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THE STEM CELL NICHE

Flt3-Ligand–Mobilized Peripheral Blood, but Not Flt3-Ligand–Expanded Bone Marrow, Facilitating Cells Promote Establishment of Chimerism and Tolerance

^a Institute for Cellular Therapeutics, University of Louisville, Louisville, Kentucky, USA;
^b Stem Cell Biology Program, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA

Key Words. Facilitating cells • Tolerance • Mobilization • CXCR4 • Stromal cell–derived factor-1

Correspondence: Suzanne T. Ildstad, M.D., Director, Institute for Cellular Therapeutics, University of Louisville, 570 S. Preston Street, Suite 404, Louisville, Kentucky 40202-1760, USA. Telephone: 502-852-2080; Fax: 502-852-2085; e-mail: suzanne.ildstad{at}louisville.edu

Received August 16, 2005; accepted for publication November 22, 2005.
Facilitating cells (CD8⁺/TCR^–) (FCs) enhance engraftment of limiting numbers of hematopoietic stem cells (HSCs). The primary component of FCs is precursor-plasmacytoid dendritic cells (p-preDCs), a tolerogenic cell expanded by Flt3-ligand (FL). In this study, we evaluated the function and composition of FL-expanded FCs. FL treatment resulted in a significant increase of FCs in bone marrow (BM) and peripheral blood (PB). When FL-expanded FCs were transplanted with c-Kit⁺/Sca-1⁺/Lin^– (KSL) cells into allogeneic recipients, BM-FCs exhibited significantly impaired function whereas PB-FCs were potently functional. A significant upregulation of P-selectin expression and downregulation of VCAM-1 (vascular cell adhesion molecule 1) were present on FL-expanded PB-FCs compared with FL BM-FCs. Stromal cell–derived factor-1 (SDF-1), and CXCR4 transcripts were significantly increased in FL PB-FCs and decreased in FL BM-FCs. Supernatant from FL PB-FCs primed HSC migration to SDF-1, confirming production of the protein product. The FL PB-FCs contained a predominance of p-preDCs and natural killer (NK)–FCs, and NK-FCs were lacking in FL BM-FCs. The impaired function for BM-FCs was restored within 5 days after cessation of treatment. Taken together, these data suggest that FCs may enhance HSC homing and migration via the SDF-1/CXCR4 axis and adhesion molecule modulation. These findings may have implications in development of strategies for retaining function of ex vivo manipulated FCs and HSCs.