Hematopoietic stem cells: Identity, regulation, and leukemogenesis.

Hematopoietic stem cells (HSCs) are self-renewing, multipotent progenitors that give rise to all lineages of blood and immune system cells. To improve our ability to identify HSCs and their localization in vivo we compared the gene expression profiles of highly purified HSCs and non-self-renewing multipotent hematopoietic progenitors (MPPs). Cell surface receptors of the SLAM family, including CD150, CD244, and CD48, were differentially expressed among functionally distinct progenitors. HSCs were highly purified as CD 150+CD244 -CD48- cells while MPPs were CD244+CD150 -CD48- and most restricted progenitors were CD48 +CD244+CD150-. The primitiveness of hematopoietic progenitors could thus be predicted based on the combination of SLAM family members they expressed. This is the first family of receptors whose combinatorial expression precisely distinguishes stem and progenitor cells. We also found that SLAM family receptor expression is conserved among HSCs from diverse contexts where commonly used HSC markers yielded poor purity. SLAM receptors dramatically enhanced the purity of HSCs isolated from old, reconstituted, and cytokine mobilized mice. Our ability to purify HSCs based on a simple combination of SLAM receptors also allowed us to identify HSCs in tissue sections. Many HSCs were associated with sinusoidal endothelium in spleen and bone marrow, though some HSCs were associated with endosteum. HSCs thus occupy multiple niches, including sinusoidal endothelium in diverse tissues. Recent advances have highlighted extensive phenotypic and functional similarities between normal stem cells and cancer stem cells. This raises the question of whether therapies can be developed that eliminate cancer stem cells without eliminating normal stem cells. We addressed this by conditionally deleting the Pten tumor suppressor in adult hematopoietic cells. This led to myeloproliferative disease within days and transplantable leukemias within weeks. Pten deletion also promoted hematopoietic stem cell proliferation. However, this cell-autonomously led to HSC depletion, preventing these cells from stably reconstituting irradiated mice. In contrast to leukemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were largely mediated by mTor as they were inhibited by rapamycin. Rapamycin not only depleted leukemia-initiating cells but also restored normal HSC function. Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.Ph.D.Biological SciencesCellular biologyHealth and Environmental SciencesMolecular biologyOncologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/127040/2/3305114.pd