title: Human reconstituting hematopoietic stem cells up-regulate Fas expression upon active cell cycling but remain resistant to Fas-induced suppression.
abstract: The Fas receptor and its ligand have been implicated in mediating the bone marrow (BM) suppression observed in graft-versus-host disease and a number of other BM-failure syndromes. However, previous studies have suggested that Fas is probably not expressed on human hematopoietic stem cells (HSCs), but up-regulated as a consequence of their commitment and differentiation, suggesting that progenitors or differentiated blood cells, rather than HSCs, are the targets of Fas-mediated suppression. The present studies confirm that candidate HSCs in human cord blood and BM lack constitutive expression of Fas, but demonstrate that Fas expression on CD34+ progenitor and stem cells is correlated to their cell cycle and activation status. With the use of recently developed in vitro conditions promoting HSC self-renewing divisions, Fas was up-regulated on virtually all HSCs capable of multilineage reconstituting nonobese diabetic/severe combined immunodeficiency (NOD-SCID) mice in vivo, as well as on long-term culture-initiating cells (LTC-ICs). Similarly, in vivo cycling of NOD-SCID repopulating cells upon transplantation, resulted in up-regulation of Fas expression. However, repopulating HSCs expressing high levels of Fas remained highly resistant to Fas-mediated suppression, and HSC function was compromised only upon coactivation with tumor necrosis factor. Thus, reconstituting human HSCs up-regulate Fas expression upon active cycling, demonstrating that HSCs could be targets for Fas-mediated BM suppression.
authors.affiliation: Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, BMC B10, Lund University Hospital, 22184 Lund, Sweden.
authors.forename: Ingunn
authors.initials: I
authors.lastname: Dybedal
authors.forename: Liping
authors.initials: L
authors.lastname: Yang
authors.forename: David
authors.initials: D
authors.lastname: Bryder
authors.forename: Ingbritt
authors.initials: I
authors.lastname: Aastrand-Grundstrom
authors.forename: Karin
authors.initials: K
authors.lastname: Leandersson
authors.forename: Sten Eirik W
authors.initials: SE
authors.lastname: Jacobsen
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D002453:Cell Cycle; D002455:Cell Division; D036101:Cord Blood Stem Cell Transplantation; D016207:Cytokines / Q000494:pharmacology; D005312:Fetal Blood; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D039902:Multipotent Stem Cells; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D019014:fas Receptor / Q000032:analysis* / Q000502:physiology*
chemical_list: D016207:Cytokines; D019014:fas Receptor