The Journal of Experimental Medicine
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Published 5 December 2005. doi:10.1084/jem.20050967
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 11, 1599-1611
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ARTICLE

 Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates

Emmanuelle Passegué1,2,3, Amy J. Wagers1,2,3, Sylvie Giuriato4, Wade C. Anderson1,2,3, and Irving L. Weissman1,2,3

1 Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305
2 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305
3 Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305
4 Division of Oncology, Stanford University School of Medicine, Stanford, CA 94305

CORRESPONDENCE Emmanuelle Passegué: passegue{at}stanford.edu

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.

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.


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