title: Impairment of fetal hematopoietic stem cell function in the absence of Fancd2.
abstract: Fanconi anemia (FA) results from mutations in the genes necessary for DNA damage repair and often leads to progressive bone marrow failure. Although the exhaustion of the bone marrow leads to cytopenias in FA patients as they age, evidence from human FA and mouse model fetal livers suggests that hematopoietic defects originate in utero, which may lead to deficient seeding of the bone marrow. To address this possibility, we examined the consequences of loss of Fancd2, a central component of the FA pathway. Examination of embryonic day 14.5 (E14.5) Fancd2 knockout (KO) fetal livers showed a decrease in total cellularity and specific declines in long-term and short-term hematopoietic stem cell (LT-HSC and ST-HSC, respectively) numbers. Fancd2 KO fetal liver cells display similar functional defects to Fancd2 adult bone marrow cells, including reduced colony-forming units, increased mitomycin C sensitivity, increased LT-HSC apoptosis, and heavily impaired competitive repopulation, implying that these defects are intrinsic to the fetal liver and are not dependent on the accumulation of DNA damage during aging. Telomere shortening, an aging-related mechanism proposed to contribute to HSC apoptosis and bone marrow failure in FA, was not observed in Fancd2 KO fetal livers. In summary, loss of Fancd2 yields significant defects to fetal liver hematopoiesis, particularly the HSC population, which mimics key phenotypes from adult Fancd2 KO bone marrow independently of aging-accrued DNA damage.
authors.affiliation: Division of Hematology-Oncology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Division of Hematology-Oncology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Ronny R
authors.initials: RR
authors.lastname: Racine
authors.affiliation: Division of Hematology-Oncology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Manalo
authors.affiliation: Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Cantor
authors.affiliation: Division of Hematology-Oncology, University of Massachusetts Medical School, Worcester, MA, USA. Electronic address: glen.raffel@umassmed.edu.
authors.forename: Glen D
authors.initials: GD
authors.lastname: Raffel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000172:deficiency* / Q000235:genetics; D016332:Fetal Tissue Transplantation; D005333:Fetus; D005838:Genotype; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000196:embryology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016685:Mitomycin / Q000494:pharmacology; D013234:Stem Cells
chemical_list: D052236:Fanconi Anemia Complementation Group D2 Protein; D016685:Mitomycin