Hematopoietic stem cell mobilization: updated conceptual renditions

Abstract

Despite its specific clinical relevance, the field of hematopoietic stem cell mobilization has received broad attention, owing mainly to the belief that pharmacologic stem cell mobilization might provide clues as to how stem cells are retained in their natural environment, the bone marrow 'niche'. Inherent to this knowledge is also the desire to optimally engineer stem cells to interact with their target niche (such as after transplantation), or to lure malignant stem cells out of their protective niches (in order to kill them), and in general to decipher the niche's structural components and its organization. Whereas, with the exception of the recent addition of CXCR4 antagonists to the armamentarium for mobilization of patients refractory to granulocyte colony-stimulating factor alone, clinical stem cell mobilization has not changed significantly over the last decade or so, much effort has been made trying to explain the complex mechanism(s) by which hematopoietic stem and progenitor cells leave the marrow. This brief review will report some of the more recent advances about mobilization, with an attempt to reconcile some of the seemingly inconsistent data in mobilization and to interject some commonalities among different mobilization regimes.

Figure 1

Irradiation destroys marrow integrity and shifts the stem cell niche toward the endosteal region: mice were lethally irradiated (b) or not (a). Identical numbers of carboxyfluoroscein succinimidyl ester (green)-labeled lineage-negative/kit + cells were injected intravenously within 3 h of irradiation. Note the severe vascular distortion, particularly in the central regions of bones, and the preferentially endosteal localiztion of transplanted cells in tibiae of irradiated mice. Moreover, the total number of cells homing to non-irradiated BM was considerably larger than in irradiated hosts, in keeping with previous reports. Z-stack sections (a total of consecutive 25 sections from tibiae) were done 20 h after cell transfer. Blood vessels were labeled with CD31 (red) and nuclei were counter-stained with 4′,6-diamidino-2-phenylindole.

Figure 2

Modification of sympathetic input does not affect mobilization efficiency with G-CSF: volunteer stem cell donors receiving noradrenalin reuptake inhibitors for depression (NRI, n =14) or β-blockers for hypertension (β-Bl., n =24), or 559 concurrent donors not receiving any drugs interfering with sympathetic tone (ctrl.) received a 5-day course of standard-dose G-CSF (9 doses q12 h, 7.5–10 μg/kgBW*day) in preparation for matched-unrelated stem cell apheresis at our facility. Circulating CD34 + cells were enumerated using single-platform flow cytometry 2–4 h after the ninth dose, as described. Donors receiving NRI or β-blockers were typical for MURD donors, that is, in terms of donor epidemiology (age, sex and body mass index), there were no differences between the groups. Mobilization was neither enhanced by NRI nor suppressed by β-blockers (mean + s.d.).