Gaining access to the hematopoietic stem cell niche : novel non-myeloablative conditioning approaches
Abstract/Contents
- Abstract
- Sickle Cell Anemia, Beta Thalassemia, Severe Combined Immunodeficiency (SCID), and Type I Diabetes share one commonality: these diverse disorders can all be attributed to faulty hematolymphoid effector cells which are largely caused by genetic mutations that alter hematopoietic cell-intrinsic function. These defective blood cells inherit their genetic deficiencies from hematopoietic stem cells (HSC) as they differentiate. Thus, each of these unique diseases should be theoretically curable through the same strategy: replacement of patients' HSCs carrying the problematic mutation with normal HSCs from disease-free donors, thereby generating entire new, healthy hematolymphoid systems. Replacement of disease-causing stem cells with healthy ones has been achieved clinically via hematopoietic cell transplantation (HCT) for the last 50 years, as a treatment modality for a variety of cancers and immunodeficiencies with moderate, but increasing success. However this technique bears high morbidity and mortality severely limiting its utilization. Purified hematopoietic stem cell transplantation is associated with high toxicity primarily attributed to the myeloablative pre-conditioning necessary to facilitate engraftment of the donor HSCs. However the function and mechanistic role of these reagents has been up until now poorly understood. This thesis deconstructs the current barriers in HCT and pure HSC transplantation, and suggests that in addition to the immune barrier, hematopoietic stem cell niche availability is another critical obstacle that needs to be overcome to allow for efficient hematolymphoid replacement. In this thesis I show that in the homeostatic state, most hematopoietic stem cell niches are occupied by host HSCs limiting the ability of incoming HSC engraftment. However, a limited number of HSC niches are vacated by HSC that are egressing from the peripheral blood into the bone marrow in a division independent manner, allowing for true but minimal HSC engraftment without myeloablative pre-conditioning. This thesis illustrates new, up-and-coming strategies to combat the obstacle of HSC niche availability. Here I prove that one non-myeloablative conditioning approach that capitalizes upon physiological HSC egress is repetitive transplantation of purified HSCs. However, this approach is rather laborious and inefficient, and I show that another more efficient novel non-myeloablative conditioning approach to vacate the HSC niche is antibody-mediated depletion of host HSCs. Furthermore, in this thesis I demonstrate that antibody-mediated inhibition of c-kit effectively depletes host HSCs and allows for efficient, non-toxic HSC transplantation. These novel non-myeloablative conditioning methods illustrate new means of overcoming the current barriers to hematolymphoid replacement thereby allowing for the potential expansion of this technique to treat a variety of inherited diseases of hematopoietic and immune function.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2010 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Czechowicz, Agnieszka |
|---|---|
| Associated with | Stanford University, Department of Developmental Biology. |
| Primary advisor | Weissman, Irving L |
| Thesis advisor | Weissman, Irving L |
| Thesis advisor | Crabtree, Gerald R |
| Thesis advisor | Shizuru, Judith Anne |
| Advisor | Crabtree, Gerald R |
| Advisor | Shizuru, Judith Anne |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Agnieszka Dorota Czechowicz. |
|---|---|
| Note | Submitted to the Department of Developmental Biology. |
| Thesis | Ph. D. Stanford University 2010 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2010 by Agnieszka Czechowicz
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