Dissertation/Thesis Abstract

Dormant and Activated Hematopoietic Stem Cells during Homeostasis: Divisional History vs. Phenotype and Quiescence
by Qiu, Jiajing, Ph.D., Mount Sinai School of Medicine, 2013, 107; 3597245
Abstract (Summary)

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.

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Indexing (document details)
Advisor: Moore, Kateri
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
Subjects: Cellular biology
Keywords: Divisional history, Dormant, Hematopoietic stem cells, Phenotype, Quiescence
Publication Number: 3597245
ISBN: 978-1-303-45033-4
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