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. 2006 Oct 1;108(7):2190-7.
doi: 10.1182/blood-2005-12-010272. Epub 2006 Jun 1.

Increased hematopoietic stem cell mobilization in aged mice

Zhenlan Xing  1 , Marnie A Ryan, Deidre Daria, Kalpana J Nattamai, Gary Van Zant, Lei Wang, Yi Zheng, Hartmut Geiger
Affiliations

Increased hematopoietic stem cell mobilization in aged mice

Zhenlan Xing et al. Blood. .

Abstract

Hematopoietic stem and progenitor cells (HSPCs) are located in the bone marrow in close association with a highly organized 3-dimensional structure formed by stroma cells, referred to as the niche. Mobilization of HSPCs from bone marrow to peripheral blood in response to granulocyte colony-stimulating factor (G-CSF) requires de-adhesion of HSPCs from the niche. The influence of aging of HSPCs on cell-stroma interactions has not been determined in detail. Using a mouse model of G-CSF-induced mobilization, we demonstrated that the ability to mobilize hematopoietic stem cells is approximately 5-fold greater in aged mice. Competitive mobilization experiments confirmed that enhanced mobilization ability was intrinsic to the stem cell. Enhanced mobilization efficiency of primitive hematopoietic cells from aged mice correlated with reduced adhesion of hematopoietic progenitor cells to stroma and with elevated levels of GTP-bound Cdc42. These results might indicate that stroma-stem cell interactions are dynamic over a lifetime and result in physiologically relevant changes in the biology of primitive hematopoietic cells with age.

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Figures

Figure 1.
Figure 1.
Aged mice mobilize increased numbers of HPCs to PB in response to G-CSF. (A) Frequency of CFCs in 20 μL PB in young and aged mobilized (5-day G-CSF at 100 μg/kg per day intraperitoneally; PB analysis on day 6) and nonmobilized mice, n = 10 for young nonmobilized and mobilized mice, n = 3 for 22-month-old mobilized mice, and n = 7 (3 at 20 months, 1 at 23 months, 3 at 26 months) for mobilized aged mice. (B) White blood cell (WBC) and RBC counts in young and aged mobilized and nonmobilized mice, n = at least 4 per value. (C) CFC frequency in spleen in young and aged mobilized and nonmobilized mice, n = 3. (D) CFC frequency in BM in young and aged mobilized and nonmobilized mice, n = 3. Values shown are mean ± 1 SEM. *P < .05.
Figure 2.
Figure 2.
Aged mice mobilize a higher number of HSCs to PB in response to G-CSF. (A) Experimental setup of competitive transplantation of mobilized PB cells. (B) Flow cytometric analysis of chimerism in PB of mice that underwent competitive (50/50) transplantation with mPB from aged (Ly5.2+) and young (Ly5.1+) mice 5 months after transplantation. (C) Determination of the percentages of T, B, and myeloid (MY) cells in PB cells derived from the transplanted mobilized HSCs from aged mice in the recipient 5 months after transplantation by flow cytometry. Data are a summary of 2 independent experiments; in each, n = 3 for the number of donors per age group from which PB was collected and n = 4 for the number of recipients. One recipient animal had graft failure and was excluded from the analysis. Values shown are mean ± 1 SEM. *P < .05.
Figure 3.
Figure 3.
Experimental setup of the competitive mobilization experiment. Data are presented in Table 2.
Figure 4.
Figure 4.
Young and aged HPCs do not differ with respect to their ability to cross an endothelial cell layer. (A) Experimental setup for the transwell-migration assay. (B) Percentage of CFCs from mobilized young (2-3 months) and aged (24 months) mice migrating in 18 hours into the lower well of the transwell. n = 3. Values shown are mean ± 1 SEM. LDBM indicates low-density BM cells.
Figure 5.
Figure 5.
HPCs from aged mice are reduced in their ability to adhere to stroma. (A) BM cells from mobilized and nonmobilized aged (21-27 months) and young (2-3 months) mice were subjected to CAFC adhesion assay. Experimental setup. (B) Percentage of adherent HPCs after 2 or 4 hours determined as CAFC day 7 cells using the CAFC adhesion assay. n = at least 3 for each age group. Values shown are mean ± 1 SEM. (C). Ratio of the MFI of CXCR4, CD49d, CD49e on HPCs and HSCs from aged (21-22 months) and young (2-3 months) mice. No change in the MFI of expression between cells from young and aged animals resulted in ratio of 1, indicated by the dashed line. n = 3 mice each aged and young for CXCR4, and n = 4 mice each aged and young for CD49d and CD49e. *P < .05.
Figure 6.
Figure 6.
Increased activity of Cdc42 in primitive hematopoietic cells in aged mice. (A) BM cells from young (2- to 4-month-old) and aged (20- to 27-month-old) mice were subjected to an effector domain pull-down assay and subsequently probed by immunoblotting. (B) Quantification of the relative amount of the active Cdc42-GTP bound form by densitometry. n = 3 for young mice, and n = 4 for aged mice. Values shown are mean ± 1 SEM. *P < .05. (C) Lin–BM cells (enriched for HPCs) isolated from pooled BM cells from each experiment in which 4 young, middle-aged, and aged mice (2, 13, and 22 months, respectively) were subjected to an effector domain pull-down assay and subsequently probed by immunoblotting. Data are representative of 2 independent experiments.
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