title: Interleukin-7-induced Stat-5 acts in synergy with Flt-3 signaling to stimulate expansion of hematopoietic progenitor cells.
abstract: The development of lymphoid cells from bone marrow progenitors is dictated by interplay between internal cues such as transcription factors and external signals like the cytokines Flt-3 ligand and Il-7. These proteins are both of large importance for normal lymphoid development; however, it is unclear if they act in direct synergy to expand a transient Il-7R(+)Flt-3(+) population or if the collaboration is created through sequential activities. We report here that Flt-3L and Il-7 synergistically stimulated the expansion of primary Il-7R(+)Flt-3(+) progenitor cells and a hematopoietic progenitor cell line ectopically expressing the receptors. The stimulation resulted in a reduced expression of pro-apoptotic genes and also mediated survival of primary progenitor cells in vitro. However, functional analysis of single cells suggested that the anti-apoptotic effect was additive indicating that the synergy observed mainly depends on stimulation of proliferation. Analysis of downstream signaling events suggested that although Il-7 induced Stat-5 phosphorylation, Flt-3L caused activation of the ERK and AKT signaling pathways. Flt-3L could also drive proliferation in synergy with ectopically expressed constitutively active Stat-5. This synergy could be inhibited with either receptor tyrosine kinase or MAPK inhibitors suggesting that Flt-3L and Il-7 act in synergy by activation of independent signaling pathways to expand early hematopoietic progenitors.
authors.affiliation: Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty for Health Sciences, IKE Linköping University, 58185 Linköping, Sweden.
authors.forename: Josefine
authors.initials: J
authors.lastname: Åhsberg
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Tsapogas
authors.forename: Hong
authors.initials: H
authors.lastname: Qian
authors.forename: Jenny
authors.initials: J
authors.lastname: Zetterblad
authors.forename: Sasan
authors.initials: S
authors.lastname: Zandi
authors.forename: Robert
authors.initials: R
authors.lastname: Månsson
authors.forename: Jan-Ingvar
authors.initials: JI
authors.lastname: Jönsson
authors.forename: Mikael
authors.initials: M
authors.lastname: Sigvardsson
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004357:Drug Synergism; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015851:Interleukin-7 / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D015851:Interleukin-7; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3