Pluripotent Cell Models of Fanconi Anemia Identify the Early Pathological Defect in Human Hemoangiogenic Progenitors

Stem Cells Transl Med. 2015 Apr;4(4):333-8. doi: 10.5966/sctm.2013-0172. Epub 2015 Mar 11.

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 patients with FA and 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.

Keywords: Differentiation; Fanconi anemia; Hematopoietic progenitors; Induced pluripotent stem cells; Transcription factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Marrow / pathology
  • Cell Differentiation / genetics
  • Cell Lineage / genetics
  • Cellular Reprogramming / genetics
  • Fanconi Anemia / genetics*
  • Fanconi Anemia / pathology
  • Fanconi Anemia Complementation Group A Protein / genetics*
  • Fanconi Anemia Complementation Group A Protein / metabolism
  • Fibroblasts / metabolism
  • Genetic Therapy
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Induced Pluripotent Stem Cells / pathology

Substances

  • Fanconi Anemia Complementation Group A Protein