Hematopoiesis is a dynamic process where billions of blood cells are replenished on a daily basis. These cells emanate from a population of hematopoietic stem cells (HSCs) that anchor a hierarchy of progenitor cells with varying self-renewal and differentiation capacities. Cell fate decisions are manifested after cell division, yet it is largely unknown how these processes are controlled and correlated. Transplantation assays are the standard methodology to assess the self-renewal and differentiation properties of HSC and progenitor cell (HSPC) populations. This involves a complex set of behaviors in an immuno-compromised host animal that does not exist during normal homeostatic hematopoiesis. As such these assays would not reflect normal cell fate decisions taken upon cell division. In order to investigate the normal homeostatic behaviors of HSPC populations our laboratory has developed a model system that allows the study of viable labeling retaining cells (LRCs) specifically in HSPC populations. This system has revealed that there are both dormant (rarely dividing) and active (routinely dividing) HSC within the bone marrow. My study seeks to determine how divisional history impacts on HSC cell fate decisions. The amount of label retained is a reflection of cell division over time and allows the isolation of HSPCs with varying degrees of label retention for phenotypic characterization, functional activity and molecular profiling. Together the studies presented here provide novel and significant insights into the biology of HSC during homeostasis, these are: 1. Dormant HSCs are heterogeneous in both phenotype and function. 2. Homeostatic HSCs lose repopulating potential in relationship to their divisional history. 3. Divisional history overrides both phenotype and immediate quiescence in determining functional activity. 4. Activated HSCs do not return to steady state quiescence. 5. Expression signatures parallel divisional history and loss of repopulating potential. Taken together these studies suggest that normal homeostatic HSCs do not self-renew. Once they become activated and initiate a divisional cascade they are slated for extinction by differentiation. As such, this may provide an important control mechanism to maintain the genomic integrity of the HSC pool throughout life.
Some files may require a special program or browser plug-in. More Information
|Commitee:||Baron, Margaret, Ghaffari, Saghi, Lemischka, Ihor, Shahin, Rafii, Yu, Qin|
|School:||Mount Sinai School of Medicine|
|Department:||Developmental and Stem Cell Biology (DSCB)|
|School Location:||United States -- New York|
|Source:||DAI-B 75/01(E), Dissertation Abstracts International|
|Keywords:||Divisional history, Dormant, Hematopoietic stem cells, Phenotype, Quiescence|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be