Figure 1 In vitro model of CN and CN/AML using EB-based myeloid differentiation method of patients iPSCs. (A) Scheme of the protocol for EB-based hematopoietic and neutrophilic differentiation of iPSCs. (B) Production of hematopoietic cells from iPSCs over time in the EB-based differentiation system. Hematopoietic cells were harvested from EB culture supernatants starting from day 14 to day 28 and counted using trypan blue dye exclusion. Data represent means ± SD from two independent experiments. Two-sided, unpaired Student t test p values to HD are shown. *p < 0.05. (C) Flow cytometry analysis of suspension cells harvested from EBs culture on day 28 of differentiation. Data represent means ± SD from two independent experiments. *p < 0.05. (D) Morphological analysis of suspension cells harvested from iPSCs at day 28 of differentiation (Wright-Giemsa Stain). Representative cytospin slide pictures are shown. HD, healthy donor. Experimental Hematology 2019 71, 51-60DOI: (10.1016/j.exphem.2018.12.006) Copyright © 2019 ISEH -- Society for Hematology and Stem Cells Terms and Conditions

Figure 2 Analysis of ER stress and unfolded protein response (UPR) in CD34+ and CD45+ cells derived from CN- and CN/AML-iPSCs. (A) qRT-PCR analysis of ELANE mRNA expression in CD45+CD34+ cells at day 14 of iPSC differentiation. Data represent means ± SD from two independent experiments. *p < 0.05, **p < 0.001. (B) qRT-PCR analysis of mRNA expression of UPR-related genes in CD45+CD34+ cells at day 14 of iPSC differentiation, as indicated. Data represent means ± SD from two independent experiments. *p < 0.05, **p <0.01, ***p < 0.001. (C) Representative Western blot images of NE and CHOP protein expression in CD45+ cells at day 28 of iPSC differentiation, as indicated. Numbers below Western blot images indicate protein expression levels normalized to β-Actin. Experimental Hematology 2019 71, 51-60DOI: (10.1016/j.exphem.2018.12.006) Copyright © 2019 ISEH -- Society for Hematology and Stem Cells Terms and Conditions

Figure 3 Quantification of DNA damage and p21 expression in CD34+ and CD45+ cells derived from patient-specific iPSCs. (A) Scheme for DNA damage measurements in HD- and CN-iPSCs derived CD34+CD45+ cells. (B,C) Measurement of DNA damage loci for mitochondrial DNA (mtDNA) and DNA of TP53 or GAPDH gene loci of CN-iPSC-derived CD45+CD34+ cells upon 5-min treatment with 0.1 and 1 µmol/L bleomycin. DNA lesions were assessed directly 5 min (DNA damage (B)) and 2 hours (DNA repair (C)) after bleomycin treatment. Data are shown as means ± SD from two independent experiments. *p < 0.05, **p < 0.01, ***p < 0.001. (D) qRT-PCR analysis of selected genes in CD45+CD34+ cells generated from different iPSCs clones on day 14 of iPSC differentiation. mRNA expression of target genes was normalized to β-actin and shown relative to HD. Data represent means ± SD from two independent experiments. *p < 0.05, **p < 0.01, ***p < 0.001. (E) Representative Western blot images of p21 protein and ß-actin expression in CD45+ cells at day 28 of iPSC differentiation. Numbers below the Western blot images indicate protein expression levels normalized to β-actin. Experimental Hematology 2019 71, 51-60DOI: (10.1016/j.exphem.2018.12.006) Copyright © 2019 ISEH -- Society for Hematology and Stem Cells Terms and Conditions