Studies in an Early Development Window Unveils a Severe HSC Defect in Both Murine and Human Fanconi Anemia

Stem Cell Reports. 2018 Nov 13;11(5):1075-1091. doi: 10.1016/j.stemcr.2018.10.001. Epub 2018 Oct 25.

Abstract

Fanconi anemia (FA) causes bone marrow failure early during childhood, and recent studies indicate that a hematopoietic defect could begin in utero. We performed a unique kinetics study of hematopoiesis in Fancg-/- mouse embryos, between the early embryonic day 11.5 (E11.5) to E12.5 developmental window (when the highest level of hematopoietic stem cells [HSC] amplification takes place) and E14.5. This study reveals a deep HSC defect with exhaustion of proliferative and self-renewal capacities very early during development, together with severe FA clinical and biological manifestations, which are mitigated at E14.5 due to compensatory mechanisms that help to ensure survival of Fancg-/- embryos. It also reports that a deep HSC defect is also observed during human FA development, and that human FA fetal liver (FL) HSCs present a transcriptome profile similar to that of mouse E12.5 Fancg-/- FL HSCs. Altogether, our results highlight that early mouse FL could represent a good alternative model for studying Fanconi pathology.

Keywords: Fanconi anemia; HSC; fetal liver; human embryonic development; mouse embryonic development; placenta; transcriptome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Cycle
  • DNA Damage
  • Embryo, Mammalian / pathology
  • Embryonic Development*
  • Erythrocytes / metabolism
  • Fanconi Anemia / pathology*
  • Fanconi Anemia Complementation Group G Protein / deficiency
  • Fanconi Anemia Complementation Group G Protein / metabolism
  • Female
  • Gene Ontology
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology*
  • Humans
  • Liver / embryology
  • Liver / metabolism
  • Mice, Inbred C57BL
  • Phenotype
  • Placenta / metabolism
  • Pregnancy
  • Transcriptome / genetics

Substances

  • Fanconi Anemia Complementation Group G Protein