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Pluripotent cell models of Fanconi anemia identify the early pathological defect in human hemoangiogenic progenitors

ABSTRACT: Fanconi anemia (FA) is a disorder of genomic instability characterized by progressive bone marrow failure (BMF), developmental abnormalities and an increased susceptibility to cancer. Although various consequences in hematopoietic stem/progenitor cells have been attributed to FA-BMF, the quest to identify the initial pathological event is still ongoing. To address this issue, we established induced pluripotent stem cells (iPSCs) from fibroblasts of six FA patients with FANCA mutations. An improved reprogramming method yielded iPSC-like colonies from all patients, and iPSC clones were propagated from two patients. Quantitative evaluation of the differentiation ability demonstrated that the differentiation propensity toward the hematopoietic and endothelial lineages is already defective in early hemoangiogenic progenitors. The expression levels of critical transcription factors were significantly downregulated in these progenitors. These data indicate that the hematopoietic consequences in FA patients originate from the early hematopoietic stage, and highlight the potential usefulness of iPSC technology for elucidating the pathogenesis of FA-BMF. The investigation of the RNA-seq analysis of iPSC-derived HAPCs.

ORGANISM(S): Homo sapiens

SUBMITTER: Megumu Saito

PROVIDER: E-GEOD-65507 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Pluripotent cell models of Fanconi anemia identify the early pathological defect in human hemoangiogenic progenitors

Project description:Fanconi anemia (FA) is a disorder of genomic instability characterized by progressive bone marrow failure (BMF), developmental abnormalities and an increased susceptibility to cancer. Although various consequences in hematopoietic stem/progenitor cells have been attributed to FA-BMF, the quest to identify the initial pathological event is still ongoing. To address this issue, we established induced pluripotent stem cells (iPSCs) from fibroblasts of six FA patients with FANCA mutations. An improved reprogramming method yielded iPSC-like colonies from all patients, and iPSC clones were propagated from two patients. Quantitative evaluation of the differentiation ability demonstrated that the differentiation propensity toward the hematopoietic and endothelial lineages is already defective in early hemoangiogenic progenitors. The expression levels of critical transcription factors were significantly downregulated in these progenitors. These data indicate that the hematopoietic consequences in FA patients originate from the early hematopoietic stage, and highlight the potential usefulness of iPSC technology for elucidating the pathogenesis of FA-BMF.

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