Research Article: Molecular Signatures of Quiescent, Mobilized and Leukemia-Initiating Hematopoietic Stem Cells

Date Published: January 20, 2010

Publisher: Public Library of Science

Author(s): E. Camilla Forsberg, Emmanuelle Passegué, Susan S. Prohaska, Amy J. Wagers, Martina Koeva, Joshua M. Stuart, Irving L. Weissman, Catherine M. Verfaillie. http://doi.org/10.1371/journal.pone.0008785

Abstract: Hematopoietic stem cells (HSC) are rare, multipotent cells capable of generating all specialized cells of the blood system. Appropriate regulation of HSC quiescence is thought to be crucial to maintain their lifelong function; however, the molecular pathways controlling stem cell quiescence remain poorly characterized. Likewise, the molecular events driving leukemogenesis remain elusive. In this study, we compare the gene expression profiles of steady-state bone marrow HSC to non-self-renewing multipotent progenitors; to HSC treated with mobilizing drugs that expand the HSC pool and induce egress from the marrow; and to leukemic HSC in a mouse model of chronic myelogenous leukemia. By intersecting the resulting lists of differentially regulated genes we identify a subset of molecules that are downregulated in all three circumstances, and thus may be particularly important for the maintenance and function of normal, quiescent HSC. These results identify potential key regulators of HSC and give insights into the clinically important processes of HSC mobilization for transplantation and leukemic development from cancer stem cells.

Partial Text: Hematopoietic stem cells (HSC) are rare, multipotent, self-renewing precursor cells capable of generating each and every specialized cell of the blood system. Precise regulation of HSC proliferation and cell fate decisions is necessary to maintain ongoing production of mature blood cells throughout adult life and for rapid, regenerative responses to hematologic injury. Several lines of evidence indicate the importance of active maintenance of HSC stem cell function. The regulation of HSC quiescence in the bone marrow (BM) niche is of particular importance [1], [2]. Several recently identified genes that perturb HSC quiescence also disrupt stem cell maintenance and homeostatic blood cell production. Many of these encode transcription factors or cell cycle regulators that directly modulate the proliferative activity of HSC. Others encode soluble mediators, produced by niche cells that act extrinsically to activate HSC proliferation. Together, these data suggest that precise control of cell division is crucial for appropriate stem cell behavior and that the proliferative activity of HSC is normally restricted by both HSC intrinsic factors and extrinsic factors produced in the HSC niche. Elucidating the molecular pathways that maintain HSC quiescence will thus enable directed manipulation of HSC function endogenously and in the context of hematopoietic cell transplantation.

Gene expression data from highly purified HSC at steady-state compared to non-self-renewing, multipotent progeny, to mobilized HSC, and to leukemic HSC provide an intriguing set of novel target molecules that are commonly induced or repressed as HSC differentiate, expand and mobilize, and undergo leukemic transformation. Each of the pair-wise datasets provide important insights into these specific individual processes at the genome-wide level, and identify new targets to enable specific manipulation of HSC in desired directions. Comparative analysis between datasets identified numerous genes specific for each of the processes, as well as mechanisms or families of downregulated genes common to HSC transition into either of the three fates. In addition to identifying specific molecular regulators and potential targets for manipulation, these datasets also provide insights into how gene expression changes are coordinated at a genome-wide level.

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http://doi.org/10.1371/journal.pone.0008785

 

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