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Hematopoietic stem –and progenitor cells are differentially mobilized dependent on the the duration of Flt3-ligand administration

Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, Leiden, The Netherlands

Correspondence: Melissa van Pel, PhD, Section of Stem Cell Biology, Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center PO Box 9600, 2300 RC Leiden The Netherlands. Phone: international (+31) 71-5265277. Fax: international (+31) 71-5265267. E-mail: m.van_pel{at}lumc.nl

ABSTRACT

Background: Flt3-ligand (FL) is a cytokine that induces relatively slow mobilization of hematopoietic cells in animals and humans in vivo. This provides a time-frame to study hematopoietic stem and progenitor cell (HSC/HPC) migration kinetics in detail.

Design and Methods: Mice were injected with FL (10µg/day, intraperitoneally) for 3, 5, 7 and 10 days. Mobilization of HSC/HPC was studied using colony-forming-unit granulocyte/monocyte (CFU-GM) and cobblestone-area-forming-cell (CAFC) assays. The radioprotective capacity of mobilized peripheral blood mononuclear cells (PBMC) was studied by transplantation of 1.5 x 10⁶ FL-mobilized PBMC into lethally irradiated (9.5 Gy) recipients.

Results: HPC mobilization was detected from day 3 onwards and prolonged administration of FL showed a steady increase in mobilized progenitor cells. Administration of FL for 10 days lead to a 5.5-fold increase in CAFC-week 4 and a 5.0-fold increase in CAFC-week 5, compared to FL administration for 5 days. Furthermore, transplantation of 5-day FL-mobilized PBMC did not radioprotect lethally irradiated recipients, whereas 10-day FL-mobilized PBMC radioprotected 100% of the recipients with significant multilineage donor chimerism.

Co-administration of IL-8 and FL led to a synergistic enhancement of HSC/HPC mobilization on day 3 and 5, compared to FL or IL-8 alone.

Conclusions: These results indicate that HPC and HSC show different mobilization kinetics in response to FL, resulting in preferential mobilization of HPC at day 5, followed by HSC mobilization at day 10.