title: Gaucher Disease-Induced Pluripotent Stem Cells Display Decreased Erythroid Potential and Aberrant Myelopoiesis.
abstract: Gaucher disease (GD) is the most common lysosomal storage disease resulting from mutations in the lysosomal enzyme glucocerebrosidase (GCase). The hematopoietic abnormalities in GD include the presence of characteristic Gaucher macrophages that infiltrate patient tissues and cytopenias. At present, it is not clear whether these cytopenias are secondary to the pathological activity of Gaucher cells or a direct effect of GCase deficiency on hematopoietic development. To address this question, we differentiated induced pluripotent stem cells (iPSCs) derived from patients with types 1, 2, and 3 GD to CD34(+)/CD45(+)/CD43(+)/CD143(+) hematopoietic progenitor cells (HPCs) and examined their developmental potential. The formation of GD-HPCs was unaffected. However, these progenitors demonstrated a skewed lineage commitment, with increased myeloid differentiation and decreased erythroid differentiation and maturation. Interestingly, myeloid colony-formation assays revealed that GD-HPCs, but not control-HPCs, gave rise to adherent, macrophage-like cells, another indication of abnormal myelopoiesis. The extent of these hematologic abnormalities correlated with the severity of the GCase mutations. All the phenotypic abnormalities of GD-HPCs observed were reversed by incubation with recombinant GCase, indicating that these developmental defects were caused by the mutated GCase. Our results show that GCase deficiency directly impairs hematopoietic development. Additionally, our results suggest that aberrant myelopoiesis might contribute to the pathological properties of Gaucher macrophages, which are central to GD manifestations. The hematopoietic developmental defects we observed reflect hematologic abnormalities in patients with GD, demonstrating the utility of GD-iPSCs for modeling this disease.
authors.affiliation: Department of Microbiology and Immunology and Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA; Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Judi A
authors.initials: JA
authors.lastname: Sgambato
authors.affiliation: Department of Microbiology and Immunology and Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA; Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Tea Soon
authors.initials: TS
authors.lastname: Park
authors.affiliation: Department of Microbiology and Immunology and Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA; Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Miller
authors.affiliation: Department of Microbiology and Immunology and Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA; Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Leelamma M
authors.initials: LM
authors.lastname: Panicker
authors.affiliation: Department of Microbiology and Immunology and Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA; Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Sidransky
authors.affiliation: Department of Microbiology and Immunology and Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA; Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lun
authors.affiliation: Department of Microbiology and Immunology and Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA; Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Ola
authors.initials: O
authors.lastname: Awad
authors.affiliation: Department of Microbiology and Immunology and Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA; Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Søren M
authors.initials: SM
authors.lastname: Bentzen
authors.affiliation: Department of Microbiology and Immunology and Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA; Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Elias T
authors.initials: ET
authors.lastname: Zambidis
authors.affiliation: Department of Microbiology and Immunology and Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA; Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA rfeldman@som.umaryland.edu.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Feldman
mesh_terms: D002454:Cell Differentiation; D019070:Cell Lineage; D005776:Gaucher Disease / Q000473:pathology / Q000628:therapy*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000637:transplantation*; D008264:Macrophages / Q000473:pathology; D038042:Myelopoiesis / Q000502:physiology*
keywords: Erythropoiesis; Hematopoiesis; Hematopoietic stem cells; Induced pluripotent stem cells; Monocyte; Myeloid cells; Stem/progenitor cell