Content:
Lifelong hematopoiesis is supported by hematopoietic stem cells (HSCs) differentiating within the bone marrow (BM) down all blood cell lineages including erythrocytes, platelets, myeloid and lymphoid cells. Although most blood cells are generated entirely within the BM, T cells complete their development in the thymus, a primary lymphoid organ within the mediastinal cavity. Together, B and T cells represent the lymphoid arm of the immune system and are vital in the adaptive protection against foreign pathogens. While hematopoiesis is continuous for the lifespan of the organism, it is currently well established that, paradoxical to its fundamental importance for establishing and maintaining good health, the adaptive immune system degenerates very early with age; a phenomenon temporally linked to sex steroid exposure. Beginning from birth, but accelerated at the onset of puberty, both the primary lymphoid organs – the BM and thymus, gradually deteriorate, resulting in a decline in the generation of new naïve B and T cells. In healthy adults this does not pose a major threat, however in patients who are immunocompromised following cytoreductive treatments, such as chemo- or radiation- therapy or chronic infections best exemplified by acquired immunodeficiency syndrome (AIDS), immune recovery is considerably delayed leaving these individuals susceptible to opportunistic infections and malignant relapses. As a corollary to the hypothesized underlying cause of immune atrophy, our laboratory and others have previously demonstrated that removing the negative effects of sex steroids by either surgical or chemical (reversible) castration (sex steroid ablation; SSA) facilitates significant immune regeneration in aged mice and can enhance lymphoid recovery post HSC transplantation (HSCT) or treatment with chemotherapy. 3 This thesis aimed to elucidate the mechanisms underlying SSA-mediated lymphoid recovery by comprehensively assessing the impact of SSA on (1) the function of hematopoietic stem and progenitor cells in the BM, (2) the ability of the supporting BM stromal microenvironment to support hematopoiesis, and (3) the function of the earliest T-lineage progenitors in the thymus. Consistent with previous reports, we observed an age-associated accumulation of HSCs that demonstrated inferior self-renewal capacity and lymphoid differentiation potential when compared to young HSCs. We further demonstrated both a numerical and functional enhancement of the primitive long-term HSC (LT-HSC) population following SSA. Not only did these LT-HSCs show enhanced self-renewal, they were also more efficient at differentiating into downstream lymphoid cells with SSA. Detailed molecular analysis revealed important cell intrinsic changes pertaining to quiescence, self-renewal, lymphoid differentiation and DNA replication processes occurring within these primitive HSCs, collectively suggesting their role in establishing SSA-mediated immune regeneration. Since HSCs rely heavily on their stromal cell-based microenvironmental niches" for signals governing their differentiation and survival, the effects of SSA on the the endosteal and vascular (central marrow) compartments were profiled. Interestingly, a population of osteoblasts (OBLs) with high Runx2 expression was revealed within the vascular niche of the BM that numerically increased with age
Note:
Dissertation Monash University. Faculty of Medicine, Nursing and Health Sciences. Monash Immunology and Stem Cell Laboratories 2012
Language:
English
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