title: Flt3-ligand-mobilized peripheral blood, but not Flt3-ligand-expanded bone marrow, facilitating cells promote establishment of chimerism and tolerance.
abstract: 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.
authors.affiliation: Institute for Cellular Therapeutics, University of Louisville, 570 S. Preston Street, Suite 404, Louisville, Kentucky 40202-1760, USA.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Huang
authors.forename: Magda
authors.initials: M
authors.lastname: Kucia
authors.forename: Francine
authors.initials: F
authors.lastname: Rezzoug
authors.forename: Janina
authors.initials: J
authors.lastname: Ratajczak
authors.forename: Michael K
authors.initials: MK
authors.lastname: Tanner
authors.forename: Mariusz Z
authors.initials: MZ
authors.lastname: Ratajczak
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Schanie
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.forename: Isabelle
authors.initials: I
authors.lastname: Fugier-Vivier
authors.forename: Suzanne T
authors.initials: ST
authors.lastname: Ildstad
mesh_terms: D000818:Animals; D001773:Blood Cells / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics; D002678:Chimera; D003114:Colony-Forming Units Assay; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000378:metabolism; D036102:Peripheral Blood Stem Cell Transplantation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D014184:Transplantation, Homologous
chemical_list: D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D008565:Membrane Proteins; D019007:P-Selectin; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; C084881:flt3 ligand protein