The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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© The Rockefeller University Press, 0022-1007/1998/7/393/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 2, July 20, 1998 393-398

Brief Definitive Reports

The Fluctuating Phenotype of the Lymphohematopoietic Stem Cell with Cell Cycle Transit

Houri K. Habibian*, Stefan O. Peters*, C.C. Hsieh{ddagger}, Joanne Wuu*, Kristin Vergilis*, Christina I. Grimaldi*, Judith Reilly*, Jane E. Carlson*, Angela E. Frimberger*, F.M. Stewart{ddagger}, and Peter J. Quesenberry{ddagger},§

From the * Cancer Center, the {ddagger} Department of Medicine, and the § Department of Cell Biology, University of Massachusetts Medical Center, Worcester, Massachusetts 01605

The most primitive engrafting hematopoietic stem cell has been assumed to have a fixed phenotype, with changes in engraftment and renewal potential occurring in a stepwise irreversible fashion linked with differentiation. Recent work shows that in vitro cytokine stimulation of murine marrow cells induces cell cycle transit of primitive stem cells, taking 40 h for progression from G0 to mitosis and 12 h for subsequent doublings. At 48 h of culture, progenitors are expanded, but stem cell engraftment is markedly diminished. We have investigated whether this effect on engraftment was an irreversible step or a reversible plastic feature correlated with cell cycle progression. Long-term engraftment (2 and 6 mo) of male BALB/c marrow cells exposed in vitro to interleukin (IL)-3, IL-6, IL-11, and steel factor was assessed at 2–4-h intervals of culture over 24–48 h using irradiated female hosts; the engraftment phenotype showed marked fluctuations over 2–4-h intervals, with engraftment nadirs occurring in late S and early G2. These data show that early stem cell regulation is cell cycle based, and have critical implications for strategies for stem cell expansion and engraftment or gene therapy, since position in cell cycle will determine whether effective engraftment occurs in either setting.

Key Words: hematopoietic stem cell • BALB/c mice • cell cycle • competitive engraftment • cytokines

Address correspondence to Peter J. Quesenberry, Director, Cancer Center, University of Massachusetts Medical Center, University of Massachusetts Cancer Center, Two BioTech, Suite 202, 373 Plantation St., Worcester, MA 01605. Phone: 508-856-6956; Fax: 508-856-1310; E-mail: peter.quesenberry{at}banyan.ummed.edu

P.J. Quesenberry was supported by grants from the National Institutes of Diabetes and Kidney Diseases (P0-1 DK 50222-01, R0-1 DK 49650-03, and R0-1 DK 27424-15) and from the National Heart, Lung and Blood Institute (P0-1 HL 56920-01).


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