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. 1997 Mar 4;94(5):1908-13.
doi: 10.1073/pnas.94.5.1908.

Cyclophosphamide/granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization

S J Morrison  1 , D E Wright, I L Weissman
Affiliations

Cyclophosphamide/granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization

S J Morrison et al. Proc Natl Acad Sci U S A. .

Abstract

We isolated hematopoietic stem cells (HSC) from mice treated with cyclophosphamide (CY) and granulocyte colony-stimulating factor (G-CSF). All mobilized multipotent progenitor activity was contained in two populations: Thy-1(lo) Sca-1+ Lin- Mac-1- CD4- c-kit+ long-term reconstituting progenitors and Thy-1(lo) Sca-1+ Lin- Mac-1(lo) CD4- transiently reconstituting progenitors. CY/G-CSF treatment drove both long-term and transient multipotent progenitors into cycle, leading to a more than 12-fold expansion in the number of long-term self-renewing HSC prior to mobilization. After CY and 2 days of G-CSF treatment the number of bone marrow HSC began to decline and the number of blood and splenic HSC increased. HSC continued to proliferate in the bone marrow and spleen through 8 days of G-CSF treatment, but HSC released into the blood tended to be in G0/G1 phase. Mobilized multipotent progenitors isolated from the spleen were less efficient than normal bone marrow multipotent progenitors in engrafting irradiated mice but did not differ in colony forming unit-spleen (CFU-S) activity or single cell in vitro assays of primitive progenitor activity. The data suggest that mobilized HSC isolated from the spleen are less efficient at homing to and engrafting the bone marrow of irradiated recipient mice.

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Figures

Figure 1
Figure 1
Donor myeloid, B, and T lineage reconstitution profiles of 10 mice injected with by 150 donor-type Thy-1.1loSca-1+Lin−Mac-1−CD4−c-kit+ cells (purified from the spleens of donor mice on day 7 of CY/G-CSF treatment) plus 200,000 recipient-type WBM cells. Each line represents a separate mouse, and the shaded area represents the range of background signals based on negative control mice reconstituted only with recipient-type WBM cells. Donor cells are presented as a percentage of all white blood cells.
Figure 2
Figure 2
Donor myeloid, B, and T lineage reconstitution profiles of 9 mice injected with 50 donor-type Thy-1.1loSca-1+Lin−Mac-1loCD4− cells (purified from the spleens of donor mice on day 7 of CY/G-CSF treatment) plus 200,000 recipient-type WBM cells. Each line represents a separate mouse, and the shaded area represents the range of background signals based on negative control mice reconstituted only with recipient-type WBM cells. Donor cells are presented as a percentage of all white blood cells.
Figure 3
Figure 3
The frequency (A) and total number (B) of Thy-1.1loSca-1+Lin−Mac-1−CD4−c-kit+ HSC in the bone marrow, spleen, and blood of mice on successive days of CY/G-CSF treatment. CY was administered on day −1 and G-CSF was administered on each successive day. Mice were sacrificed to determine HSC levels, so measurements were performed in lieu of drug administration on that day. Thus, HSC measurements presented for day −1 correspond to normal mice (0.017% of WBM or 74,000 HSC/bone marrow whole body) and mice sacrificed on day 1 had received CY plus one dose of G-CSF. Variation is presented as the standard error of the mean. Total bone marrow HSC were calculated by assuming that the femurs and tibias (less the epiphyses) contained 15% of all bone marrow in the mouse (34). Total HSC in the blood was calculated by assuming that the total blood volume was 1.8 ml (35). Frequencies of HSC in the blood are expressed as a proportion of nucleated cells; frequencies in bone marrow and spleen are expressed as a proportion of all cells.
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