Document Type


Degree Name



Dept. of Cell and Developmental Biology


Oregon Health & Science University


The role of prenatal development in programming adult cardiovascular and endocrine disease is increasingly well-characterized, and neurological programming has been a popular topic of research as well. However, despite rising pediatric hematological and immune disease rates, the potential contribution of developmental origins of disease in the blood system has been largely unexplored. The most common cause of inherited bone marrow failure, usually diagnosed in childhood, is Fanconi anemia (FA), a recessive, multisystem syndrome. While the conventional assumption was that hematopoietic stem cells were lost from the bone marrow postnatally, precipitating bone marrow failure, evidence from in vitro studies suggests an earlier loss of stem cells. Using the Fancc-deficient mouse model of FA, we demonstrate a developmental deficit in the hematopoietic stem and progenitor cells (HSPC) of the liver, the main hematopoietic organ in the fetus, and a significant reduction in their serial repopulating capacity. While we did not detect increased apoptosis or elevation of inflammatory cytokines in the fetal liver, which are two culprits of the postnatal FA pathology, an increased proportion of Fancc-/- fetal HSPCs were in G1 phase of cell cycle, suggesting cell cycle arrest. We further corroborated the FA fetal liver defect in two other mouse models. As the FA pathway functions in coordination of DNA repair, we assayed HSPC-enriched populations for DNA damage response and found increased γH2AX nuclear x foci and upregulation of several genes involved in nonhomologous end-joining and homologous recombination. Taken together, this suggests that FA fetal liver HSPCs are susceptible to DNA damage in the absence of chemical or radiological induction and that the hematopoietic compartment is a target for congenital defects. As an alternative approach to the study of developmental vulnerability, we then chose a non-genetic model to further test self-renewal of the HSPC pool. As in FA, DNA damage plays a role in the pathology arising from a high-fat diet (HFD), which drives oxidative stress. The spread of the Western diet, which is composed of an excess of fat, has been accompanied by an epidemic of obesity. Interestingly, epidemiologists have documented a concurrent rise in pediatric diseases involving the immune system, which is derived from HSPCs, and this, along with studies from animal models and patients, suggests a role for excess lipid intake and maternal obesity in the nutritional programming of the hematopoietic system. We investigated the previously unexplored roles of these factors in the developing blood system, using an established mouse model of overnutrition. Maternal obesity and HFD induced losses in fetal liver HSPCs and short-term repopulation defects. Gene expression studies revealed perturbations in several genes involved in DNA repair. Finally, nutritional and genetic mechanisms of developmental origins of disease were assayed together in a study of FA mice programmed under a HFD. Fancc-/- fetal mice receiving a HFD appeared to be inhibited from the late gestational growth spurt observed in their wildtype littermates, and both fetal and juvenile mice had modest quantitative defects in the hematopoietic progenitor compartment. Altogether, these studies reveal that HSPCs are programmable via both genetic and metabolic modification, highlighting an intrauterine vulnerability in hematopoietic cells and revealing a unique opportunity for preventative therapy.




School of Medicine



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