Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Developmental, Regenerative and Stem Cell Biology

Language

English (en)

Date of Award

January 2009

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Kyunghee Choi

Abstract

Hematopoietic cells are essential for growth and survival throughout adult life. Two different aspects of hematopoiesis are addressed in this dissertation. I. The regulation of primitive hematopoiesis by Runx1 and TGF-beta signaling. Primitive hematopoiesis, occurring exclusively in the yolk sac, is characterized by its transient nature. As the primitive hematopoiesis declines in the yolk sac, definitive hematopoietic progenitors generated in the yolk sac and/or embryo take over in blood cell production. Whether the transition from primitive to definitive hematopoietic program reflects a mere shift in hematopoietic sites or whether it is an actively regulated process is currently unknown. Runx1 is necessary for the establishment of definitive hematopoiesis. Most studies on Runx1 have focused on its role in generating hematopoietic stem cells. Intriguingly, Runx1 expression can be detected in the yolk sac blood-islands where primitive erythroid: EryP) progenitors emerge. The function of Runx1 in primitive hematopoiesis has not been carefully investigated. Herein, we determined if Runx1 plays a role in primitive hematopoiesis by utilizing in vitro embryonic stem: ES) cell differentiation system and by examining EryP development in Runx1 mutant mice. We demonstrated that Runx1 deficient mice contained a significantly reduced number of EryP progenitors compared to controls. Nonetheless, Runx1 deficient mice survived until they required definitive hematopoietic cells. We demonstrated that a high level of enforced Runx1 expression in the in vitro differentiation model of embryonic stem: ES) cells suppressed EryP progenitor generation. We also identified TGF-beta1 as a cooperative signal of Runx1 in negatively regulating EryP development. Our studies revealed an unexpected role of Runx1 in both initiation and termination of primitive hematopoiesis. II. The relationship between hematopoietic stem cells and bone marrow microenvironment. There is an intricate relationship between hematopoiesis and bone homeostasis in normal physiological states during adulthood. By utilizing mice undergoing chronic inflammatory arthritis, we investigated the relationship between hematopoiesis and bone homeostasis in pathological conditions. We demonstrated that mice with chronic inflammatory arthritis are osteoporotic due to a severe defect in osteoblast function. Despite the defective osteoblast function, the hematopoietic stem cells from these mice exhibited normal properties in HSC frequency, cell cycling and long-term repopulating ability. Therefore, the bone forming capacity of osteoblasts is disassociated from their ability to maintain HSCs in a chronic inflammatory condition. These observations suggest other cell types, such as endothelial cells in the bone marrow, might serve as HSC niches under pathological conditions.

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Permanent URL: http://dx.doi.org/10.7936/K7513W6Q

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