Knowledge of the molecular networks controlling the proliferation and fate of hematopoietic stem cells (HSC) is essential to understand their function in maintaining blood cell production during normal hematopoiesis and upon clinical transplantation. Using highly purified stem and progenitor cell populations, we define the proliferation index and status of the cell cycle machinery at discrete stages of hematopoietic differentiation and during cytokine-mediated HSC mobilization. We identify distinct sets of cell cycle proteins that specifically associate with differentiation, self-renewal, and maintenance of quiescence in HSC and progenitor cells. Moreover, we describe a striking inequality of function among in vivo cycling and quiescent HSC by demonstrating that their long-term engraftment potential resides predominantly in the G0 fraction. These data provide a direct link between HSC proliferation and function and identify discrete molecular targets in regulating HSC cell fate decisions that could have implications for both the therapeutic use of HSC and the understanding of leukemic transformation.
Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates
Abbreviations used: BrdU, bromodeoxyuridine; Cdk, cyclin-dependent kinase; Cki, Cdk inhibitor; CLP, common lymphoid progenitors; CMP, common myeloid progenitors; Cy, cyclophosphamide; G, granulocyte-CSF; GMP, myelomonocytic progenitors; Gr, granulocytes; H/PY, HOECHST 33342/Pyronin Y; HSC, hematopoietic stem cells; KTLS HSC, Lin−/c-Kit+/Sca-1+/Thy1.1int HSC; LT-HSC, long-term reconstituting Flk-2− HSC; MEP, megakaryocytic/erythroid progenitors; mpb, mobilized peripheral blood; MPPF, nonself- renewing Flk-2+ multipotent progenitor; PI, propidium iodide; qRT-PCR, quantitative real-time RT-PCR; ST-HSCF, short-term reconstituting Flk-2int HSC.
E. Passegué and A.J. Wagers contributed equally to this work.
A.J. Wagers's present address is Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA 02215.
Emmanuelle Passegué, Amy J. Wagers, Sylvie Giuriato, Wade C. Anderson, Irving L. Weissman; Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates . J Exp Med 5 December 2005; 202 (11): 1599–1611. doi: https://doi.org/10.1084/jem.20050967
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