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

Carine Domenech (1) , Loïc Maillard (1) , Alix Rousseau (2, 3) , Fabien Guidez (4, 2) , Laurence Petit (5, 6) , Marika Pla (4, 2) , Denis Clay (7) , Fabien Guimiot (8) , Sandra Sanfilippo (1) , Sebastien Jacques , Pierre de La Grange , Noemie Robil , Jean Soulier (2, 3) , Michele Souyri (1)

1 IBPS - Institut de Biologie Paris Seine
2 IUH - Institut Universitaire d'Hématologie
3 Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire
4 UMR 1131 - Hémopathies Myéloïdes : Cellules Souches, Modèles Pré-Cliniques et Recherche Translationnelle
5 LBD-E06 - Migration et différenciation des cellules souches hématopoiétiques = Migration and differentiation of hematopoietic stem cells
6 IBPS-IP - Imagerie Cellulaire et Cytométrie de Flux [IBPS]
7 Les cellules souches : de leurs niches à leurs applications thérapeutiques
8 Hôpital Robert Debré

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.

Domaines: Embryologie et organogenèse; Hématologie

Carine Domenech, Loïc Maillard, Alix Rousseau, Fabien Guidez, Laurence Petit, et al.. Studies in an Early Development Window Unveils a Severe HSC Defect in both Murine and Human Fanconi Anemia. Stem Cell Reports, 2018, 11 (5), pp.1075-1091. ⟨10.1016/j.stemcr.2018.10.001⟩. ⟨hal-01945976⟩